AOP-Wiki

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<div id="title">
<h2>AOP ID and Title:</h2>
~~<div class="title">AOP 277: Impaired IL-1R1 signaling leading to increased susceptibility to infection</div>~~
~~Short Title: IL-1 inhibition~~
<div class="title">AOP 277: Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response</div>
Short Title: Impaired IL-1R1 signaling leading to impairment of TDAR
</div>
<h2>Graphical Representation</h2>
~~<img src="https://aopwiki.org/system/dragonfly/production/2020/12/22/6p4rh5yv4e_20201222_AOP_IL_1.jpg" height="500" width="700" alt=""/>~~
<img src="https://aopwiki.org/system/dragonfly/production/2022/10/18/74xt5wravz_201222_AOP_4_.jpg" height="500" width="700" alt=""/>
<div id="authors">
<h2>Authors</h2>
~~Yutaka Kimura (1) Setsuya Aiba (1) ~~
Yutaka Kimura (1) Setsuya Aiba (1) Takao ashikaga (2) Takumi Ohishi (2) Kiyoshi Kushima (2)
(1) Depertment of Dermatology, Tohoku University Graduate School of Medicine
~~Corresponding author: Setsuya Aiba~~
(2) The Japanese Society of Immunotoxiclology
Corresponding author: Takao Ashikaga 
</div>
<div id="status">
<h2>Status</h2>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Author status</th>
<th scope="col">OECD status</th>
<th scope="col">OECD project</th>
<th scope="col">SAAOP status</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Open for citation & comment</td>
~~<td>EAGMST Under Review</td>~~
<td>WPHA/WNT Endorsed</td>
<td>1.48</td>
<td>Included in OECD Work Plan</td>
</tr>
</tbody>
</table>
</div>
</div>
<div id="abstract">
<h2>Abstract</h2>
The pleiotropic cytokine IL-1 mediates its biological functions via association with the signaling receptor IL-1R1. These may include initiation of innate immunity as well as acquired immunity, which are essential for assistance of host defense against infection. The trimeric complex consists of IL-1, IL-1R1 and IL-1R3 (a coreceptor, formerly IL-1R accessory protein) allows for the approximation of the Toll-IL-1-Receptor (TIR) domains of each receptor chain. MyD88 then binds to the TIR domains. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB. The activation of NF-κB plays a principal role in the immunological function of IL-1. Namely, it stimulates innate immunity such as activation of dendritic cells and macrophages. It also stimulates T cells via activated dendritic function or directly. The activation of T cells is crucial for B cell proliferation and their antibody production. The cooperation by T cells and B cells constitutes a main part of host defense against infection. Therefore, the impaired IL-1R1 signaling either by the decreased IL-1 production or the inhibition of IL-1β binding to IL-1R1 by IL-1 receptor antagonist（IL-1Ra）or anti-IL-1β antibody) results in the blockade of the effects of the pleiotropic cytokine IL-1β leading to increased susceptibility to infection.
The pleiotropic cytokine IL-1 mediates its biological functions via association with the signaling receptor IL-1R1. These may include initiation of innate immunity as well as acquired immunity, which are essential for assistance of host defense against infection. The trimeric complex consists of IL-1, IL-1R1 and IL-1R3 (a coreceptor, formerly IL-1R accessory protein) allows for the approximation of the Toll-IL-1-Receptor (TIR) domains of each receptor chain. MyD88 then binds to the TIR domains. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB. In addition to the NF-κB pathway,  IL-1 receptor-associated kinase (IRAK) , which is one of the kinase consisting of the cascade, activates a variety of transcription factors, including Adaptor protein-1 (AP-1). The activation of NF-κB plays a principal role in the immunological function of IL-1. Namely, it stimulates innate immunity such as activation of dendritic cells and macrophages. It also stimulates T cells via activated dendritic function or directly. The activation of T cells is crucial for B cell proliferation and their antibody production. The cooperation by T cells and B cells constitutes a main part of host defense against infection. Therefore, the impaired IL-1R1 signaling either by the decreased IL-1 production or the inhibition of IL-1β binding to IL-1R1 by IL-1 receptor antagonist（IL-1Ra）or anti-IL-1β antibody) results in the blockade of the effects of the pleiotropic cytokine IL-1β leading to suppressed T cell dependent antibody response (TDAR).
In this AOP, we selected the impaired IL-1R signaling as a molecular initiating event (MIE), and suppression of NF-κB, suppression of T cell activation, and increased susceptibility to infection as key events (KE).
In this AOP, we selected the impaired IL-1R signaling as a molecular initiating event (MIE) in T cell, and suppression of NF-κB (and/or AP-1), suppression of T cell activation, and suppression of TDAR as key events (KE).
Although the purpose of this AOP is to elucidate biological pathways that lead to immune suppression caused by impaired IL-1R signaling by chemicals, most of the stressors presented in this AOP were limited to pharmaceuticals because of the lack of information on chemicals.
</div>
~~<div id="background">~~
~~<h3>Background</h3>~~
The pleiotropic cytokine IL-1 mediates its biological functions via association with the signaling receptor IL-1R1. These may include initiation of innate immunity and assistance of host defense against infection, and sometimes, mediation of autoinflammatory, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. The trimeric complex consists of IL-1, IL-1R1 and IL-1R3 (a coreceptor, formerly IL-1R accessory protein) allows for the approximation of the Toll-IL-1-Receptor (TIR) domains of each receptor chain. MyD88 then binds to the TIR domains. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB and fundamental inflammatory responses such as the induction of cyclooxygenase type 2, production of multiple cytokines and chemokines, increased expression of adhesion molecules, or synthesis of nitric oxide. (Dinarello, 2018; Weber et al., 2010a, b)</span>.</span>

Molecules like nuclear or mitochondrial DNA, adenosine triphosphate (ATP), uridine triphosphate (UTP), uric acid and high mobility group box 1 (HMGB1) are classified as damage associated molecular patterns (DAMPs). DAMPs are secreted or produced upon cellular injury or death and induce sterile inflammation. On the other hand, bacterial products like lipopolysaccharide (LPS), peptidoglycans, lipoprotein flagellins, bacterial RNA and DNA are some of the well-characterized pathogen associated molecular patterns (PAMPs). These DAMPs and PAMPs with a few exceptions bind to pattern recognition receptors (PRRs) such as toll-like receptor (TLRs) and nucleotide oligomerization domain (NOD) like receptors (NLRs). Proinflammatory mediators such as DAMPs, PAMPs, and various inflammatory cytokines or mediators including IL-1β itself activate innate immune mechanisms in the host leading to IL-1b production (Handa et al., 2016; Newton and Dixit, 2012; Yang et al., 2017). Besides transcriptional regulation and posttranscriptional level by RNA-binding proteins, pro-IL-1b</span> protein requires proteolytic cleavage by active caspase-1 as the effector component of stimulation-induced multi-protein inflammasomes to acquire functional activity. Altogether, these different layers of regulation allow to fine tune IL-1b production under different pathophysiological conditions (Bent et al., 2018)</span><span style="font-family:"Times New Roman",serif">.
<h2>AOP Development Strategy</h2>
<div id="context">
<h3>Context</h3>
The pleiotropic cytokine IL-1 mediates its biological functions via association with the signaling receptor IL-1R1. These may include initiation of innate immunity and assistance of host defense, and sometimes, mediation of autoinflammatory, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. The trimeric complex consists of IL-1, IL-1R1 and IL-1R3 (a coreceptor, formerly IL-1R accessory protein) allows for the approximation of the Toll-IL-1-Receptor (TIR) domains of each receptor chain. MyD88 then binds to the TIR domains. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB and/or AP-1 </span>and fundamental inflammatory responses such as the induction of cyclooxygenase type 2, production of multiple cytokines and chemokines, increased expression of adhesion molecules, or synthesis of nitric oxide. (Dinarello, 2018; Weber et al., 2010a, b; Jain et al., 2014). 
Therefore, the inhibition of various targets in different layers from the stimulation of PRPs or the receptors of proinflammatory cytokines, e.g., IL-1, IL-18, or TNFa, to the activation of NF-&kappa;B or the inhibition of posttranscriptional regulation of pro-IL-1b cause impaired IL-1R1 signaling. In addition, since IL-1 also mediates autoinflammatory syndromes, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever, several inhibitors against IL-1R1 have been developed. They are IL-1 receptor antagonist（IL-1Ra）, anakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R). Several reports described that the administration of these drugs led to increased susceptibility to infection(De Benedetti et al., 2018; Fleischmann et al., 2003; Genovese et al., 2004; Imagawa et al., 2013; Kullenberg et al., 2016; Lachmann et al., 2009; Lequerre et al., 2008; Migkos et al., 2015; Schlesinger et al., 2012; Yokota et al., 2017). In addition to these human data, the experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection(Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000).
Molecules like nuclear or mitochondrial DNA, adenosine triphosphate (ATP), uridine triphosphate (UTP), uric acid and high mobility group box 1 (HMGB1) are classified as damage associated molecular patterns (DAMPs). DAMPs are secreted or produced upon cellular injury or death and induce sterile inflammation. On the other hand, bacterial products like lipopolysaccharide (LPS), peptidoglycans, lipoprotein flagellins, bacterial RNA and DNA are some of the well-characterized pathogen associated molecular patterns (PAMPs). These DAMPs and PAMPs with a few exceptions bind to pattern recognition receptors (PRRs) such as toll-like receptor (TLRs) and nucleotide oligomerization domain (NOD) like receptors (NLRs). Proinflammatory mediators such as DAMPs, PAMPs, and various inflammatory cytokines or mediators including IL-1β itself activate innate immune mechanisms in the host leading to IL-1&beta; production (Handa et al., 2016; Newton and Dixit, 2012; Yang et al., 2017). Besides transcriptional regulation and posttranscriptional level by RNA-binding proteins, pro-IL-1β protein requires proteolytic cleavage by active caspase-1 as the effector component of stimulation-induced multi-protein inflammasomes to acquire functional activity. Altogether, these different layers of regulation allow to fine tune IL-1β production under different pathophysiological conditions (Bent et al., 2018)</span><span style="font-family:"Times New Roman",serif">.</span></p>
 In addition to these human data, the experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection. (Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000).
Therefore, the inhibition of various targets in different layers from the stimulation of PRRs or the receptors of proinflammatory cytokines, e.g., IL-1, IL-18, or TNFa, to the activation of NF-κB and/or AP-1 or the inhibition of posttranscriptional regulation of pro-IL-1β cause impaired IL-1R1 signaling. In addition, since IL-1 also mediates autoinflammatory syndromes, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever, several inhibitors against IL-1R1 have been developed. They are IL-1 receptor antagonist（IL-1Ra）, anakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R). Several reports described that the administration of these drugs led to increased susceptibility to infection(De Benedetti et al., 2018; Fleischmann et al., 2003; Genovese et al., 2004; Imagawa et al., 2013; Kullenberg et al., 2016; Lachmann et al., 2009; Lequerre et al., 2008; Migkos et al., 2015; Schlesinger et al., 2012; Yokota et al., 2017). In addition to these human data, the experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection(Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000)</span>.</span></p>
~~</div>~~
</div>
<div id="aop_summary">
<h2>Summary of the AOP</h2>
<h3>Events</h3>
<h3>Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sequence</th>
<th scope="col">Type</th>
<th scope="col">Event ID</th>
<th scope="col">Title</th>
<th scope="col">Short name</th>
</tr>
</thead>
<tbody>
<tr>
<td>1</td>
<td>MIE</td>
<td>1700</td>
~~<td><a href="/events/1700">Impaired IL-1R1 signaling</a></td>~~
<td><a href="/events/1700">Impaired IL-1R1 signaling in T cell</a></td>
<td>Impaired IL-1R1 signaling</td>
</tr>
<tr><td></td><td></td><td></td><td></td><td></td></tr>
<tr>
<td>2</td>
<td>KE</td>
<td>202</td>
<td><a href="/events/202">Inhibition, Nuclear factor kappa B (NF-kB)</a></td>
<td>Inhibition, Nuclear factor kappa B (NF-kB)</td>
</tr>
<tr>
<td>3</td>
<td>KE</td>
<td>1702</td>
<td><a href="/events/1702">Suppression of T cell activation</a></td>
<td>Suppression of T cell activation</td>
</tr>
<tr><td></td><td></td><td></td><td></td><td></td></tr>
<tr>
~~<td>4</td>~~
<td></td>
<td>AO</td>
~~<td>986</td>~~
~~<td><a href="/events/986">Increase, Increased susceptibility to infection</a></td>~~
~~<td>Increase, Increased susceptibility to infection</td>~~
<td>984</td>
<td><a href="/events/984">Impairment, T-cell dependent antibody response</a></td>
<td>Impairment, T-cell dependent antibody response</td>
</tr>
</tbody>
</table>
</div>
<h3>Key Event Relationships</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Upstream Event</th>
<th scope="col">Relationship Type</th>
<th scope="col">Downstream Event</th>
<th scope="col">Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
~~<td><a href="/relationships/2002">Impaired IL-1R1 signaling</a></td>~~
<td><a href="/relationships/2002">Impaired IL-1R1 signaling in T cell</a></td>
<td>adjacent</td>
<td>Inhibition, Nuclear factor kappa B (NF-kB)</td>
<td>High</td>
<td>Moderate</td>
</tr>
<tr>
<td><a href="/relationships/2003">Inhibition, Nuclear factor kappa B (NF-kB)</a></td>
<td>adjacent</td>
<td>Suppression of T cell activation</td>
<td>High</td>
<td>Moderate</td>
</tr>
<tr>
~~<td><a href="/relationships/2004">Suppression of T cell activation</a></td>~~
<td><a href="/relationships/2928">Suppression of T cell activation</a></td>
<td>adjacent</td>
~~<td>Increase, Increased susceptibility to infection</td>~~
<td>Impairment, T-cell dependent antibody response</td>
<td>High</td>
<td>High</td>
~~<td>Not Specified</td>~~
</tr>
<tr>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>
</div>
<h3>Stressors</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Name</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>IL-1 receptor antagonist（IL-1Ra）(Anakinra)</td>
<td>High</td>
</tr>
<tr>
<td>anti-IL-1b antibody (Canakinumab)</td>
<td>High</td>
</tr>
<tr>
<td>soluble IL-1R (Rilonacept)</td>
<td>High</td>
</tr>
<tr>
<td>anti-IL-1b antibody (Gevokizumab)</td>
<td>High</td>
</tr>
<tr>
<td>Dexamethasone</td>
<td>High</td>
</tr>
<tr>
<td>minocycline</td>
<td>High</td>
</tr>
<tr>
<td>Belnacasan (VX-765)</td>
<td>High</td>
</tr>
<tr>
<td>Pralnacasan (VX-740, HMR3480)</td>
<td>High</td>
</tr>
<tr>
<td>cinnamic aldehyde</td>
<td>High</td>
</tr>
<tr>
<td>Dimethyl fumarate</td>
<td>High</td>
</tr>
<tr>
<td>curcumin</td>
<td>High</td>
</tr>
<tr>
<td>iguratimod</td>
<td>High</td>
</tr>
<tr>
<td>(-)-Epigallocatechin gallate</td>
<td>High</td>
</tr>
<tr>
<td>TAK-242</td>
<td>High</td>
</tr>
<tr>
<td>IRAK4 inhibitors</td>
<td>High</td>
</tr>
<tr>
<td>Dehydroxymethylepoxyquinomicin (DHMEQ)</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div id="overall_assessment">
<h2>Overall Assessment of the AOP</h2>
<h3>Domain of Applicability</h3>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Not Otherwise Specified</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Mus musculus</td>
<td>Mus musculus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Rattus norvegicus</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Mixed</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent.  Again, age-dependent difference in IL-1 signaling is not known.
The IL1B gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (<a href="https://www.ncbi.nlm.nih.gov/homologene/481">https://www.ncbi.nlm.nih.gov/homologene/481</a>), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (<a href="https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849">https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849</a>).
The IL1B gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (<a href="https://www.ncbi.nlm.nih.gov/homologene/481">https://www.ncbi.nlm.nih.gov/homologene/481</a>), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (<a href="https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849">https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849</a>).
The NFKB1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, and frog.
275 organisms have orthologs with human gene NFKB1.
(<a href="https://www.ncbi.nlm.nih.gov/gene/4790">https://www.ncbi.nlm.nih.gov/gene/4790</a>)
The RELB gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog.
216 organisms have orthologs with human gene RELB.</p>
The lower level of stress-induced IL-1b expression is demonstrated in the aged murine keratinocytes (Pilkington et al., 2018).
~~(<a href="https://www.ncbi.nlm.nih.gov/gene/5971">https://www.ncbi.nlm.nih.gov/gene/5971</a>)~~
The IL-1b production by mouse oral mucosal leukocytes stimulated with candida albicans was reduced with aging (Bhaskaran et al., 2020).
~~These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.</p>~~
The baseline IL-1 signaling of the upper respiratory tract lavage was reduced in murine newborn mice (Kuipers et al., 2018).
<h3>Essentiality of the Key Events</h3>
The experiments using knockout mice revealed that the deficiency of IL-1 signaling led to bacterial, tuberculosis or viral infection (Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000). 
The experiments using knockout mice revealed that the deficiency of IL-1 signaling led to bacterial, tuberculosis or viral infection (Bohrer et al., 2018; Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Labow et al., 1997; Tian, Jin and Dubin, 2017; Yamada et al., 2000). 
IL-1 receptor antagonist（IL-1Ra）was purified in 1990, and the cDNA reported that same year. IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction (Dripps et al., 1991). Recombinant IL-1Ra (generic anakinra) is fully active in blocking the IL-1R1, and therefore, the activities of IL-1α and IL-1β. Anakinra is approved for the treatment of rheumatoid arthritis and cryopyrin-associated periodic syndrome (CAPS). Since its introduction in 2002 for the treatment of rheumatoid arthritis, anakinra has had a remarkable record of safety. However, Fleischmann et al. (Fleischmann et al., 2003) reported that serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group) and other authors reported the increased susceptibility to bacterial or tuberculosis infection (Genovese et al., 2004; Kullenberg et al., 2016; Lequerre et al., 2008; Migkos et al., 2015). Two IL-1 signaling antagonists, canakinumab (anti-IL-1b antibody) and rilonacept (soluble IL-1R) had been reported to increase susceptibility to infection (De Benedetti et al., 2018; Imagawa et al., 2013; Lachmann et al., 2009; Schlesinger et al., 2012). 
IL-1 receptor antagonist（IL-1Ra）was purified in 1990, and the cDNA reported that same year. IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction (Dripps et al., 1991). Recombinant IL-1Ra (generic anakinra) is fully active in blocking the IL-1R1, and therefore, the activities of IL-1α and IL-1β. Anakinra is approved for the treatment of rheumatoid arthritis and cryopyrin-associated periodic syndrome (CAPS). Since its introduction in 2002 for the treatment of rheumatoid arthritis, anakinra has had a remarkable record of safety. However, Fleischmann et al. (Fleischmann et al., 2003) reported that serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group) and other authors reported the increased susceptibility to bacterial or tuberculosis infection (Genovese et al., 2004; Kullenberg et al., 2016; Lequerre et al., 2008). As IL-1 signaling antagonists, two drugs went up to the market, canakinumab (anti-IL-1b antibody) and rilonacept (soluble IL-1R). Several reports described that the administration of these drugs led to immunosuppression or increased susceptibility to infection (De Benedetti et al., 2018; Imagawa et al., 2013; Lachmann et al., 2009; Schlesinger et al., 2012). 
In a similar way, defect of MyD88 signaling caused by knockout of mice gene or deficiency in human patient leads to the increased susceptibility to bacterial or tuberculosis infection (Fremond et al., 2004; Picard et al., 2010; Scanga et al., 2004; von Bernuth et al., 2008). Although MyD88 is also known to be involved in TLR signaling pathway, several reports suggested that MyD88-dependent response was IL-1 receptor-mediated but not TLR-mediated. These data suggest to essentiality of IL-1-MyD88 signaling pathway in host defense against infection.
 
In a similar way, defect of MyD88 signaling caused by knockout of mice gene or deficiency in human patient leads to the increased susceptibility to bacterial or tuberculosis infection (von Bernuth et al., 2012).
Mice lacking NF-kB p50 are unable effectively to clear L. monocytogenes and are more susceptible to infection with S. peumoniae (Sha et al., 1995).
 
Mice lacking NF-kB p50 are unable effectively to clear L. monocytogenes and are more susceptible to infection with S. peumoniae (Sha et al., 1995).
<h3>Weight of Evidence Summary</h3>
The recent review of IL-1 pathway by Weber et al. has clearly described the intracellular signaling event from the binding of IL-1a or IL-1b to IL-1R to the activation of NF-kB through the assemble of MyD88 to the trimelic complex composed of IL-1, IL-R1, and IL-1RacP. The sequentiality and essentiality of each signaling molecule have been demonstrated by mice lacking relevant molecules (Weber et al., 2010a, b).</p>
The recent review of IL-1 pathway by Weber et al. (Weber, Wasiliew and Kracht, 2010a) has clearly described the intracellular signaling event from the binding of IL-1α or IL-1β to IL-1R to the activation of NF-κB through the assemble of MyD88 to the trimeric complex composed of IL-1, IL-R1, and IL-1RacP. The sequentiality and essentiality of each signaling molecule have been demonstrated by mice lacking relevant molecules (Dinarello, 2018; Weber, Wasiliew and Kracht, 2010a, b).</p>
There were several reports that described that administration of IL-1R antagonist or neutralizing antibody led to the suppression of downstream phenomena, which included internalization of IL-1 (Dripps et al., 1991), production of PGE2 (Hannum et al., 1990; Seckinger et al., 1990b), IL-6 (Goh et al., 2014), and T cell proliferation (Seckinger et al., 1990a).
There were several reports that described that administration of IL-1R antagonist or neutralizing antibody led to the suppression of downstream phenomena, which included internalization of IL-1 (Dripps et al., 1991), production of PGE2 (Hannum et al., 1990; Seckinger, Kaufmann and Dayer, 1990), IL-6 (Goh et al., 2014), and T cell proliferation (Seckinger, Kaufmann and Dayer, 1990).
Several reports described that the administration of IL-1 receptor antagonist（IL-1Ra）, canakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R) led to increased susceptibility to infection (De Benedetti et al., 2018; Fleischmann et al., 2003; Genovese et al., 2004; Imagawa et al., 2013; Kullenberg et al., 2016; Lachmann et al., 2009; Lequerre et al., 2008; Schlesinger et al., 2012; Yokota et al., 2017). In addition to these human data, the experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection(Bohrer et al., 2018; Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Labow et al., 1997; Tian, Jin and Dubin, 2017; Yamada et al., 2000). Moreover, polymorphism of IL-1b or IL-1Ra leads to the increased susceptibility to tuberculosis, severe sepsis or fungal infection (Fang et al., 1999; Motsinger-Reif et al., 2010; Wojtowicz et al., 2015).
~~Biological plausibility~~
Biological plausibility</span></p>
~~Inhibition of IL-1 binding to IL-1 receptor leads to Inhibition, Nuclear factor kappa B (NF-kB)~~
Inhibition of IL-1 binding to IL-1 receptor leads to Inhibition, Nuclear factor kappa B (NF-kB)</span></p>
IL-1α and IL-1β independently bind the type I IL-1 receptor (IL-1R1), which is ubiquitously expressed. The IL-1R3 (formerly IL-1R accessory protein (IL-1RAcP)) serves as a co-receptor that is required for signal transduction of IL-1/IL-1RI complexes.
IL-1α and IL-1β independently bind the type I IL-1 receptor (IL-1R1), which is ubiquitously expressed. The IL-1R3 (formerly IL-1R accessory protein (IL-1RAcP)) serves as a co-receptor that is required for signal transduction of IL-1/IL-1RI complexes.</span></p>
The initial step in IL-1 signal transduction is a ligand-induced conformational change in the first extracellular domain of the IL-1RI that facilitates recruitment of IL-1R3. the trimeric complex rapidly assembles two intracellular signaling proteins, myeloid differentiation primary response gene 88 (MYD88) and interleukin-1 receptor–activated protein kinase (IRAK) 4. This is paralleled by the (auto)phosphorylation of IRAK4, which subsequently phosphorylates IRAK1 and IRAK2, and then this is followed by the recruitment and oligomerization of tumor necrosis factor–associated factor (TRAF) 6. Activation of NF-κB by IL-1 requires the activation of inhibitor of nuclear factor B (IκB) kinase 2 (IKK2). Activated IKK phosphorylates IκBα, which promotes its K48-linked polyubiquitination and subsequent degradation by the proteasome. IκB destruction allows the release of p50 and p65 NF-κB subunits and their nuclear translocation, which is the central step in activation of NF-κB. Both NF-κBs bind to a conserved DNA motif that is found in numerous IL-1–responsive genes. (Weber et al., 2010a, b)
The initial step in IL-1 signal transduction is a ligand-induced conformational change in the first extracellular domain of the IL-1RI that facilitates recruitment of IL-1R3. the trimeric complex rapidly assembles two intracellular signaling proteins, myeloid differentiation primary response gene 88 (MYD88) and interleukin-1 receptor–activated protein kinase (IRAK) 4. This is paralleled by the (auto)phosphorylation of IRAK4, which subsequently phosphorylates IRAK1 and IRAK2, and then this is followed by the recruitment and oligomerization of tumor necrosis factor–associated factor (TRAF) 6. Activation of NF-κB by IL-1 requires the activation of inhibitor of nuclear factor B (IκB) kinase 2 (IKK2). Activated IKK phosphorylates IκBα, which promotes its K48-linked polyubiquitination and subsequent degradation by the proteasome. IκB destruction allows the release of p50 and p65 NF-κB subunits and their nuclear translocation, which is the central step in activation of NF-κB. Both NF-κBs bind to a conserved DNA motif that is found in numerous IL-1–responsive genes (Weber, Wasiliew and Kracht, 2010a, b)</span>. </p>
~~Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation~~
Inhibition, Nuclear factor kappa B (NF-κB) leads to Suppression of T cell activation</span></p>
In T lineage cells, the temporal regulation of NF-kb controls the stepwise differentiation and antigen-dependent selection of conventional and specialized subsets of T cells in response to T cell receptor and costimulatory, cytokines and growth factor signals. Cytokines include cytokines produced from macrophage or monocyte such as IL-1b. (Gerondakis et al., 2014)
In T lineage cells, the temporal regulation of NF-κB controls the stepwise differentiation and antigen-dependent selection of conventional and specialized subsets of T cells in response to T cell receptor and costimulatory, cytokines and growth factor signals. Cytokines include cytokines produced from macrophage or monocyte such as IL-1β (Gerondakis et al., 2014)</span>.</p>
~~Suppression of T cell activation leads to Increase, Increased susceptibility to infection~~
Suppression of T cell activation leads to supression of TDAR
First type immunity drives resistance to viruses and intracellular bacteria, such as Listeria monocytogenes, Salmonella spp. and Mycobacteria spp., as well as to intracellular protozoan parasites such as Leishmania spp. The T helper 1 signature cytokine interferon-γ has a central role in triggering cytotoxic mechanisms including macrophage polarization towards an antimicrobial response associated with the production of high levels of reactive oxygen species and reactive nitrogen species, activation of CD8 cytotoxic T lymphocytes and natural killer cells to kill infected cells via the perforin and/or granzyme B-dependent lytic pathway or via the ligation of surface death receptors; and B cell activation towards the production of cytolytic antibodies that target infected cells for complement and Fc receptor-mediated cellular cytotoxicity.
T cell-derived cytokines play important roles in TDAR. Among them, IL-2 promotes proliferation of B cells, and IL-4 affects maturation and class switching of B cells as well as proliferation.
Resistance to extracellular metazoan parasites and other large parasites is mediated and/or involves second type immunity. Pathogen neutralization is achieved via different mechanisms controlled by T 2 signature cytokines, including interleukin-4, IL-5 and IL-13, and by additional type 2 cytokines such as thymic stromal lymphopoietin, IL-25 or IL-33, secreted by damaged cell. T 2 signature cytokines drive B cell activation towards the production of high-affinity pathogen-specific IgG1 and IgE antibodies that function via Fc-dependent mechanisms to trigger the activation of eosinophils, mast cells and basophils, expelling pathogens across epithelia.
Th2 cells produce cytokines including IL-4. Suplatast tosilate (IPD) is known as an inhibitor of the production of IL-4 and IL-5 in Th2 cells and reduces the production of antigen specific IgE in human cell culture and mice (Yanagihara, 2013). These findings suggests that the reduction of IL-4 production by the inhibitor of
T17 immunity confers resistance to extracellular bacteria such as Klebsiella pneumoniae, Escherichia coli, Citrobacter rodentium, Bordetella pertussis, Porphyromonas gingivalis and Streptococcus pneumoniae, and also to fungi such as Candida albicans, Coccidioides posadasii, Histoplasma capsulatum and Blastomyces dermatitidis. Activation of T 17 cells by cognate T cell receptor (TCR–MHC class II interactions and activation of group 3 innate lymphoid cells (ILC3s) via engagement of IL-1 receptor (IL-1R) by IL-1β secreted from damaged cells lead to the recruitment and activation of neutrophils. T 17 immunopathology is driven to a large extent by products of neutrophil activation, such as ROS and elastase (reviewed by Soares et al. (Soares et al., 2017).
Th2 cell cytokines results in reduced production of IgE and/or IgG1 through inhibitions of maturation, proliferation and class switching of B cells.
~~Based on these evidences, the insufficient T cell or B cell function causes impaired resistance to infection.~~
IL-2 binds to IL-2 receptor (IL-2R) and acts on T cells. CD25 is one the of IL-2R. Basiliximab (Simulect) is known as anti-CD25antibody. Basiliximab binds to IL-2R and blocks IL-2 signaling. Clinical transplantation study of basiliximab reveals decreases in rejections. On the other hand, basiliximab inhibits the activation of antigen specific T cells (Kircher, 2003).
~~Empirical support~~
Based on these evidences, the insufficient T cell or B cell function causes suppression of TDAR
~~<p>This table summarizes the empirical support obtained from the experiment using several inhibitor or gene targeting mice.  </p>~~
<h2>Empirical support</h2>
<table border="1" cellpadding="1" cellspacing="1" style="width:500px">
~~<tbody>~~
~~<tr>~~
~~<td>~~
~~<table border="0" cellpadding="0" cellspacing="0" style="width:2341px">~~
~~<tbody>~~
~~<tr>~~
~~<td>concordance table ~~
~~empirical data</td>~~
~~<td> </td>~~
~~<td> </td>~~
<td> </td>
<td> </td>
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td rowspan="2">Reference</td>~~
<td rowspan="2">Chmical Initiator or deleted gene</td>
<td rowspan="2">dose</td>
<td rowspan="2">Species</td>
~~<td>MIE</td>~~
<td>KE1</td>
~~<td>KE2</td>~~
<td>AO</td>
</tr>
~~<tr>~~
~~<td>Inhibition of IL-1 binding to IL-1 receptor</td>~~
~~<td>Inhibition, Nuclear factor kappa B (NF-kB)</td>~~
~~<td>Suppression of T cell activation</td>~~
<td>Increase, Increased susceptibility to infection</td>
~~</tr>~~
~~<tr>~~
<td>Dripps et al. 1991</td>
<td>IL-1Ra (anakinra)</td>
<td> </td>
~~<td> </td>~~
<td>Equilibrium binding and kinetic experiments show that IL-1ra binds to the 80-kDa IL-1 receptor on the murine thymomcae ll line EL4 with an affinity (KD = 150 pM) approximately equal to that of IL-la and IL-1b for this receptor</td>
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Sigma-Aldrich Specification Sheet</td>~~
~~<td>IL-1Ra (anakinra)</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>Determined by its ability to inhibit the IL-1alpha stimulation of murine D10S cell. The expected ED50 is 20-40 ng/ml in the presence of 50 pg/ml of IL-1alpha.</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Fleischmann et al. 2003</td>~~
~~<td>IL-1Ra (anakinra)</td>~~
~~<td>100 mg of anakinra or ~~
placebo, administered daily by subcutaneous injection</td>
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>Serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group). </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Genovese et al. 2004</td>~~
~~<td>IL-1Ra (anakinra)</td>~~
<td>treated with subcutaneous etanercept only (25 mg twice weekly), full-dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months</td>
~~<td>human</td>~~
<td> </td>
~~<td> </td>~~
<td> </td>
~~<td>The incidence of serious infections (0% for etanercept alone, 3.7-7.4% for combination therapy), injection-site reactions, and neutropenia was increased with combination therapy.</td>~~
~~</tr>~~
~~<tr>~~
~~<td>Kullenberg et al. 2016</td>~~
~~<td>IL-1Ra (anakinra)</td>~~
~~<td>administered as daily s.c. injections</td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
<td>In total, 14 patients experienced 24 serious AEs (SAEs), all of which resolved during the study period. The most common types of SAEs were infections such as pneumonia and gastroenteritis. </td>
~~</tr>~~
~~<tr>~~
~~<td>Lequerre et al. 2008</td>~~
~~<td>IL-1Ra (anakinra)</td>~~
~~<td>treated with anakinra (1–2 mg/kg/day in children, 100 mg/day in adults)</td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>Two patients stopped anakinra due to severe ~~
~~skin reaction, and two patients due to infection: one ~~
~~visceral leishmaniasis and one varicella.</td>~~
~~</tr>~~
~~<tr>~~
~~<td>Migkos et al. 2015</td>~~
~~<td>IL-1Ra (anakinra)</td>~~
~~<td> </td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>a case of tuberculous pyomyositis in a 85-year-old Caucasian patient with rheumatoid arthritis (RA) ~~
~~treated with steroids and anakinra.</td>~~
~~</tr>~~
~~<tr>~~
~~<td>Settas et al. 2007</td>~~
~~<td>IL-1Ra (anakinra)</td>~~
~~<td> </td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>reactivation of previous pulmonary tuberculosis (TBC) after 23 months of treatment with the IL-1 receptor antagonist anakinra.</td>~~
~~</tr>~~
~~<tr>~~
~~<td>Lee et al. 2004</td>~~
~~<td>IL-1Ra (anakinra)</td>~~
~~<td> </td>~~
~~<td>intrathecal administration of IL-1ra (6 mg)</td>~~
~~<td> </td>~~
<td>intrathecal pretreatment with IL-1ra (6 mg) or YVAD (0.5 mg) significantly inhibited NF-kB DNA-binding activity upregulation bilaterally (Fig. 3C). The intrathecal administration of IL-1ra or YVAD into non-inflamed animals produced no significant change in the DNA-binding activity of NF-kB p65.</td>
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Vallejo et al. 2014</td>~~
~~<td>IL-1Ra (anakinra)</td>~~
~~<td>In diabetic rats treated with anakinra (100 or 160 mg/Kg/day for 3 or 7 days before sacrifice)</td>~~
~~<td>rat</td>~~
~~<td> </td>~~
<td>In diabetic rats treated with anakinra (100 or 160 mg/Kg/day for 3 or 7 days before sacrifice) a partial improvement of diabetic endothelial dysfunction occurred, together with a reduction of vascular NADPH oxidase and NF-κB activation.</td>
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Dhimolea et al. 2010</td>~~
~~<td>canakinumab</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>Canakinumab binds to human IL-1β with high affinity; the antibody-antigen dissociation equilibrium constant is approximately 35–40 pM. ~~
~~Cmax was 1.2, 1.2 and 1.5 pM for 1, 3 and 10 mg/kg antibody respectively, at days 42–56 after the first infusion.</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>De Benedetti et al. 2018</td>~~
~~<td>canakinumab</td>~~
~~<td>150 mg subcutaneously every 4 weeks</td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase ~~
~~deficiency, and those with TRAPS, respectively), with a few being serious infections ~~
~~(6.6, 13.7, and 0.0 per 100 patient-years).</td>~~
~~</tr>~~
~~<tr>~~
~~<td>Imagawa et al. 2013</td>~~
~~<td>canakinumab</td>~~
~~<td>either 150 mg s.c. or 2 mg/kg for patients with a body weight ≤ 40 kg every 8 weeks for 24 weeks</td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>Two patients had serious adverse events, which resolved with standard treatment. </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Lachmann et al. 2009</td>~~
~~<td>canakinumab</td>~~
~~<td>received ~~
~~150 mg of canakinumab subcutaneously every 8 weeks for up to 24 weeks</td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
<td>the incidence of suspected infections was greater in the canakinumab group than in the placebo group (P = 0.03). Two serious adverse events occurred during treatment with canakinumab: one case of urosepsis and an episode of vertigo.</td>
~~</tr>~~
~~<tr>~~
~~<td>Schlesinger et al. 2012</td>~~
~~<td>canakinumab</td>~~
~~<td>one dose of canakinumab 150 mg</td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
<td>Over the 24-week period, adverse events were reported in 66.2% (canakinumab) and 52.8% (TA) and serious adverse events were reported in 8.0% (canakinumab) and 3.5% (TA) of patients. Adverse events reported more frequently with canakinumab included infections, low neutrophil count and low platelet count.</td>
~~</tr>~~
~~<tr>~~
~~<td>Textbook of Pediatric Rheumatology (Sixth Edition), 2011</td>~~
~~<td>rilonacept</td>~~
~~<td> </td>~~
~~<td>human</td>~~
~~<td>Rilonacept has a very high binding affinity for IL-1 (dissociation constant ~1 pM), and it is specific for IL-1β and IL-1α.</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Hoffman et al. 2008</td>~~
~~<td>rilonacept</td>~~
~~<td>weekly subcutaneous ~~
~~injections (160 mg)</td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
<td>The incidence of patients reporting any type of infection was higher during study 1 in patients treated with rilonacept as compared with patients treated with placebo (48% versus 17%), with upper respiratory tract infections being the most frequently reported infection</td>
~~</tr>~~
~~<tr>~~
~~<td>Roell et al. 2010</td>~~
~~<td>gevokizumab (XOMA 052)</td>~~
~~<td> </td>~~
~~<td>human</td>~~
~~<td> </td>~~
<td>XOMA 052 neutralizes IL-1b stimulation of NFkB activation in HeLa cells stably expressing an NFkB-luciferase reporter construct with an IC50 of ~1 pM at the EC50 for this assay (25 pg/ml IL-1b).</td>
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Mansouri et al. 2015</td>~~
~~<td>gevokizumab (XOMA 052)</td>~~
~~<td>receive gevokizumab ~~
~~60 mg subcutaneously every 4 weeks for a total of three injections ~~
~~(12 weeks) with a 4-week follow-up period</td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>There were no significant adverse events related to the study medication, although one patient developed an abscess in a haematoma secondary to an injury.</td>~~
~~</tr>~~
~~<tr>~~
~~<td>Issafras et al. 2014</td>~~
~~<td>gevokizumab (XOMA 052)</td>~~
~~<td> </td>~~
~~<td>human (HeLa cells stably transfected ~~
~~with a nuclear factor-kB (NF-kB) luciferase reporter plasmid)</td>~~
~~<td> </td>~~
~~<td>an average KB value (mean±S.D., n=3) of 4.8±4.4 pM</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Palombella et al. 1994</td>~~
~~<td>MG-132</td>~~
~~<td> </td>~~
~~<td>human (in vitro)</td>~~
~~<td> </td>~~
~~<td>Both MG115 and MG132 (at 20-40 mM) markedly inhibited the formation of p50 in HeLa S100 extracts (Figure 4A, lanes 8-13).</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Hellerbrand et al. 1998</td>~~
~~<td>MG-132</td>~~
~~<td> </td>~~
~~<td>rat (in vitro)</td>~~
~~<td> </td>~~
~~<td>ALLN (Fig. 3A) and MG132 (Fig. 3B) (10 mg/mL = 21mM) reduced the cytokine-mediated NFkB activation.</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Arlt et al. 2001</td>~~
~~<td>MG-132</td>~~
~~<td> </td>~~
~~<td>human (in vitro)</td>~~
~~<td> </td>~~
~~<td>In all cell lines, gliotoxin, MG132 (10 mM) or sulfasalazine strongly reduced VP16-induced NF-kB-driven luciferase expression.</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Ortiz-Lazareno et al. 2008</td>~~
~~<td>MG-132</td>~~
~~<td> </td>~~
~~<td>human (in vitro)</td>~~
~~<td> </td>~~
<td>The increase in NF-kB activation induced by LPS+PMA diminished significantly from 3.27-fold to 0.94-fold in the group treated with MG132(10 mM) and later stimulated with LPS+PMA (P < 0.002). The activation of NF-kB induced by LPS+PMA was blocked by MG132.</td>
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Yu and Malek 2001</td>~~
~~<td>MG-132</td>~~
~~<td> </td>~~
~~<td>mice (in vitro)</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>MG132 (50mM) stabilized IL-2-induced activation of phosphorylated STAT5, which was especially evident after 2 h in culture (Fig. 5A, lane 7 versus 8).</td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Wang et al. 2011</td>~~
~~<td>MG-132</td>~~
~~<td> </td>~~
~~<td>human (in vitro)</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>CMV-specific cytotoxicity of CD8(+) T cells was decreased in the presence of MG132.</td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Ohkusu-Tsukada et al. 2018</td>~~
~~<td>MG-132</td>~~
~~<td>repeatedly i.p. injected 200 ~~
~~nmol of MG132 on days 0, 3, 5, 7, 9, 11, 13, 15, 17, and 19.</td>~~
~~<td>mice (in vivo)</td>~~
~~<td> </td>~~
~~<td> </td>~~
<td>In vivo MG132 administration to NC/Nga mice with DNFB-induced dermatitis reduced Th17 cells but maintained the level of Th1 cells, resulting in the alleviation of dermatitis lesions by decreasing both serum IgE hyperproduction and mast cell migration.</td>
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Satou et al. 2004</td>~~
~~<td>bortezomib</td>~~
~~<td> </td>~~
~~<td>human (in vitro, in vivo)</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>potently inhibits the growth of adult T-cell leukemia ~~
~~cells both in vivo and in vitro</td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Orciuolo et al. 2007</td>~~
~~<td>bortezomib</td>~~
~~<td>0.1 mM, 1 mM, 10 mM</td>~~
~~<td>human (in vitro)</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>the percentage of CD69/TNFa positive T-cell reduces with the increment of bortezomib concentration.</td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Matsumoto et al. 2005</td>~~
~~<td>dehydroxymethylepoxyquinomicin ~~
~~(DHMEQ)</td>~~
~~<td> </td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td>The addition of DHMEQ (10 mg/mL) completely inhibited the activated NF-KB for at least 8 hours.</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Nishioka et al. 2008</td>~~
~~<td>dehydroxymethylepoxyquinomicin ~~
~~(DHMEQ)</td>~~
~~<td> </td>~~
~~<td>human (in vitro)</td>~~
~~<td> </td>~~
~~<td>DHMEQ (1mg/mL) blocked PHA-induced nuclear translocation of NF-kB in Jurkat cells via inhibition of degradation of IkBa.</td>~~
~~<td>Exposure of PBMC to PHA greatly stimulated expression ~~
~~of IFN-g, IL-2 and TNF-a (Fig. 3a). Pre-incubation of these cells with DHMEQ (1 mg/ml, 3 hr) greatly reduced ~~
~~PHA-stimulated expression of these cytokine genes ~~
~~(Fig. 3a). Similarly, PHA increased expression of IL-2 ~~
~~and IFN-c in Jurkat cells and pre-incubation of these ~~
~~cells with DHMEQ (1 mg/ml) decreased these levels ~~
~~by approximately half (Fig. 3b).</td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Alessiani et al. 1991</td>~~
~~<td>FK 506</td>~~
~~<td> </td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>Five of eight deaths were due to infection (62.5%). Overall, 50% of patients developed infection of which 38% suffered severe ones.</td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Fung et al. 1991</td>~~
~~<td>FK 506</td>~~
~~<td> </td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
<td>The incidence of serious infections, despite the potency of FK 506, has not appeared to be alarming. The incidence of serious infections was about 50% less than seen in a historical group of patients given CyA. Of note is that the incidence of cytomegalovirus infections did not appear to be increased when compared with patients on CyA.</td>
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Ekberg et al. 2007</td>~~
~~<td>cyclosporine</td>~~
~~<td> </td>~~
~~<td>human</td>~~
~~<td> </td>~~
~~<td> </td>~~
<td>The most commonly reported serious adverse events were cytomegalovirus (CMV) viremia, urinary tract infection and lymphocele (Table 3). The number of patients with opportunistic infections (serious and non-serious) was also similar amongst the groups, and cytomegalovirus infection was the most common opportunistic infection (Table 3).</td>
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>Guler et al. 2011</td>~~
~~<td>i) IL-1RI-/- ~~
~~ii) Autologous Qb virus-like particle-based vaccines against IL-1a and IL-1b</td>~~
~~<td>ii) immunized s.c. three times before (at week: −5, −3 and −1) and once at week 10 post-infection</td>~~
~~<td>mice</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>i) drastically increases mortality not only to high-dose intranasal infection but also to natural low-dose aerosol infection with Mycobacterium tuberculosis. ~~
~~ii) Blocking of IL-1a resulted in increased susceptibility to chronic infection with Mycobacterium tuberculosis. ~~
~~Increased listerial growth following IL-1aneutralization.</td>~~
~~</tr>~~
~~<tr>~~
~~<td>Parnet et al. 2003</td>~~
~~<td>IL-1RI-/-</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
<td>Activation of NFkB in response to IL-1b was no longer apparent in IL-1RI knockout mice, confirming that this receptor is essential for the transduction of IL-1 signal in the pituitary, </td>
~~<td> </td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
<td>Yamada et al. 2001</td>
~~<td>NF-kB p50-/-</td>~~
~~<td>knockout mice</td>~~
~~<td>mice</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td> </td>~~
<td>NF-kB p50 knockout mice were infected with Mycobacterium tuberculosis by placing them in the exposure chamber of an airborneinfection apparatus. These mice developed multifocal necrotic pulmonary lesions or lobar pneumonia. Compared with the levels in wild-type mice, pulmonary inducible nitric oxide synthase, interleukin-2 (IL-2), gamma interferon, and tumor necrosis factor alpha mRNA levels were significantly low but expression of IL-10 and transforming growth factor b mRNAs were within the normal ranges. The pulmonary IL-6 mRNA expression level was higher.
~~ ~~
C57BL/6 WT mice survived the entire 12-week experimental period, but NF-kB KO mice began to succumb to the disease at 6 weeks after infection, and all mice had died by 10 weeksafter infection (Fig. 1). </td>
~~</tr>~~
~~<tr>~~
~~<td>Weih et al. 1995</td>~~
~~<td>RelB-/-</td>~~
~~<td>knockout mice</td>~~
~~<td>mice</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>RelB-deficient animals also had an impaired cellular ~~
~~immunity, as observed in contact sensitivity experiments.</td>~~
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
<td>Lin et al. 2015</td>
~~<td>Secreted IL-1α expression</td>~~
~~<td> </td>~~
~~<td>mice</td>~~
~~<td> </td>~~
~~<td> </td>~~
<td>Both the percent and number of CD69+ T cells, CD69+ CD8+ T cells, and CD69+ CD4+ T cells increased by the expression of secreted IL-1α in the spleen</td>
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
<td>Nambu et al. 2006</td>
<td>IL-1a-/-, IL-1b-/-, IL-1a/b-/-</td>
~~<td>knockout mice</td>~~
~~<td>mice</td>~~
~~<td> </td>~~
~~<td> </td>~~
~~<td>IL-1b, but not IL-1a, is required for antigen-specific ~~
~~T cell activation and the induction of local ~~
~~inflammation in the delayed-type hypersensitivity ~~
~~responses</td>~~
~~<td> </td>~~
~~</tr>~~
~~</tbody>~~
~~</table>~~
~~</td>~~
~~</tr>~~
~~</tbody>~~
</table>
<ol>
<li><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Impaired IL-1R signaling.</li>
</ol>
<span style="color:black">Decreased production of IL-1 or inhibition of the binding of IL-1 to IL-1R impair IL-1R signaling.
<ol>
<li style="list-style-type:none">
<ol>
<li>Decreased IL-1 production </li>
</ol>
</li>
</ol>
Decreased IL-1 production by macrophages or dendritic cells can be induced by suppressed IL-1β mRNA induction or suppressed maturation of pro-IL-1β. Dexamethasone is one of the representative drugs that significantly suppress IL-1β production from monocytes (Finch-Arietta and Cochran, 1991). Other than dexamethasone, the inhibition of various targets in different layers from the stimulation of PRRs or the receptors of proinflammatory cytokines to the activation of NF-κB or the inhibition of posttranscriptional regulation of pro-IL-1β cause impaired decreased IL-1β production.
Quite a few compounds have been reported to inhibit NF-κB signaling by several different mechanisms reviewed by Fuchs (Fuchs, 2010). In fact, dimethyl fumarate inhibits the activation of NF‐κB, resulting in a loss of proinflammatory cytokine production, distorted maturation and function of antigen‐presenting cells, and immune deviation of T helper cells (Th) from the type 1 (Th1) and type 17 (Th17) profiles to a type 2 (Th2) phenotype (McGuire et al., 2016; Peng et al., 2012). Several studies have shown intriguing pharmacologic effects associated with curcumin, which inhibits NF-κB expression by regulating NF-κB/IκB pathway and down-regulates expression of pro-inflammatory cytokines, such as IL-1, IL-6, IL-8, and TNFα (Wang et al., 2018). Iguratimod, a methanesulfonanilide, that is a novel disease-modifying antirheumatic drug, inhibits NF-κB but not its inhibitor, IκBα, and inhibits the production of IL-1b (Mucke, 2012). Epigalocathechin gallate (EGCG) has been reported to inhibit NF-κB activation through inhibition of p65 phosphorylation (Wheeler et al., 2004) and suppress the production of LPS-stimulated IL-1b (Wang et al., 2020). DHMEQ inhibits LPS-induced NF-κB activation by inhibiting its nuclear translocation from the cytoplasm. It also inhibits LPS-induced secretion of IL-1b (Suzuki and Umezawa, 2006).
Other than the inhibitors for NF-κB signaling, which can be stimulated by various stimulations other than TLR4 stimulation, there are signaling molecules that are specific to TLR4 signaling, such as TLR4, Mal, TRAM, Myd88, IRAK4, and IRAK1/2 (Vallabhapurapu and Karin, 2009). There are several chemicals that targe some of these molecules, an inhibitors of TLR4 such as TAK-242 (Matsunaga et al., 2011) and various IRAK4 inhibitors (Lee et al., 2017). IRAK4 has recently attracted attention as a therapeutic target for inflammation and tumor diseases (Chaudhary, Robinson and Romero, 2015).
Beside transcriptional regulation of IL-1b production, minocycline, and two prodrugs, pralnacasan (VX-740) and belnacasan (VX-765) that are orally absorbed and converted into the active principle, VRT-018858 and VRT-043198, respectively (Fenini, Contassot and French, 2017) suppress IL-1 signaling by the inhibition of caspase-1 activation. Caspase-1 is an essential enzyme for maturation of pro- IL-1β and the secretion of mature IL-1β (Vincent and Mohr, 2007). Recently, it has been reported that cinnamic aldehyde suppresses serum IL-1β level in endotoxin poisoning mice (Xu et al., 2017).
<ol>
<li style="list-style-type:none">1-2. Blocking of binding of IL-1 to IL-1R1</li>
</ol>
IL-1α and IL-1β independently bind the type I IL-1 receptor (IL-1R1), which is ubiquitously expressed. IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction (Dripps et al., 1991). Recombinant IL-1Ra (anakinra) is fully active in blocking the IL-1R1, and therefore, the biological activities of IL-1α and IL-1β. The binding of IL-1α and IL-1β to IL-1R1 can be suppressed by soluble IL-1R like rilonacept (Kapur and Bonk, 2009). The binding of IL-1β to IL-1R1 can be inhibited by anti-IL-1β antibody (canakinumab and gevokizumab) (Church and McDermott, 2009) (Roell et al., 2010).
Several reports described that the administration of IL-1 receptor antagonist（IL-1Ra）, canakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R) led to increased susceptibility to infection (De Benedetti et al., 2018; Fleischmann et al., 2003; Genovese et al., 2004; Imagawa et al., 2013; Kullenberg et al., 2016; Lachmann et al., 2009; Lequerre et al., 2008; Schlesinger et al., 2012; Yokota et al., 2017).
<ol start="2">
<li>Immunosuppression by impaired IL-1 receptor signaling</li>
</ol>
In addition to these human data, the experiments using knockout mice revealed that the lack of IL-1 signaling either by the lack of IL-1a or IL-1b or the lack of IL-1 receptor led to bacterial, tuberculosis or viral infection(Bohrer et al., 2018; Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Labow et al., 1997; Tian, Jin and Dubin, 2017; Yamada et al., 2000). Moreover, polymorphism of IL-1b or IL-1Ra leads to the increased susceptibility to tuberculosis, severe sepsis or fungal infection (Fang et al., 1999; Motsinger-Reif et al., 2010; Wojtowicz et al., 2015).
<h3>Quantitative Consideration</h3>
IL-1Ra blocks IL-1 signaling:
IL-lra alone at concentrations as high as 1 mg/mL did not induce IL-la, IL-lβ, TNFa, or IL-6 synthesis. Suppression of IL-1-induced IL-1, TNFa, or IL-6 synthesis was dose-dependent (P ≦ .0001). At a twofold molar excess, IL-lra inhibited IL-1-induced IL-1 or TNFa synthesis by 50% (P < .01); an equimolar concentration of IL-lra inhibited synthesis of these two cytokines by over 20% (P < .05). A 10-fold molar excess of IL-lra over IL-lβ reduced IL-lβ-induced IL-la by 95% (P = .01) and IL-la-induced IL-1β by 73% (P < .01). In elutriated monocytes, a 10-fold molar excess of IL-lra reduced IL-lβ-induced IL-la by 82% (P < .05), TNFa by 64% (P = .05), and IL-6 by 47% (P < .05). (Granowitz et al., 1992)
Canakinumab (ACZ885, Ilaris):
The antibody binds to human IL-1β with high affinity (about 40 pmol/l). The antibody was found to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro 44.6 pmol/l (7.1 ± 0.56 ng/ml; n = 6) of ED50. Application of Canakinumab intraperitoneally 2 hours before injecting the IL-1β producing cells completely suppressed joint swelling (0.06 mg/kg of EC50) (Alten et al., 2008).
Primary human fibroblasts are stimulated with recombinant IL-1b or conditioned medium obtained from LPS-stimulated human PBMCs in the presence of various concentrations of Cankinumab or IL-1RA ranging from 6 to 18,000 pM. Supernatant is taken after 16 h stimulation and assayed for IL-6 by ELISA. Canakinumab typically have 1 nM or less of EC50 for inhibition of IL-6 production (Canakinumab Patent Application WO02/16436.)
Rilonacept (IL-1 Trap, Arcalyst):
Incubation of the human MRC5 fibroblastic cell line with IL-1β induces secretion of IL-6. At a constant amount of IL-1β (4 pM), the IC50 of the IL-1 trap is &sim;2 pM. Another unique property of the IL-1 trap is that it not only blocks IL-1β, but also blocks IL-1α with high affinity (KD = &sim;3 pM; data not shown). The titration curve of IL-1 trap in the presence of 10 pM IL-1β shows an IC50 of 6.5 pM, which corresponds to a calculated KD of 1.5 pM (This affinity is 100 times higher than that of the soluble single component receptor IL-1RI (Economides et al., 2003).
</div>
<div id="considerations_for_potential_applicaitons">
<h2>Considerations for Potential Applications of the AOP (optional)</h2>
The impaired IL-1 signaling can lead to decreased host resistance to various infections. Therefore, the test guideline to detect chemicals that decrease IL-1 signaling is required to support regulatory decision-making. This AOP can promote the understanding of the usefulness of the test guideline.
The impaired IL-1 signaling can lead to immunosuppression. Therefore, the test guideline to detect chemicals that decrease IL-1 signaling is required to support regulatory decision-making. This AOP can promote the understanding of the usefulness of the test guideline.</span></p>
</div>
<div id="references">
<h2>References</h2>
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</div>
<div id="appendicies">
<h2>Appendix 1</h2>
<h3>List of MIEs in this AOP</h3>
~~<h4><a href="/events/1700">Event: 1700: Impaired IL-1R1 signaling</a></h4>~~
<h4><a href="/events/1700">Event: 1700: Impaired IL-1R1 signaling in T cell</a></h4>
<h5>Short Name: Impaired IL-1R1 signaling</h5>
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>interleukin-1 receptor activity</td>
<td>interleukin-1 receptor type I</td>
<td>decreased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
~~<td><a href="/aops/277">Aop:277 - Impaired IL-1R1 signaling leading to increased susceptibility to infection</a></td>~~
<td><a href="/aops/277">Aop:277 - Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Stressors</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Name</th></tr>
</thead>
<tbody>
<tr><td>IL-1 receptor antagonist（IL-1Ra）(Anakinra)</td></tr>
<tr><td>anti-IL-1b antibody (Canakinumab)</td></tr>
<tr><td>soluble IL-1R (Rilonacept)</td></tr>
<tr><td>curcumin</td></tr>
<tr><td>iguratimod</td></tr>
<tr><td>epigallocathechin gallate</td></tr>
<tr><td>TAK-242</td></tr>
<tr><td>IRAK4 inhibitors</td></tr>
<tr><td>Dehydroxymethylepoxyquinomicin (DHMEQ)</td></tr>
<tr><td>Dimethyl fumarate</td></tr>
<tr><td>anti-IL-1b antibody (Gevokizumab)</td></tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Molecular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
~~<tr><td>macrophage</td></tr>~~
<tr><td>T cell</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>immune system</td></tr>
</tbody>
</table>
</div>
~~<h3>Evidence for Perturbation by Stressor</h3>~~
~~<h4>Overview for Molecular Initiating Event</h4>~~
Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-κB/Rel and AP-1 activation(Jeon et al., 2000).
Dex suppresses LPS-induced gene expression of IL-1β in rat lung. (in vivo) (Qiu et al., 1997)
Dex inhibits the release of IL-1β by human leukocyte stimulated with Streptococcus pneumoniae stimulation (van Furth et al., 1995).
Treatment of peripheral blood monocytes with 2 mg/ml LPS potently increased IL-1β release (p= 0.001) and Dex (10 -7M) significantly reduced both resting and stimulated IL-1β release (p 0.009).) (Morand et al., 1993)
Dex effectively blocks the glutamine antagonist acivicin-induced expression of IL-1β mRNA by HL-60 leukemia cells (Weinberg et al., 1992).
LPS treatment induced a significant upregulation of the mRNA and release of IL-1β from retinal microglia. Minocycline inhibited its releases. Thus, minocycline might exert its antiinflammatory effect on microglia by inhibiting the expression and release of IL-1β (Wang et al., 2005).
~~ ~~
Caspase-1 inhibition reduced the release of IL-1β in organotypic slices exposed to LPS+ATP. Administration of pralnacasan (intracerebroventricular, 50 μg) or belnacasan (intraperitoneal, 25–200 mg/kg) to rats blocked seizure-induced production of IL-1β in the hippocampus, and resulted in a twofold delay in seizure onset and 50% reduction in seizure duration (Ravizza et al., 2006).
Belnacasan, an orally active IL-1β converting enzyme/caspase-1 inhibitor, blocked IL-1β secretion with equal potency in LPS-stimulated cells from familial cold urticarial associated symdrome and control subjects (Stack et al., 2005).
~~ ~~
In LPS-induced acute lung injury (ALI) mice model, LPS induced inflammatory cytokines such as TNF-α, IL-6, IL-13 and IL-1β were significantly decreased by cinnamaldehyde (CA) (Huang and Wang, 2017).
The suppressing capacities of six cinnamaldehyde-related compounds were evaluated and compared by using the LPS-primed and ATP-activated macrophages. At concentrations of 25~100 mM, cinnamaldehyde and 2-methoxy cinnamaldehyde dose-dependently inhibited IL-1β secretion (Ho et al., 2018).
In vitro, CA decreased the levels of pro-IL-1β and IL-1β in cell culture supernatants, as well as the expression of NLRP3 and IL-1β mRNA in cells. In vivo, CA decreased IL-1β production in serum. Furthermore, CA suppressed LPS-induced NLRP3, p20, Pro-IL-1β, P2X7 receptor (P2X7R) and cathepsin B protein expression in lung, as well as the expression of NLRP3 and IL-1β mRNA (Xu et al., 2017).
~~ ~~
IL-1 is known to mediates autoinflammatory syndrome, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. Blocking of binding of IL-1 to IL-1R1 by anakinra, canakinumab, and rilonacept have been already used to treat these autoinflammatory syndrome associated with overactivation of IL-1 signaling (Quartier, 2011).
~~ ~~
Various IRAK4 inhibitors are currently under the investigation on the possibility of clinical use for autoimmune disorders (Chaudhary et al., 2015).
<h4>Domain of Applicability</h4>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Mus musculus</td>
<td>Mus musculus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Rattus norvegicus</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent. Age-dependent difference in IL-1 signaling is not known.
The IL1B gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, and frog (<a href="https://www.ncbi.nlm.nih.gov/homologene/481" style="color:#954f72; text-decoration:underline">https://www.ncbi.nlm.nih.gov/homologene/481</a>), and the Myd88 gene is conserved in human, chimpanzee, rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (<a href="https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849" style="color:#954f72; text-decoration:underline">https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849</a>).
The IL1B gene is conserved in human, chimpanzee, rhesus monkey, dog, cow, mouse, rat, and frog (<a href="https://www.ncbi.nlm.nih.gov/homologene/481" style="color:#954f72; text-decoration:underline">https://www.ncbi.nlm.nih.gov/homologene/481</a>), and the Myd88 gene is conserved in chimpanzee, rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (<a href="https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849" style="color:#954f72; text-decoration:underline">https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849</a>).
These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.
The lower level of stress-induced IL-1β expression is demonstrated in the aged murine keratinocytes (Pilkington et al., 2018).
The IL-1β production by mouse oral mucosal leukocytes stimulated with candida albicans was reduced with aging (Bhaskaran et al., 2020).
The baseline IL-1 signaling of the upper respiratory tract lavage was reduced in murine newborn mice (Kuipers et al., 2018).</u></p>
<h4>Key Event Description</h4>
<ol>
<li>Decreased IL-1 production </li>
</ol>
Decreased IL-1 production by macrophages or dendritic cells can be induced by suppressed IL-1β mRNA induction or suppressed maturation of pro-IL-1β. Dexamethasone is one of the representative drugs that significantly suppress IL-1β production from monocytes (Finch-Arietta and Cochran, 1991). Other than dexamethasone, the inhibition of various targets in different layers from the stimulation of PRPs or the receptors of proinflammatory cytokines lto the activation of NF-κB or the inhibition of posttranscriptional regulation of pro-IL-1β cause impaired IL-1R1 signaling. Among various PRPs, the signaling through TLR4 is best characterized. In addition, it is beyond the scope of this AOP to cover all signaling through each PRP. So, this AOP focuses on TLR4 signaling.
Decreased IL-1 production by macrophages or dendritic cells can be induced by suppressed IL-1β mRNA induction or suppressed maturation of pro-IL-1β. Dexamethasone is one of the representative drugs that significantly suppress IL-1β production from monocytes (Finch-Arietta and Cochran, 1991). Other than dexamethasone, the inhibition of various targets in different layers from the stimulation of PRRs or the receptors of proinflammatory cytokines lto the activation of NF-κB or the inhibition of posttranscriptional regulation of pro-IL-1β cause impaired IL-1R1 signaling. Among various PRRs, the signaling through TLR4 is best characterized. In addition, it is beyond the scope of this AOP to cover all signaling through each PRR. So, this AOP focuses on TLR4 signaling.
Binding of LPS to TLR4 and the coreceptor MD2 triggers interactions between the cytoplasmic TIR domain of TLR4 and TIR-containing adaptor proteins (Mal, MyD88, and TRAM). MyD88 binds IRAK4, which requires its kinase activity to bind the kinases IRAK1 and IRAK2 sequentially. The MyD88–IRAK complex also engages the ubiquitin ligase TRAF6 to make polyubiquitin chains that activate the IKK complex for NF-kB- and ERK-dependent gene transcription. Ubiquitin ligases cIAP1 and cIAP2 recruited to the TLR4 signaling complex regulate translocation of a subset of signaling components to the cytoplasm, where TAK1 activation initiates a MAPK cascade, p38a and JNK, which stimulates gene expression. TLR4 activated at the plasma membrane is endocytosed but can signal within the endosomal compartment via the adaptors TRAM and TRIF. The kinase and ubiquitin ligase combination of RIP1 and Peli1 interacts with TRIF to signal NF-kB activation, whereas TBK1 and TRAF3 stimulate IRF3-dependent transcription. Through these signaling cascades, NF‑κB, activator protein-1 (AP-1), cAMP responsive element binding protein (CREB)/ activating transcription factor
<u><span style="font-size:10.5pt">Lipopolysaccharide (LPS) from the bacteria binds to TLR4 in complex with myeloid differentiation factor-2 (MD2), and this complex initiates signalling by recruiting the adaptor proteins MyD88, TIR domain containing adaptor protein (TIRAP), TIR-domain-containing adapter-inducing interferon-β (TRIF) and TIR-domain containing adaptor (TRAM). MYD88 associates with IL‑1R‑associated kinase 1 (IRAK1) and IRAK4 and recruits TNFR-associated factor 6 (TRAF6). This complex recruits TGF-β-activated kinase 1 (TAK1), leading to phosphorylation of NF-κB inhibitor (IκB), activation of nuclear factor-κB (NF-κB) and consequent transcription of a range of genes coding for pro-inflammatory cytokines, including tumour necrosis factor (TNF), IL-6, pto-IL-1b, and pro-IL-18 (Mills, 2011).</u></p>
(ATF), CCAAT-enhancer-binding protein b (c/EBP b), and interferon regulatory factor 3 (IRF3) are activated. These transcription factors induce the expression of various inflammatory cytokines e.g., IL-1β, TNFα, IL-6 and several chemokines (reviewed by Newton and Dixit (Newton and Dixit, 2012)).
Therefore, chemicals that affect the signaling pathway leading to the activation of these transcription factors are supposed to suppress IL-1β production. Among them, the chemical substances that affect NF-κB signaling have been investigated most thoroughly. Quite a few compounds have been reported to inhibit NF-κB signaling by several different mechanisms reviewed by Fuchs (Fuchs, 2010). The list of representative chemicals and their mechanism to inhibit NF-κB is shown in Table 1. In fact, dimethyl fumarate inhibits the activation of NF‐κB, resulting in a loss of proinflammatory cytokine production, distorted maturation and function of antigen‐presenting cells, and immune deviation of T helper cells (Th) from the type 1 (Th1) and type 17 (Th17) profiles to a type 2 (Th2) phenotype (McGuire et al., 2016; Peng et al., 2012). Several studies have shown intriguing pharmacologic effects associated with curcumin, which inhibits NF-κB expression by regulating NF-κB/IκB pathway and down-regulates expression of pro-inflammatory cytokines, such as IL-1, IL-6, IL-8, and TNFα (Wang et al., 2018). Iguratimod, a methanesulfonanilide, that is a novel disease-modifying antirheumatic drug, inhibits NF-κB but not its inhibitor, IκBα (Mucke, 2012). Epigalocathechin gallate (EGCG) has been reported to inhibit NF-κB activation through inhibition of p65 phosphorylation (Wheeler et al., 2004).
Therefore, chemicals that affect the signaling pathway leading to the activation of these transcription factors are supposed to suppress IL-1β production. Among them, the chemical substances that affect NF-κB signaling have been investigated most thoroughly. Quite a few compounds have been reported to inhibit NF-κB signaling by several different mechanisms reviewed by Fuchs (Fuchs, 2010).  In fact, dimethyl fumarate inhibits the activation of NF‐κB, resulting in a loss of proinflammatory cytokine production, distorted maturation and function of antigen‐presenting cells, and immune deviation of T helper cells (Th) from the type 1 (Th1) and type 17 (Th17) profiles to a type 2 (Th2) phenotype (McGuire et al., 2016; Peng et al., 2012). Several studies have shown intriguing pharmacologic effects associated with curcumin, which inhibits NF-κB expression by regulating NF-κB/IκB pathway and down-regulates expression of pro-inflammatory cytokines, such as IL-1, IL-6, IL-8, and TNFα (Wang et al., 2018). Iguratimod, a methanesulfonanilide, that is a novel disease-modifying antirheumatic drug, inhibits NF-κB but not its inhibitor, IκBα, and inhibits the production of IL-1</span><span style="font-family:"Times New Roman",serif">β</span> <span style="font-family:"Times New Roman",serif">(Mucke, 2012). Epigalocathechin gallate (</span><span style="font-family:"Times New Roman",serif">EGCG) has been reported to inhibit NF-</span><span style="font-family:"Times New Roman",serif">κ</span><span style="font-family:"Times New Roman",serif">B activation through inhibition of p65 phosphorylation </span><span style="font-family:"Times New Roman",serif">(Wheeler et al., 2004) and suppress the production of LPS-stimulated IL-1β (Wang et al., 2020). DHMEQ inhibits lLPS-induced NF-κB activation by inhibiting its nuclear translocation from the cytoplasm. It also inhibits LPS-induced secretion of IL-1β (Suzuki and Umezawa, 2006).
Other than the inhibitors for NF-κB signaling, which can be stimulated by various stimulations other than TLR4 stimulation, there are signaling molecules that are specific to TLR4 signaling, such as TLR4, Mal, TRAM, Myd88, IRAK4, and IRAK1/2 (Vallabhapurapu and Karin, 2009). There are several chemicals that targe some of these molecules, an inhibitors of TLR4 such as TAK-242 (Matsunaga et al., 2011) and various IRAK4 inhibitors (Lee et al., 2017). IRAK4 has recently attracted attention as a therapeutic target for inflammation and tumor diseases.
Beside transcriptional regulation of IL-1b production, minocycline, and two prodrugs, pralnacasan (VX-740) and belnacasan (VX-765) that are orally absorbed and converted into the active principle, VRT-018858 and VRT-043198, respectively (Fenini et al., 2017) suppress IL-1 signaling by the inhibition of caspase-1 activation. Caspase-1 is an essential enzyme for maturation of pro- IL-1β and the secretion of mature IL-1β (Vincent and Mohr, 2007). Recently, it has been reported that cinnamicaldehyde suppresses serum IL-1β level in endotoxin poisoning mice (Xu et al., 2017).
Beside transcriptional regulation of IL-1β production, minocycline, and two prodrugs, pralnacasan (VX-740) and belnacasan (VX-765) that are orally absorbed and converted into the active principle, VRT-018858 and VRT-043198, respectively (Fenini et al., 2017) suppress IL-1 signaling by the inhibition of caspase-1 activation. Caspase-1 is an essential enzyme for maturation of pro- IL-1β and the secretion of mature IL-1β (Vincent and Mohr, 2007). Recently, it has been reported that cinnamicaldehyde suppresses serum IL-1β level in endotoxin poisoning mice (Xu et al., 2017).
<ol start="2">
<li>Blocking of binding of IL-1 to IL-1R1</li>
</ol>
IL-1α and IL-1β independently bind the type I IL-1 receptor (IL-1R1), which is ubiquitously expressed. IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction (Dripps et al., 1991). Recombinant IL-1Ra (anakinra) is fully active in blocking the IL-1R1, and therefore, the biological activities of IL-1α and IL-1β. The binding of IL-1α and IL-1β to IL-1R1 can be suppressed by soluble IL-1R like rilonacept (Kapur and Bonk, 2009). The binding of IL-1β to IL-1R1 can be inhibited by anti-IL-1β antibody (anti-IL-1β antibody) (Church and McDermott, 2009).
IL-1α and IL-1β independently bind the type I IL-1 receptor (IL-1R1), which is ubiquitously expressed. IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction (Dripps et al., 1991). Recombinant IL-1Ra (anakinra) is fully active in blocking the IL-1R1, and therefore, the biological activities of IL-1α and IL-1β. The binding of IL-1α and IL-1β to IL-1R1 can be suppressed by soluble IL-1R like rilonacept (Kapur and Bonk, 2009). The binding of IL-1β to IL-1R1 can be inhibited by anti-IL-1β antibody (canakinumab and gevokizumab) (Church and McDermott, 2009)</span> <span style="font-family:"Times New Roman",serif">(Roell et al., 2010).
This AOP focus on the blocking of binding of IL-1 to IL-1R1, and an inhibition or suppression of IL-1 signaling is out of scope, because the molecular initiating event of IL-1 blocking is simple and appropriate for developing AOP. This AOP is expected to be applicable to any chemicals which bind to IL-1R, although such stressor has not been reported.
<h4>How it is Measured or Detected</h4>
<ol>
<li>Real time polymerase chain reaction to measure IL-1a</span> or IL-1b</span> mRNA</li>
<li>Enzyme-linked immunosorbent assay (ELISA) to detect IL-1a or IL-1 b protein</li>
<li>Competitive inhibition binding experiments using 125I-IL-1 a to type I IL-1R present on EL4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R (McIntyre et al., 1991; Shuck et al., 1991).</li>
<li>Real time polymerase chain reaction to measure IL-1</span><span style="font-size:medium"><span style="color:#000000">α</span> or IL-1β mRNA</li>
<li>Enzyme-linked immunosorbent assay (ELISA) to detect IL-1α or IL-1 b protein</li>
<li>Competitive inhibition binding experiments using 125I-IL-</span><span style="font-family:"ＭＳＰゴシック",sans-serif">1α to type I IL-1R present on EL4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R (McIntyre et al., 1991; Shuck et al., 1991).</li>
<li>Measure the ability of the reagent to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro(Alten et al., 2008)</li>
</ol>
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Wang, A.L., Yu, A.C., Lau, L.T., Lee, C., Wu le, M., Zhu, X., Tso, M.O., 2005. Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47, 152-158.
Stack, J.H., Beaumont, K., Larsen, P.D., et al. (2005), IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol 175: 2630-2634, 10.4049/jimmunol.175.4.2630
Wang, Y., Tang, Q., Duan, P., Yang, L., 2018. Curcumin as a therapeutic agent for blocking NF-kappaB activation in ulcerative colitis. Immunopharmacol Immunotoxicol 40, 476-482.
Suzuki, E., Umezawa, K. (2006), Inhibition of macrophage activation and phagocytosis by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin. Biomed Pharmacother 60: 578-586, 10.1016/j.biopha.2006.07.089
Weinberg, J.B., Mason, S.N., Wortham, T.S., 1992. Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by pentoxifylline and dexamethasone: dissociation of acivicin-induced TNF-alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid differentiation. Blood 79, 3337-3343.
Vallabhapurapu, S., Karin, M. (2009), Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27: 693-733, 10.1146/annurev.immunol.021908.132641
Wheeler, D.S., Catravas, J.D., Odoms, K., Denenberg, A., Malhotra, V., Wong, H.R., 2004. Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1 beta-dependent proinflammatory signal transduction in cultured respiratory epithelial cells. J Nutr 134, 1039-1044.
van Furth, A.M., Seijmonsbergen, E.M., Langermans, J.A., et al. (1995), Effect of xanthine derivates and dexamethasone on Streptococcus pneumoniae-stimulated production of tumor necrosis factor alpha, interleukin-1 beta (IL-1 beta), and IL-10 by human leukocytes. Clin Diagn Lab Immunol 2: 689-692,
Xu, F., Wang, F., Wen, T., Sang, W., Wang, D., Zeng, N., 2017. Inhibition of NLRP3 inflammasome: a new protective mechanism of cinnamaldehyde in endotoxin poisoning of mice. Immunopharmacol Immunotoxicol 39, 296-304.
Vincent, J.A., Mohr, S. (2007), Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes 56: 224-230, 10.2337/db06-0427
Wang, A.L., Yu, A.C., Lau, L.T., et al. (2005), Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47: 152-158, 10.1016/j.neuint.2005.04.018
Wang, F., Han, Y., Xi, S., et al. (2020), Catechins reduce inflammation in lipopolysaccharide-stimulated dental pulp cells by inhibiting activation of the NF-kappaB pathway. Oral Dis 26: 815-821, 10.1111/odi.13290
Wang, Y., Tang, Q., Duan, P., et al. (2018), Curcumin as a therapeutic agent for blocking NF-kappaB activation in ulcerative colitis. Immunopharmacol Immunotoxicol 40: 476-482, 10.1080/08923973.2018.1469145
Weinberg, J.B., Mason, S.N., Wortham, T.S. (1992), Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by pentoxifylline and dexamethasone: dissociation of acivicin-induced TNF-alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid differentiation. Blood 79: 3337-3343,
Wheeler, D.S., Catravas, J.D., Odoms, K., et al. (2004), Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1 beta-dependent proinflammatory signal transduction in cultured respiratory epithelial cells. J Nutr 134: 1039-1044, 10.1093/jn/134.5.1039
Xu, F., Wang, F., Wen, T., et al. (2017), Inhibition of NLRP3 inflammasome: a new protective mechanism of cinnamaldehyde in endotoxin poisoning of mice. Immunopharmacol Immunotoxicol 39: 296-304, 10.1080/08923973.2017.1355377
<h3>List of Key Events in the AOP</h3>
<h4><a href="/events/202">Event: 202: Inhibition, Nuclear factor kappa B (NF-kB)</a></h4>
<h5>Short Name: Inhibition, Nuclear factor kappa B (NF-kB)</h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>I-kappaB kinase/NF-kappaB signaling</td>
<td>transcription factor NF-kappa-B subunit</td>
<td>decreased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/14">Aop:14 - Glucocorticoid Receptor Activation Leading to Increased Disease Susceptibility</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/278">Aop:278 - IKK complex inhibition leading to liver injury</a></td>
<td>KeyEvent</td>
</tr>
<tr>
~~<td><a href="/aops/277">Aop:277 - Impaired IL-1R1 signaling leading to increased susceptibility to infection</a></td>~~
<td><a href="/aops/277">Aop:277 - Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/447">Aop:447 - Kidney failure induced by inhibition of mitochondrial electron transfer chain through apoptosis, inflammation and oxidative stress pathways</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/618">Aop:618 - PPARgamma activation leads to a diminished vaccine response</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Stressors</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Name</th></tr>
</thead>
<tbody>
<tr><td>IL-1 receptor antagonist（IL-1Ra）(Anakinra)</td></tr>
<tr><td>anti-IL-1b antibody (Canakinumab)</td></tr>
<tr><td>soluble IL-1R (Rilonacept)</td></tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Molecular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
~~<tr><td>macrophage</td></tr>~~
<tr><td>T cell</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>immune system</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Mus musculus</td>
<td>Mus musculus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Rattus norvegicus</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
The binding of sex steroids to their respective steroid receptors directly influences NF-κB signaling, resulting in differential production of cytokines and chemokines (McKay and Cidlowski, 1999; Pernis, 2007). 17b-estradiol regulates pro-inflammatory responses that are transcriptionally mediated by NF‑κB through a negative feedback and/or transrepressive interaction with NF-κB (Straub, 2007). Progesterone suppresses innate immune responses and NF-κB signal transduction reviewed by Klein et al. (Klein and Flanagan, 2016). Androgen-receptor signaling antagonises transcriptional factors NF-κB(McKay and Cidlowski, 1999).
The binding of sex steroids to their respective steroid receptors directly influences NF-κB signaling, resulting in differential production of cytokines and chemokines (McKay and Cidlowski, 1999; Pernis, 2007). 17b-estradiol regulates pro-inflammatory responses that are transcriptionally mediated by NF‑κB through a negative feedback and/or transrepressive interaction with NF-κB (Straub, 2007). Progesterone suppresses innate immune responses and NF-κB signal transduction reviewed by Klein et al. (Klein and Flanagan, 2016). Androgen-receptor signaling antagonises transcriptional factors NF-κB(McKay and Cidlowski, 1999).</span>
Evidence for perturbation of this molecular initiating event by stressor
Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-κB/Rel and AP-1 activation (Jeon et al., 2000).
Various inhibitors for NF‐κB, such as dimethyl fumarate, curcumin, iguratimod, epigalocathechin gallate (EGCG), and DHMEQ inhibits lLPS-induced NF-κB activation and LPS-induced secretion of IL-1β (McGuire et al., 2016; Mucke, 2012; Peng et al., 2012; Suzuki and Umezawa, 2006; Wang et al., 2020; Wang et al., 2018; Wheeler et al., 2004).
TAK-242 (Matsunaga et al., 2011) inhibit TLR4 itself. There are several IRAK4 inhibitors (Lee et al., 2017). These molecules block the upstream signal to NF‐κB activation. IRAK4 has recently attracted attention as a therapeutic target for inflammation and tumor diseases (Chaudhary et al., 2015).
LPS treatment induced a significant upregulation of the mRNA and release of IL-1β from retinal microglia. Minocycline inhibited its releases. Thus, minocycline might exert its antiinflammatory effect on microglia by inhibiting the expression and release of IL-1β (Wang et al., 2005).
Caspase-1 inhibition reduced the release of IL-1β in organotypic slices exposed to LPS+ATP. Administration of pralnacasan (intracerebroventricular, 50 μg) or belnacasan (intraperitoneal, 25–200 mg/kg) to rats blocked seizure-induced production of IL-1β in the hippocampus, and resulted in a twofold delay in seizure onset and 50% reduction in seizure duration (Ravizza et al., 2006).
Belnacasan, an orally active IL-1β converting enzyme/caspase-1 inhibitor, blocked IL-1β secretion with equal potency in LPS-stimulated cells from familial cold urticarial associated symdrome and control subjects (Stack et al., 2005).
In LPS-induced acute lung injury (ALI) mice model, LPS induced inflammatory cytokines such as TNF-α, IL-6, IL-13 and IL-1β were significantly decreased by cinnamaldehyde (CA) (Huang and Wang, 2017).
The suppressing capacities of six cinnamaldehyde-related compounds were evaluated and compared by using the LPS-primed and ATP-activated macrophages. At concentrations of 25~100 mM, cinnamaldehyde and 2-methoxy cinnamaldehyde dose-dependently inhibited IL-1β secretion (Ho et al., 2018).
In vitro, CA decreased the levels of pro-IL-1β and IL-1β in cell culture supernatants, as well as the expression of NLRP3 and IL-1β mRNA in cells. In vivo, CA decreased IL-1β production in serum. Furthermore, CA suppressed LPS-induced NLRP3, p20, Pro-IL-1β, P2X7 receptor (P2X7R) and cathepsin B protein expression in lung, as well as the expression of NLRP3 and IL-1β mRNA (Xu et al., 2017).
IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction (Dripps et al., 1991). Recombinant IL-1Ra (anakinra) is fully active in blocking the IL-1R1, and therefore, the biological activities of IL-1α and IL-1β. The binding of IL-1α and IL-1β to IL-1R1 can be suppressed by soluble IL-1R like rilonacept (Kapur and Bonk, 2009). The binding of IL-1β to IL-1R1 can be inhibited by anti-IL-1β antibody (canakinumab and gevokizumab) (Church and McDermott, 2009) (Roell et al., 2010).
IL-1 is known to mediates autoinflammatory syndrome, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. Blocking of binding of IL-1 to IL-1R1 by anakinra, canakinumab, and rilonacept have been already used to treat these autoinflammatory syndrome associated with overactivation of IL-1 signaling (Quartier, 2011).
Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF‐κB/Rel and AP-1 activation (Jeon et al., 2000).
Inhibition of IL-1 binding to IL-1R or the decreased production of IL-1b leads to the suppression of IL-1R signaling leading to NF‐κB activation.
<h4>Key Event Description</h4>
The NF-kB pathway consists of a series of events where the transcription factors of the NF-kB family play the key role. The NF-κB pathway can be activated by a range of stimuli, including TNF receptor activation by TNF-a, or IL-1R1 activation by IL-1a or b. Upon pathway activation, the IKK complex will be phosphorylated, which in turn phosphorylates IkBa. This NF-kB inhibitor will be K48-linked ubiquitinated and degradated, allowing NF-kB to translocate to the nucleus. There, this transcription factor can express pro-inflammatory and anti-apoptotic genes. Furthermore, negative feedback genes are also transcribed and include IkBa and A20. When the NF-kB pathway is inhibited, its translocation will be delayed (or absent), resulting in less or no regulation of NF-kB target genes. This can be achieved by IKK inhibitors, proteasome inhibitors, nuclear translocation inhibitors or DNA-binding inhibitors. (Frederiksson 2012)(Gupta et al. 2010)(Huppelschoten 2017)(Liu et al. 2017). Therefore, inhibition of IL-1R1 activation suppresses activation of NF-kB.</p>
The NF-κB pathway consists of a series of events including IRAK (IL-1 receptor-associated kinase) signaling, where the transcription factors of the NF-κB family play the key role. The canonical NF-κB pathway can be activated by a range of stimuli, including TNF receptor activation by TNF-a. Upon pathway activation, the IKK complex will be phosphorylated, which in turn phosphorylates IkBa. This NF-κB inhibitor will be K48-linked ubiquitinated and degradated, allowing NF-κB to translocate to the nucleus. There, this transcription factor can express pro-inflammatory and anti-apoptotic genes. Furthermore, negative feedback genes are also transcribed and include IkBa and A20. When the NF-κB pathway is inhibited, its translocation will be delayed (or absent), resulting in less or no regulation of NF-κB target genes. This can be achieved by IKK inhibitors, proteasome inhibitors, nuclear translocation inhibitors or DNA-binding inhibitors (Gupta et al., 2010; Liu et al., 2017). Therefore, inhibition of IL-1R activation suppresses NF-κB.
 
In addition to the NF-kB pathway, IRAK activates a variety of transcription factors, including Interferon regulatory factor 5 (IRF5), Adaptor protein-1 (AP-1) and cAMP response element binding protein (CREB), resulting in the expression of broad array of inflammatory molecules and apoptosis-related proteins (Jain, 2014).
<h4>How it is Measured or Detected</h4>
~~NF-kB transcriptional activity: Beta lactamase reporter gene assay (Miller et al. 2010). NF-kB transcription: Lentiviral NF-kB GFP reporter with flow cytometry (Moujalled et al. 2012)~~
NF-κB transcriptional activity: Beta lactamase reporter gene assay (Miller et al. 2010)
~~NF-κB translocation: RelA-GFP reporter assay (Frederiksson 2012) (Huppelschoten 2017)~~
NF-κB transcription: Lentiviral NF-κBGFP reporter with flow cytometry (Moujalled et al. 2012)
~~IκBa phosphorylation: Western blotting (Miller et al. 2010)~~
IκBα phosphorylation: Western blotting (Miller et al. 2010)</span></p>
~~NF-κB p65 (Total/Phospho) ELISA~~
NF-κB p65 (Total/Phospho) ELISA</span>：</p>
~~ELISA for IL-6, IL-8, and Cox~~
ELISA for IL-6, IL-8, and Cox</span></p>
<h4>References</h4>
~~Frederiksson, L., 2012. TNFalpha-signaling in drug induced liver injury. University of Leiden.</p>~~
Chaudhary, D., Robinson, S., Romero, D.L. (2015), Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders. J Med Chem 58: 96-110, 10.1021/jm5016044
Church, L.D., McDermott, M.F. (2009), Canakinumab, a fully-human mAb against IL-1beta for the potential treatment of inflammatory disorders. Curr Opin Mol Ther 11: 81-89,
Dripps, D.J., Brandhuber, B.J., Thompson, R.C., et al. (1991), Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266: 10331-10336,
Gupta, S.C., Sundaram, C., Reuter, S., et al. (2010), Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta 1799: 775-787, 10.1016/j.bbagrm.2010.05.004
Ho, S.C., Chang, Y.H., Chang, K.S. (2018), Structural Moieties Required for Cinnamaldehyde-Related Compounds to Inhibit Canonical IL-1beta Secretion. Molecules 23, 10.3390/molecules23123241
Huang, H., Wang, Y. (2017), The protective effect of cinnamaldehyde on lipopolysaccharide induced acute lung injury in mice. Cell Mol Biol (Noisy-le-grand) 63: 58-63, 10.14715/cmb/2017.63.8.13
Jain, A., Kaczanowska, S., Davila, E. (2014), IL-1 receptor-associated kinase signaling and its role in inflammation, cancer, progression, and therapy resistance. Frontiers in Immunology 5:553.
Jeon, Y.J., Han, S.H., Lee, Y.W., et al. (2000), Dexamethasone inhibits IL-1 beta gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-kappa B/Rel and AP-1 activation. Immunopharmacology 48: 173-183,
Kapur, S., Bonk, M.E. (2009), Rilonacept (arcalyst), an interleukin-1 trap for the treatment of cryopyrin-associated periodic syndromes. P t 34: 138-141,
Gupta, S.C. et al., 2010. Inhibiting NF-??B activation by small molecules as a therapeutic strategy. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1799(10–12), pp.775–787. Available at: http://dx.doi.org/10.1016/j.bbagrm.2010.05.004.
Klein, S.L., Flanagan, K.L. (2016), Sex differences in immune responses. Nat Rev Immunol 16: 626-638, 10.1038/nri.2016.90
~~Huppelschoten, S., 2017. Dynamics of TNFalpha signaling and drug-related liver toxicity. Leiden University.~~
Lee, K.L., Ambler, C.M., Anderson, D.R., et al. (2017), Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoli ne-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. J Med Chem 60: 5521-5542, 10.1021/acs.jmedchem.7b00231
~~Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.~~
Liu, T., Zhang, L., Joo, D., et al. (2017), NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2, 10.1038/sigtrans.2017.23
Liu, T. et al., 2017. NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy, 2(March), p.17023. Available at: http://www.nature.com/articles/sigtrans201723.
Matsunaga, N., Tsuchimori, N., Matsumoto, T., et al. (2011), TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol 79: 34-41, 10.1124/mol.110.068064
McKay, L.I., Cidlowski, J.A., 1999. Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev 20, 435-459.
McGuire, V.A., Ruiz-Zorrilla Diez, T., Emmerich, C.H., et al. (2016), Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. Sci Rep 6: 31159, 10.1038/srep31159
Miller, S.C. et al., 2010. Identification of known drugs that act as inhibitors of NF-κB signaling and their mechanism of action. Biochemical Pharmacology, 79(9), pp.1272–1280. Available at: http://dx.doi.org/10.1016/j.bcp.2009.12.021.
McKay, L.I., Cidlowski, J.A. (1999), Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev 20: 435-459, 10.1210/edrv.20.4.0375
Moujalled, D.M. et al., 2012. In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-?B, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-?B is required to prevent it. Cell Death and Differentiation, 19(5), pp.808–815. Available at: http://dx.doi.org/10.1038/cdd.2011.151.
Mucke, H.A. (2012), Iguratimod: a new disease-modifying antirheumatic drug. Drugs Today (Barc) 48: 577-586, 10.1358/dot.2012.48.9.1855758
~~Pernis, A.B., 2007. Estrogen and CD4+ T cells. Curr Opin Rheumatol 19, 414-420.~~
Peng, H., Guerau-de-Arellano, M., Mehta, V.B., et al. (2012), Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor kappaB (NF-kappaB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. J Biol Chem 287: 28017-28026, 10.1074/jbc.M112.383380
~~Straub, R.H., 2007. The complex role of estrogens in inflammation. Endocr Rev 28, 521-574.~~
Pernis, A.B. (2007), Estrogen and CD4+ T cells. Curr Opin Rheumatol 19: 414-420, 10.1097/BOR.0b013e328277ef2a
Quartier, P. (2011), Interleukin-1 antagonists in the treatment of autoinflammatory syndromes, including cryopyrin-associated periodic syndrome. Open Access Rheumatol 3: 9-18, 10.2147/oarrr.S6696
Ravizza, T., Lucas, S.M., Balosso, S., et al. (2006), Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47: 1160-1168, 10.1111/j.1528-1167.2006.00590.x
Roell, M.K., Issafras, H., Bauer, R.J., et al. (2010), Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity. J Biol Chem 285: 20607-20614, 10.1074/jbc.M110.115790
Stack, J.H., Beaumont, K., Larsen, P.D., et al. (2005), IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol 175: 2630-2634,
Straub, R.H. (2007), The complex role of estrogens in inflammation. Endocr Rev 28: 521-574, 10.1210/er.2007-0001
Suzuki, E., Umezawa, K. (2006), Inhibition of macrophage activation and phagocytosis by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin. Biomed Pharmacother 60: 578-586, 10.1016/j.biopha.2006.07.089
Wang, A.L., Yu, A.C., Lau, L.T., et al. (2005), Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47: 152-158, 10.1016/j.neuint.2005.04.018
Wang, F., Han, Y., Xi, S., et al. (2020), Catechins reduce inflammation in lipopolysaccharide-stimulated dental pulp cells by inhibiting activation of the NF-kappaB pathway. Oral Dis 26: 815-821, 10.1111/odi.13290
Wang, Y., Tang, Q., Duan, P., et al. (2018), Curcumin as a therapeutic agent for blocking NF-kappaB activation in ulcerative colitis. Immunopharmacol Immunotoxicol 40: 476-482, 10.1080/08923973.2018.1469145
Wheeler, D.S., Catravas, J.D., Odoms, K., et al. (2004), Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1 beta-dependent proinflammatory signal transduction in cultured respiratory epithelial cells. J Nutr 134: 1039-1044, 10.1093/jn/134.5.1039
Xu, F., Wang, F., Wen, T., et al. (2017), Inhibition of NLRP3 inflammasome: a new protective mechanism of cinnamaldehyde in endotoxin poisoning of mice. Immunopharmacol Immunotoxicol 39: 296-304, 10.1080/08923973.2017.1355377
 
<h4><a href="/events/1702">Event: 1702: Suppression of T cell activation</a></h4>
<h5>Short Name: Suppression of T cell activation</h5>
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>T cell activation involved in immune response</td>
<td>T cell</td>
<td>decreased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
~~<td><a href="/aops/277">Aop:277 - Impaired IL-1R1 signaling leading to increased susceptibility to infection</a></td>~~
<td><a href="/aops/277">Aop:277 - Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Cellular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>T cell</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>immune system</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Mus musculus</td>
<td>Mus musculus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Rattus norvegicus</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent.  Again, age-dependent difference in IL-1 signaling is not known.
The IL1B gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (<a href="https://www.ncbi.nlm.nih.gov/homologene/481">https://www.ncbi.nlm.nih.gov/homologene/481</a>), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, mouse, chicken, zebrafish, mosquito, and frog (<a href="https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849">https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849</a>).
The NFKB1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, and frog.
275 organisms have orthologs with human gene NFKB1.
(<a href="https://www.ncbi.nlm.nih.gov/gene/4790">https://www.ncbi.nlm.nih.gov/gene/4790</a>)
The lower level of stress-induced IL-1b expression is demonstrated in the aged murine keratinocytes (Pilkington et al., 2018).
The IL-1b production by mouse oral mucosal leukocytes stimulated with candida albicans was reduced with aging (Bhaskaran et al., 2020).
The baseline IL-1 signaling of the upper respiratory tract lavage was reduced in murine newborn mice (Kuipers et al., 2018).
<h4>Key Event Description</h4>
T cells are key orchestrators of the response against pathogens and are also fundamental in maintaining self-tolerance. A number of clinically important conditions have been described in which T-cell functions are altered, as in AIDS or upon immunosuppression after application of various immunosuppressive drugs to treat autoimmune disorders or allogeneic graft rejection. T-cell progenitors differentiate in the thymus into immature T cells that acquire the expression of the T-cell receptor (TCR), which recognizes antigen peptides from pathogens presented along with major histocompatibility complex (MHC). In addition to the TCR, T cells are characterized by expression of the co-receptor molecules CD4 and CD8 on their cell surface. CD4+ T cells, also called T helper (Th) cells, recognize antigen/MHC-II complexes on antigen presenting cells (APCs) and coordinate the activation of other immune cells including B cells, macrophages, etc.
Therefore, CD4+ T cells are crucial for coordination of the immune response and for the elimination of invading pathogens. On the other hand, CD8+ T cells, referred to as T cytotoxic cells, recognize antigen/MHC-I complexes and are responsible for the killing of pathogen-infected cells.
T-cell activation and differentiation depends on antigen presenting cells (APCs) such as dendritic cells (DCs), macrophages and B cells. depending on the insult affecting a given tissue. Different subsets of DCs can be generated that in turn are able to coordinate the differentiation of a particular Th subset. To date, the following Th subsets have been described: Th1, Th2, Th9, Th17, Th22, Tfh (follicular helper T cells), Tr1 (type 1regulatory T cells) and Treg (regulatory T cells), each possessing a specific function in the elimination of pathogens. (reviewed by Simeoni et al. (Simeoni et al., 2016))
T-cell activation and differentiation depends on antigen presenting cells (APCs) such as dendritic cells (DCs), macrophages and B cells. Depending on the insult affecting a given tissue, . Different subsets of DCs can be generated that in turn are able to coordinate the differentiation of a particular Th subset. To date, the following Th subsets have been described: Th1, Th2, Th9, Th17, Th22, Tfh (follicular helper T cells), Tr1 (type 1regulatory T cells) and Treg (regulatory T cells), each possessing a specific function in the elimination of pathogens. (reviewed by Simeoni et al. (Simeoni et al., 2016))
Although CD4 T cells are able to commit to Th1, Th2 and Th17 lineages in the absence of IL-1R signaling at steady state, these committed CD4 T cells are unable to effectively secrete their cytokines upon TCR ligation. Namely, IL-1 is indispensable for CD4 T cell effector function. (Lin et al, 2015)
Moreover, since full activation of B cells and antibody production and class switch depends on T cell help. The impaired activation of T cells leads to impaired B cell activation and antibody production (reviewed by Mok (Mok, 2010)).
<h4>How it is Measured or Detected</h4>
T cell activation can be evaluated by measuring IL-2 production by ELISA or T cell proliferation by incorporation of the analysis of CFSE labeled T cells or [3H]thymidine incorporation.
<h4>References</h4>
Lin, D., Lei, L., Zhang, Y., et al., 2015. Secreted IL-1alpha promotes T-cell activation and expansion of CD11b(+) Gr1(+) cells in carbon tetrachloride-induced liver injury in mice. Eur J Immunol 45, 2084-2098.
Lin, D., Lei, L., Zhang, Y., et al. (2015), Secreted IL-1alpha promotes T-cell activation and expansion of CD11b(+) Gr1(+) cells in carbon tetrachloride-induced liver injury in mice. Eur J Immunol 45: 2084-2098, 10.1002/eji.201445195
Mok, M.Y. (2010), The immunological basis of B-cell therapy in systemic lupus erythematosus. Int J Rheum Dis 13: 3-11, 10.1111/j.1756-185X.2009.01458.x
~~Mok, M.Y., 2010. The immunological basis of B-cell therapy in systemic lupus erythematosus. Int J Rheum Dis 13, 3-11.~~
Simeoni, L., Thurm, C., Kritikos, A., et al. (2016), Redox homeostasis, T cells and kidney diseases: three faces in the dark. Clin Kidney J 9: 1-10, 10.1093/ckj/sfv135
~~Simeoni, L., Thurm, C., Kritikos, A., et al., 2016. Redox homeostasis, T cells and kidney diseases: three faces in the dark. Clin Kidney J 9, 1-10.~~
Weih, F., Carrasco, D., Durham, S.K., et al. (1995), Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80: 331-340, 
<h3>List of Adverse Outcomes in this AOP</h3>
~~<h4><a href="/events/986">Event: 986: Increase, Increased susceptibility to infection</a></h4>~~
~~<h5>Short Name: Increase, Increased susceptibility to infection</h5>~~
<h4><a href="/events/984">Event: 984: Impairment, T-cell dependent antibody response</a></h4>
<h5>Short Name: Impairment, T-cell dependent antibody response</h5>
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Immunosuppression</td>
<td></td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
~~<td><a href="/aops/277">Aop:277 - Impaired IL-1R1 signaling leading to increased susceptibility to infection</a></td>~~
<td><a href="/aops/154">Aop:154 - Inhibition of Calcineurin Activity Leading to Impaired T-Cell Dependent Antibody Response</a></td>
<td>AdverseOutcome</td>
</tr>
<tr>
<td><a href="/aops/277">Aop:277 - Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response</a></td>
<td>AdverseOutcome</td>
</tr>
</tbody>
</table>
</div>
<h4>Stressors</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Name</th></tr>
</thead>
<tbody>
~~<tr><td>IL-1 receptor antagonist（IL-1Ra）(Anakinra)</td></tr>~~
~~<tr><td>anti-IL-1b antibody (Canakinumab)</td></tr>~~
~~<tr><td>soluble IL-1R (Rilonacept)</td></tr>~~
<tr><td>Tacrolimus (also FK506)</td></tr>
<tr><td>Cyclosporin</td></tr>
<tr><td>1,2:5,6-dibenzanthracene</td></tr>
<tr><td>psychosocial stress</td></tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Individual</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Mus musculus</td>
<td>Mus musculus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Rattus norvegicus</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>cynomolgus monkey</td>
<td>Macaca fascicularis</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9541" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
The increased susceptibility to infection caused by IL-1RA or anti-IL-1 antibody has been reported in both humans and mice. (Fleischmann et al., 2003; De Benedetti et al., 2018; Hirsch et al., 1996)
CNIs induced impairment of TDAR is demonstrated with rodent studies. That is, oral administration of FK506 or CsA to mice for 4 days impaired the response of PFC in splenocytes after intravenous immunization with sheep erythrocytes (Kino et al. 1987). Likewise, oral administration of FK506 to rats over a four-week period reduced production of both anti-KLH-IgG and IgM antibodies after subcutaneous immunization with KLH (Ulrich et al. 2004). Moreover, Treatment with CsA at 50 mg/kg BID via oral gavage in cynomolgus monkey resulted in reduction of serum SRBC-specific IgM and IgG (Kevin, G. et al. 2014). As for humans, in vitro experiments showed that treatment with FK506 or CsA of peripheral blood mononuclear cells from blood-bank donors suppressed the production of IgM and IgG antibodies specific to T-cell–dependent antigens. (Heidt et al, 2009) Also, in SKW6.4 cells (IL-6–dependent, IgM-secreting, human B-cell line) cultures, FK506 or CsA suppressed the production of IgM antibodies in the presence of T-cell activation. (Sakuma et al. 2001b)  Considering that FKF506 and CsA reduce T cell-derived cytokines including IL-2 and IL-4, these findings strongly suggest that impairment of TDAR following reduced production of such cytokines occurs at least in common among humans monkey and rodents.
<h4>Key Event Description</h4>
The protection of host against microbial infection depends on both innate and acquired immunity. In particular, both T cell and antibody production by B cells play a principal role.
~~<h4>How it is Measured or Detected</h4>~~
By comparison of the incidence of infection between individuals exposed to stressors and non-exposed individuals.
<h4>Regulatory Significance of the AO</h4>
After L-1R antagonist or neutralizing antibody such as IL-1Ra (generic anakinra), canakinumab (anti-IL-1b antibody) and rilonacept (soluble IL-1R) became available to treat some of autoinflammatory syndromes, it became clear that these inhibitors increased the frequency of serious bacterial infection (De Benedetti et al., 2018; Genovese et al., 2004; Imagawa et al., 2013; Kullenberg et al., 2016; Lachmann et al., 2009; Lequerre et al., 2008; Migkos et al., 2015; Schlesinger et al., 2012; Yokota et al., 2017).
~~<h4>References</h4>~~
Auphan, N., DiDonato, J.A., Rosette, C., et al., 1995. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 270, 286-290.</p>
Antibody production to T-cell–dependent antigens is established through the coordination of B cells, antigen-presenting cells as well as T-cell–derived cytokines, which stimulate B cells to proliferate and differentiate. T-cell–dependent antibody response (TDAR) might be altered if any of these cell populations is affected.
Interleukin (IL)-2 stimulates B cells to proliferate through surface IL-2 receptors. IL-4 stimulates B-cells to proliferate, to switch immunoglobulin classes, and to differentiate into plasma and memory cells. Suppressing the production of these B-cell–related cytokines appears to impaire TDAR, as seen in the result of FK506 treatment (Heidt et al, 2009).</p>
~~Chatham, W.W., 2019. Glucocorticoid effects on the immune system.~~
IL-2 and IL-4 are produced and secreted by helper T cells and play important roles in the development of TDAR. IL-4 affects maturation and class switching of B cells as well as proliferation, both of which induces/enhances T cell dependent antibody production. IL-2 promotes differentiation of B cells through IL-2 stimulates differentiation of the activated T cell into T cell called Th2 cell. Therefore, suppressed production of IL-2 and IL-4 impairs TDAR (Alberts et al. 2008).
De Benedetti, F., Gattorno, M., Anton, J., et al., 2018. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med 378, 1908-1919.
In male CD-1 mice, chronic psychosocial stress (types of social outcome occurred: residents becoming subordinates) decrease in anti- keyhole limpet hemocyanine (KLH) immunoglobulin (Ig)G. (Alessandro, B. et al. 2003).
Genovese, M.C., Cohen, S., Moreland, L., et al., 2004. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50, 1412-1419.
In female B6C3F1 mice, 1,2:5,6-dibenzanthracene (DBA) exposure reduced total IgG antibody in spleen cell culture supernatants after in vitro stimulation with lipopolysaccharide (LPS) (Donna, C. et al. 2010).
Guler, R., Parihar, S.P., Spohn, G., et al., 2011. Blocking IL-1alpha but not IL-1beta increases susceptibility to chronic Mycobacterium tuberculosis infection in mice. Vaccine 29, 1339-1346.
Treatment with cyclosporin A (CsA) at 50 mg/kg BID via oral gavage in cynomolgus monkey resulted in reduction of serum sheep red blood cells (SRBC)-specific IgM and IgG (Kevin, G. et al. 2014).</p>
Horino, T., Matsumoto, T., Ishikawa, H., et al., 2009. Interleukin-1 deficiency in combination with macrophage depletion increases susceptibility to Pseudomonas aeruginosa bacteremia. Microbiol Immunol 53, 502-511.
After a 9-day culture of B cells and non-pre-activated T cell stimulation with FK506 or CsA, the levels of IgM and IgG in the culture supernatant were reduced at 0.3 and 1.0 ng/mL (0.37 and 1.24 nM) of FK506 or 50 and 100 ng/mL (41.6 and 83.2 nM) of CsA (Heidt et al, 2009).
Imagawa, T., Nishikomori, R., Takada, H., et al., 2013. Safety and efficacy of canakinumab in Japanese patients with phenotypes of cryopyrin-associated periodic syndrome as established in the first open-label, phase-3 pivotal study (24-week results). Clin Exp Rheumatol 31, 302-309.</p>
After a 4-day culture of SKW6.4 cells (IL-6-dependent IgM-secreting human B-cell line) and anti-CD3/CD28 stimulated peripheral blood mononuclear cells (PBMC) culture supernatant with FK506 or CsA, the level of IgM in the culture supernatant was reduced at concentrations of 0.01 to 100 ng/mL (0.012 to 124 nM) of FK506 or 0.1 to 1000 ng/mL (0.083 to 83.2 nM) of CsA (Sakuma et al. 2001b).</p>
Juffermans, N.P., Florquin, S., Camoglio, L., et al., 2000. Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis 182, 902-908.
Rats were treated with FK506 for over four weeks and immunized with KLH, after which serum concentration of anti-KLH IgM and IgG was reduced at the dose level of 3 mg/kg/day (Ulrich et al. 2004).</p>
Kullenberg, T., Lofqvist, M., Leinonen, M., et al., 2016. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford) 55, 1499-1506.
Mice were treated with FK506 or CsA for 4 days, and immunized with SRBC, after which antigen-specific plaque-forming splenocytes were reduced at dose levels of 3.2, 10, 32 and 100 mg/kg of FK506 or 32 and 100 mg/kg of CsA (Kino et al. 1987b).
Lachmann, H.J., Kone-Paut, I., Kuemmerle-Deschner, J.B., et al., 2009. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360, 2416-2425.
As immunosuppression-derived adverse outcomes by calcineurin inhibition, FK506 and CsA increase the frequency and/or severity of infections and allergic reactions impaired TDAR deems to be one of the causative factors for these side effects . Some clinical trials of FK506 and CsA revealed these adverse effects as follows.
<p>Lequerre, T., Quartier, P., Rosellini, D., et al., 2008. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 67, 302-308.
<ul>
<li>In clinical trials of renal transplantation using FK506 or CsA, opportunistic infections such as candida, cytomegalovirus and herpes simplex virus were reported (Ekberg et al. 2007).</li>
<li>In recipients of liver transplants treated with FK506 or CsA, opportunistic infections such as cytomegalovirus, hepatitis C virus, hepatitis B and herpes simplex virus were reported (Fung et al. 1991).</li>
<li>Cardiac transplant patients treated with cyclosporin developed pulmonary infections within the first year after surgery (Luster, M.I. et al. 1993).</li>
<li>In patients of X-linked autoimmune enteropathy treated with CsA or FK506, serum levels of IgE developed extremely high during the immunosuppressive therapy (Kawamura et al. 1997).</li>
<li>Renal transplant recipients treated with belatacepy/mycophenolate (MMF)/predonisone or FK506/MMF/prednisone showed significantly lower the geometric mean hemagglutination inhibition titer against influenza vaccine, hemagglutination-specific IgG and isotype IgG1 antibodies, and IgG-antibody secreting cells response (Gangappa et al. 2019).</li>
</ul>
<h4>How it is Measured or Detected</h4>
TDAR could be examined in vivo and in vitro.
In vivo studies of antigen-specific antibodies are usually performed by measuring serum antibody levels with Enzyme-Linked ImmunoSorbent Assay (ELISA) or with a plaque-forming cell (PFC) assay.
<ul>
<li>Rats were repeatedly administered FK506 orally for 4 weeks and immunized with KLH, after which the serum was examined for T-cell–dependent, antigen-specific, IgM and IgG levels using a Sandwich ELISA kit (Ulrich et al. 2004).</li>
<li>Mice were repeatedly administered calcineurin inhibitors (CNIs) including FK506 and CsA orally for 4 days and immunized with SRBC, after which spleen cells were examined using a PFC assay (Kino et al. 1987).</li>
<li>Cynomolgus monkeys received 50 mg/kg CsA twice a day via oral gavage (10 h apart) for 23 days and were immunized with SRBC, after which the serum was examined for Anti-SRBC IgM and IgG levels using an ELISA specific for SRBC antigen (Kevin, G. et al. 2014).</li>
<li>Mice were exposed a single pharyngeal aspiration of DBA, after which supernatants of splenocytes cultured for 24 h in the presence of LPS and assayed using a mouse IgM or IgG matched pairs antibody kit (Bethyl Laboratories, Montgomery, TX) (Donna, C. et al. 2010).</li>
</ul>
For in vitro studies, total IgM and IgG levels in culture supernatant are often measured after polyclonal T-cell activation rather than measuring antigen stimulation in immune cell cultures.
<ul>
<li>T cells and B cells isolated from human peripheral blood mononuclear cells (PBMC) were co-cultured with a CNIs for nine days in the presence of polyclonal–T-cell stimulation, after which supernatants were tested for immunoglobulin IgM and IgG levels using a Sandwich ELISA kit. Treatment with FK506 or CsA reduced the levels of IgM and IgG at the concentrations of 0.3 and 1.0 ng/mL or 50 and 100 ng/mL (Heidt et al, 2009).</li>
<li>SKW6.4 cells (IL-6-dependent IgM-secreting human B-cell line) were cultured with anti-CD3/CD28 antibody-stimulated PBMC culture supernatant. After culturing for four days, IgM produced in the culture supernatants was measured using an ELISA kit. FK506 or CsA reduced the levels of IgM at the concentrations of 0.01 to 100 ng/mL or 0.1 to 1000 ng/mL (Sakuma et al. 2001b).</li>
<li>In order to examine class switching, T cells derived from human PBMCs were cultured with CNIs, and cytokine mRNA levels of Interferon-gamma, IL-2, IL-4, IL-5, IL-10, IL-13, and other B-cell–stimulatory cytokines produced in T cells were measured by quantitative PCR (Dumont et al. 1998).</li>
</ul>
<h4>Regulatory Significance of the AO</h4>
The ICH S8 guideline, which covers immunosuppression of small molecule drugs, determines the need for immunotoxicity studies by comprehensively evaluating the findings of pharmacology, changes in the immune system in repeated-dose toxicity studies, and other factors using a Weight of Evidence approach. If there is concern about immunotoxicity, the presence or absence of immunotoxicity should be determined using an in vivo test system capable of assessing the functional changes of predicted immunotoxic target cells. If immunotoxicity is observed, additional studies including in vitro assays or clinical evaluation should be considered to assess the risk of immunotoxicity in humans. Because TDAR involves many immune cell populations, including T cells, B cells, and antigen-presenting cells, evaluation of TDAR is recommended when there is concern about immunotoxicity but the immunotoxic target cells are unclear. The S8 guidelines list KLH, SRBC, and tetanus toxin as antigens for TDAR.
Migkos, M.P., Somarakis, G.A., Markatseli, T.E., et al., 2015. Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra. Clin Exp Rheumatol 33, 734-736.
The draft FDA immunotoxicity testing guidance (2020) covers immunosuppressive and immunostimulatory drugs and biologics; evaluating immunosuppressive drugs in the draft FDA guidance is similar to that in the S8 guideline, with in vivo TDAR assays recommended when toxic target cells are unknown. The draft guidance states that TDAR assays using KLH as an antigen have been established in mice, rats, dogs, minipigs, and cynomolgus monkeys, but the use of SRBC and tetanus toxin as antigens is also acceptable.
Schlesinger, N., Alten, R.E., Bardin, T., et al., 2012. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis 71, 1839-1848.
For the assessment for pesticides, US EPA OPPTS 870.7800 immunotoxicity testing guideline recommends TDAR using SRBC. The REACH guideline does not provide for immunotoxicity testing, but it provides triggers for conducting immunotoxicity testing.
Tian, T., Jin, M.Q., Dubin, K., 2017. IL-1R Type 1-Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection.  198, 4341-4351.
The WHO/IPSS Immunotoxicity Risk assessment Guidance (2012) describes a strategy for assessing five categories of immunotoxicity risks, including immunosuppression. For risk assessment of immunosuppression, it calls for identification of immunosuppression risks, prediction of pathogenesis that may occur, and consideration of safety margins based on the WoE approach from human findings, infection resistance tests, immune function tests, general immune system assays, histopathological findings and organ weights in general toxicity studies, and hematological data.
Yamada, H., Mizumo, S., Horai, R., et al., 2000. Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice. Lab Invest 80, 759-767.
The evaluation of immunotoxicity in F1 animals in the OECD Guidelines for Extended First Generation Reproductive and Developmental Toxicity Studies (TG443) requires that PFC and ELSA assays to measure primary IgM antibody production by TDAR using T-cell dependent antigens (SRBC, KLH, etc.) be performed. Furthermore, if changes are observed, the significance of the changes should be examined by comprehensively evaluating other data.
Yokota, S., Imagawa, T., Nishikomori, R., et al., 2017. Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndrome: results from an open-label, phase III pivotal study in Japanese patients. Clin Exp Rheumatol 35 Suppl 108, 19-26.
The outcomes of immunosuppression are susceptibility to infection and tumorigenesis, and the FDA guidance requires that immunosuppressive drugs be evaluated for carcinogenic risk using WoE approach based on the results of carcinogenicity and immunotoxicity studies. Meanwhile, the ICH S1B(R1) Draft Step 2 Guidelines for Carcinogenicity Testing calls for evaluation of carcinogenicity by WoE approach instead of rat carcinogenicity testing, because rodent carcinogenicity test models are less capable of detecting carcinogenicity. On the other hand, it is difficult to define susceptibility to infection as a measurable AO with a clear mechanism, because immune responses vary among pathogens. In fact, many immunotoxicity guidelines require that the risk of immunotoxicity be identified and assessed by evaluating immune functions.
It was difficult to define susceptibility to infection as an AO, so TDAR, which is recommended as an indicator of immunosuppresoin in many guidelines, was used as an AO. It is expected that several AOPs with TDARs as AOs will be developed, and based on these AOPs, it may be possible to develop an IATA to assess the risk of immunotoxicity characterized by TDARs.
<h4>References</h4>
<ol>
<li>Alberts, B., Johnson, A., Lewis, L., Raff, M., Roberts, K. and Walter, P. (2008). Molecular Biology of the Cell. 5th ed., Garland Science, New York. 1539-1601</li>
<li>Heidt, S., Roelen, D. L., Eijsink, C., Eikmans, M., van Kooten, C., Claas, F. H. and Mulder, A. (2010). Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help. Clinical and experimental immunology. 159(2): 199-207.</li>
<li>Sakuma, S., Kato, Y., Nishigaki, F., Magari, K., Miyata, S., Ohkubo, Y., and Goto, T. (2001b). Effects of FK506 and other immunosuppressive anti-rheumatic agents on T cell activation mediated IL-6 and IgM production in vitro. International Immunopharmacology 1(4): 749-57.</li>
<li>Kino, T., Hatanaka, H., Hashimoto, M., Nishiyama, M., Goto, T., Okuhara, M., Kohsaka, M., Aoki, H. and Imanaka, H. (1987). FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. Journal of antibiotics. 40(9): 1249-1255.</li>
<li>Ulrich, P., Paul, G., Perentes, E., Mahl, A., and Roman D. (2004). Validation of immune function testing during a 4-week oral toxicity study with FK506. Toxicology Letters 149(1-3): 123-31.</li>
<li>Dumont, F.J., Staruch, M.J., Fischer, P., DaSilva, C. and Camacho, R. (1998). Inhibition of T cell activation by pharmacologic disruption of the MEK1/ERK MAP kinase or calcineurin signaling pathways results in differential modulation of cytokine production. Journal of immunology 160 (6): 2579-89.</li>
<li>Ekberg, H., Tedesco-Silva, H., Demirbas, A., Vítko, S., Nashan, B., Gürkan, A., Margreiter, R., Hugo, C., Grinyó, J.M., Frei, U., Vanrenterghem, Y., Daloze, P. and Halloran, P.F.; ELITE-Symphony Study. (2007). Reduced exposure to calcineurin inhibitors in renal transplantation. The New England journal of medicine 357 (25): 2562-75.</li>
<li>Fung, J., Abu-Elmagd, K., Jain, A., Gordon, R., Tzakis, A., Todo, S., Takaya, S., Alessiani, M., Demetris, A., Bronster, O., Martin, M., Mieles, L., Selby, R., Reyes, J., Doyle, H., Stieber, A., Casavilla, A. and Starzl, T. (1991). A randomized trial of primary liver transplantation under immunosuppression with FK 506 vs cyclosporine. Transplantation proceedings 23 (6): 2977-83.</li>
<li>Luster, M.I., and Rosenthal, G.J. (1993). Environmental Health Perspectives. 100: 219-36.</li>
<li>Alessandro B, Paola S, Alberto E. Paneraic, Tiziana P,Paola Palanzaa and Stefano P(2003). Chronic psychosocial stress-induced down-regulation of immunity depends upon individual factors Journal of Neuroimmunology 141: 58–64</li>
<li>Donna C. S, Matthew J. S and Kimber L. W Jr. (2010) Systemic immunosuppression following a single pharyngeal aspiration of 1,2:5,6-dibenzanthracene in female B6C3F1 mice, Journal of Immunotoxicology, 7:3, 219-231</li>
<li>Kevin G, Hossein S, Raju S, Valerie A, Anna K, Ming Z, Fen-Fen L, Hung Q. N, Lei Z, John K. S, Min W and Helen J. M(2015) Inhibition of CRAC with a human anti-ORAI1 monoclonal antibody inhibits T-cell-derived cytokine production but fails to inhibit a T-cell-dependent antibody response in the cynomolgus monkey, Journal of Immunotoxicology, 12:2, 164-173,</li>
<li>Gangappa S, Wrammert J, Wang D, Li ZN, Liepkalns JS, Cao W, Chen J, Levine MZ, Stevens J, Sambhara S, Begley B, Mehta A, Pearson TC, Ahmed R, Larsen CP. (2019) Kinetics of antibody response to influenza vaccination in renal transplant recipients. Transpl Immunol. 53:51-60.</li>
<li>Kawamura N, Furuta H, Tame A, Kobayashi I, Ariga T, Okano M, Sakiyama Y. (1997) Extremely high serum level of IgE during immunosuppressive therapy: paradoxical effect of cyclosporine A and tacrolimus. Int Arch Allergy Immunol. 112(4):422-4.</li>
</ol>
<h2>Appendix 2</h2>
<h2>List of Key Event Relationships in the AOP</h2>
<div id="evidence_supporting_links">
<h3>List of Adjacent Key Event Relationships</h3>
<div>
<h4><a href="/relationships/2002">Relationship: 2002: Impaired IL-1R1 signaling leads to Inhibition, Nuclear factor kappa B (NF-kB)</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
~~<td><a href="/aops/277">Impaired IL-1R1 signaling leading to increased susceptibility to infection</a></td>~~
<td><a href="/aops/277">Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response</a></td>
<td>adjacent</td>
<td>High</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Mus musculus</td>
<td>Mus musculus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Rattus norvegicus</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<h4>Key Event Relationship Description</h4>
The initial step in IL-1 signal transduction is a ligand-induced conformational change in the first extracellular domain of the IL-1RI that facilitates recruitment of IL-1RacP. Through conserved cytosolic regions called Toll- and IL-1R–like (TIR) domains, the trimeric complex rapidly assembles two intracellular signaling proteins, myeloid differentiation primary response gene 88 (MYD88) and interleukin-1 receptor–activated protein kinase (IRAK) 4. IL-1, IL-1RI, IL-RAcP, MYD88, and IRAK4 form a stable IL-1–induced first signaling module. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB. reviewed by Brikos et al. (Brikos et al., 2007) and Weber et al.  (Weber et al., 2010).
Therefore, the suppression of the binding of IL-1 to IL-1R1 suppresses activation of NF-κB.
After binding of IL-1 or IL-1 to IL-1R, IL-1 and IL-1R1 facilitates recruitment of IL-1RacP. Then this trimeric complex rapidly assembles two intracellular signaling proteins, myeloid differentiation primary response gene 88 (MYD88) and interleukin-1 receptor–activated protein kinase (IRAK) 4. IL-1, IL-1RI, IL-RAcP, MYD88, and IRAK4 form a stable IL-1–induced first signaling module. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB.
<h4>Evidence Supporting this KER</h4>
Mice lacking MYD88 or IRAK4 show severe defects in IL-1 signaling (Adachi et al., 1998; Suzuki et al., 2002). In the cell culture, lacking MYD88 show a block of NF-κB activation by IL-1 (Medzhitov et al., 1998). MyD88 can strongly activate an AP-1 and this activity is inhibited by dominant-negative TRAF6; therefore, MyD88 and TRAF6 are involved in IL-1R-mediated NF-κB activation, and both activate AP-1 (Medzhitov et al., 1998). Similarly, humans with mutations in the IRAK4 gene have defects in IL-1RI and Toll-like receptor (TLR) signaling (Picard et al., 2003).
Biological Plausibility
Mice lacking MYD88 or IRAK4 show severe defects in IL-1 signaling (Adachi et al., 1998; Medzhitov et al., 1998; Suzuki et al., 2002). Similarly, humans with mutations in the IRAK4 gene have defects in IL-1RI and Toll-like receptor (TLR) signaling (Picard et al., 2003).
The initial step in IL-1 signal transduction is a ligand-induced conformational change in the first extracellular domain of the IL-1RI that facilitates recruitment of IL-1RacP (Cavalli et al., 2015). Through conserved cytosolic regions called Toll- and IL-1R–like (TIR) domains (Radons et al., 2003), the trimeric complex rapidly assembles two intracellular signaling proteins, myeloid differentiation primary response gene 88 (MYD88) and interleukin-1 receptor–activated protein kinase (IRAK) 4 (Brikos et al., 2007; Li et al., 2002). IL-1, IL-1RI, IL-RAcP, MYD88, and IRAK4 form a stable IL-1–induced first signaling module. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB reviewed by (Brikos et al., 2007; Weber, Wasiliew and Kracht, 2010).
 
 </p>
Empirical Evidence
~~IL-1Ra blocks IL-1 signaling:~~
IL-1Ra blocks IL-1 signaling:</span></p>
~~IL-1Ra down-modulates EGF receptor (3 nM of ED50) by IL-1 stimulation (Dripps et al., 1991)~~
  IL-1Ra down modulation of EGF receptor (3 nM of ED50) (Dripps et al., 1991)</span></p>
~~IL-1Ra suppresses IL-1-induced endothelial cell-leukocyte adhesion (approximately 10 ng/ml of ED50) (Dripps et al., 1991)~~
  IL-1Ra suppression of IL-1-induced endothelial cell-leukocyte adhesion (approximately 10 ng/ml of ED50) (Dripps et al., 1991)</span></p>
~~IL-1Ra suppresses rhIL-1a-induced mouse thymocytes proliferation (ED50 almost 3 mg/mL) (Arend et al., 1990)~~
IL-1Ra suppresses rhIL-1a-induced mouse thymocytes proliferation (ED50 almost 3 mg/mL) (Arend et al., 1990)</span></p>
IL-1Ra competed for binding of 125I-IL-1a to type I IL-1R present on EL4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R. The IC50 values for IL-1ra binding (ranging from 2 to 4 ng/ml) were similar to those of IL-1a. (McIntyre et al., 1991)
IL-1Ra competed for binding of 125I-IL-1a to type I IL-1R present on EL4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R. The IC50 values for IL-1ra binding (ranging from 2 to 4 ng/ml) were similar to those of IL-1a. (McIntyre et al., 1991)</span></p>
Recombinant mIL-1Ra competitively inhibited 125I-labeled IL-1 alpha binding to murine type I IL-1R present on EL4 6.1 cells (Ki value of 0.21 nM) and antagonized IL-1-stimulated co-mitogenesis in murine thymocytes (0.7 x 10(6)-1.1 x 10(6) units/mg). (Shuck et al., 1991)
Recombinant mIL-1Ra competitively inhibited 125I-labeled IL-1 alpha binding to murine type I IL-1R present on EL4 6.1 cells (Ki value of 0.21 nM) and antagonized IL-1-stimulated co-mitogenesis in murine thymocytes (0.7 x 10(6)-1.1 x 10(6) units/mg). (Shuck et al., 1991)</span></p>
Peripheral blood mononuclear cells (PBMC) obtained after completion of the IL-lra infusion synthesized significantly less interleukin 6 ex vivo than PBMC from saline-injected controls. (Granowitz et al., 1992)
Peripheral blood mononuclear cells (PBMC) obtained after completion of the IL-lra infusion synthesized significantly less interleukin 6 ex vivo than PBMC from saline-injected controls. (Granowitz et al., 1992)</span></p>
~~Canakinumab (ACZ885, Ilaris) blocks IL-1 signaling~~
~~Canakinumab binds to human IL-1β with high affinity; the antibody-antigen dissociation equilibrium constant is approximately 35–40 pM(Dhimolea, 2010).~~
Canakinumab (ACZ885, Ilaris):
The antibody binds to human IL-1β with high affinity (about 40 pmol/l). The antibody was found to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro 44.6 pmol/l (7.1 ± 0.56 ng/ml; n = 6) of ED50. Application of Canakinumab intraperitoneally 2 hours before injecting the IL-1β producing cells completely suppressed joint swelling (0.06 mg/kg of EC50) (Alten et al., 2008).
Canakinumab binds to human IL-1β with high affinity; the antibody-antigen dissociation equilibrium constant is approximately 35–40 pM(Dhimolea, 2010).
Primary human fibroblasts are stimulated with recombinant IL-1b or conditioned medium obtained from LPS-stimulated human PBMCs in the presence of various concentrations of Cankinumab or IL-1RA ranging from 6 to 18,000 pM. Supernatant is taken after 16 h stimulation and assayed for IL-6 by ELISA. Canakinumab typically have 1 nM or less of EC50 for inhibition of IL-6 production (Canakinumab Patent Application WO02/16436.)
The antibody binds to human IL-1β with high affinity (about 40 pmol/l). The antibody was found to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro 44.6 pmol/l (7.1 ± 0.56 ng/ml; n = 6) of ED50. Application of Canakinumab intraperitoneally 2 hours before injecting the IL-1β producing cells completely suppressed joint swelling in mouse models of arthritis (0.06 mg/kg of EC50) (Alten et al., 2008).
~~Rilonacept (IL-1 Trap, Arcalyst) blocks IL-1 signaling:</strong>~~
Primary human fibroblasts are stimulated with recombinant IL-1b or conditioned medium obtained from LPS-stimulated human PBMCs in the presence of various concentrations of Canakinumab or IL-1RA ranging from 6 to 18,000 pM. Supernatant is taken after 16 h stimulation and assayed for IL-6 by ELISA. Canakinumab typically have 1 nM or less of EC50 for inhibition of IL-6 production (Canakinumab Patent Application WO02/16436.)</span>
Incubation of the human MRC5 fibroblastic cell line with IL-1β induces secretion of IL-6. At a constant amount of IL-1β (4 pM), the IC50 of the IL-1 trap is &sim;2 pM. Another unique property of the IL-1 trap is that it not only blocks IL-1β, but also blocks IL-1α with high affinity (KD = &sim;3 pM; data not shown). The titration curve of IL-1 trap in the presence of 10 pM IL-1β shows an IC50 of 6.5 pM, which corresponds to a calculated KD of 1.5 pM (This affinity is 100 times higher than that of the soluble single component receptor IL-1RI (Economides et al., 2003).
Rilonacept (IL-1 Trap, Arcalyst):
~~IRAK4 inhibitor~~
Incubation of the human MRC5 fibroblastic cell line with IL-1β induces secretion of IL-6. At a constant amount of IL-1β (4 pM), the IC50 of the IL-1 trap is &sim;2 pM. Another unique property of the IL-1 trap is that it not only blocks IL-1β, but also blocks IL-1α with high affinity (KD = &sim;3 pM; data not shown). The titration curve of IL-1 trap in the presence of 10 pM IL-1β shows an IC50 of 6.5 pM, which corresponds to a calculated KD of 1.5 pM (This affinity is 100 times higher than that of the soluble single component receptor IL-1RI (Economides et al., 2003).
By reconstituting IRAK-4-deficient cells with wild type or kinase-inactive IRAK-4, it is demonstrated that the kinase activity of IRAK-4 is required for the optimal transduction of IL-1-induced signals, including the activation of IRAK-1, NF-κB, and JNK, and the maximal induction of inflammatory cytokines (Lye et al., 2008)
IRAK4 inhibitor:
Various concentrations of kinase-active or kinase-inactive IRAK-4 were transiently  (Lye et aloverexpressed in IRAK-4-deficient cells that were also transiently transfected with an NF-κB-dependent luciferase reporter and α-galactosidase expression vector. Transfected cells were left untreated or treated with IL-1β (10 ng/ml) for 6 h before luciferase and α-galactosidase activities were measured. The luciferase activity was divided by the α-galactosidase activity, and fold activation was calculated compared with the activity of untreated cells carrying an empty α-vector (normalized as 1). The results demonstrated that kinase-active IRAK-4 dose dependently activates NF-κB (Lye et al., 2004).
By reconstituting IRAK-4-deficient cells with wild type or kinase-inactive IRAK-4, it is demonstrated that the kinase activity of IRAK-4 is required for the optimal transduction of IL-1-induced signals, including the activation of IRAK-1, NF-κB, and JNK, and the maximal induction of inflammatory cytokines (Lye et al., 2008).
NF-κB inbitiors
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style='mso-element:field-end'><![endif]-->.  Several studies have shown intriguing pharmacologic effects associated with curcumin, which inhibits NF-κB expression by regulating NF-κB/IkB pathway and down-regulation expression of pro-inflammatory cytokines, such as Interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-α <!--[if supportFields]><span
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~~style='mso-spacerun:yes'> ADDIN EN.CITE <span~~
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~~</xml><![endif]><span~~
~~style='mso-element:field-separator'><![endif]-->(Wang et al. 2018)<!--[if gte mso 9]><xml>~~
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~~style='font-size:12.0pt;font-family:"Times New Roman",serif;mso-fareast-font-family:~~
~~"ＭＳＰゴシック";mso-font-kerning:0pt;mso-ansi-language:EN-US;mso-fareast-language:~~
~~JA;mso-bidi-language:AR-SA'><![endif]-->. ~~
~~<table border="1" cellpadding="1" cellspacing="1" style="width:500px">~~
~~<tbody>~~
~~<tr>~~
<td>Chemicals                                                                                Target and Function</td>
~~<td> </td>~~
~~</tr>~~
~~<tr>~~
~~<td>~~
~~<table border="0" cellpadding="0" cellspacing="0" style="border-collapse:collapse; width:678pt">~~
~~<tbody>~~
~~<tr>~~
~~<td style="height:43.0pt; width:309pt">AS602868 (anilino-pyrimidine derivative)</td>~~
<td style="width:369pt">IKK  inhibitor, inhibitor of NF-KB nuclear translocation and induc- tion of apoptosis</td>
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">AT514 (a cyclic depsipeptide)</td>~~
~~<td style="width:369pt">AKT/NF-KB inhibitor</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">Bay117082</td>~~
~~<td style="width:369pt">Mitochondrial dysfunction and apoptosis</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:45.0pt; width:309pt">Berbamine</td>~~
<td style="width:369pt">Upregulation of A20, downregulation of IKKa and inhibition of p65 nuclear translocation</td>
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">BMS-345541</td>~~
~~<td style="width:369pt">IKB kinase inhibitor</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">Bortezomib</td>~~
~~<td style="width:369pt">Proteasome inhibition, stabilization of IKB</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">Carfilzomib (PR-171)</td>~~
~~<td style="width:369pt">Proteasome inhibition, stabilization of IKB</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:38.0pt; width:309pt">Celastrol</td>~~
~~<td style="width:369pt">IKB kinase inhibitor, inhibitor of NF-KB expression on both, the pro- tein and mRNA level</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">CEP-18770</td>~~
~~<td style="width:369pt">Proteasome inhibition, stabilization of IKB</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:39.0pt; width:309pt">Curcumin</td>~~
~~<td style="width:369pt">Inhibitor of NF-KB activation, induces G1/S arrest and induces apop- tosis</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:42.0pt; width:309pt">DHMEQ</td>~~
<td style="width:369pt">Inhibitor of both canonical and non-canonical NF-KB activating pathways at the level of nuclear translocation</td>
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">Epicatechin</td>~~
~~<td style="width:369pt">Inhibitor of NF-KB binding to DNA</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">Etodolac (SDX-101)</td>~~
<td style="width:369pt">Antiinflammatory and prostaglandin synthase inhibition</td>
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">Flavopiridol</td>~~
~~<td style="width:369pt">IKKa inhibitor</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">Kamebakaurin</td>~~
~~<td style="width:369pt">Inhibitor of p50 binding to DNA</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">LC-1 (dimethylaminoparthenolide, DMAPT)</td>~~
~~<td style="width:369pt">Inhibition of RelA binding to DNA</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:40.0pt; width:309pt">MG132 (peptidyl aldehyde of tri-leucine)</td>~~
~~<td style="width:369pt">Proteasome inhibition, stabilization of IKB, mitochondrial dysfunction and apoptosis</td>~~
~~</tr>~~
~~<tr>~~
<td style="height:20.0pt; width:309pt">MLN120B ( -carboline derivative)</td>
~~<td style="width:369pt">IKK  inhibitor</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">PS-1145 ( -carboline derivative)</td>~~
~~<td style="width:369pt">IKK  inhibitor</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:37.0pt; width:309pt">Salinosporamide A (NPI-0052 or ML858)</td>~~
~~<td style="width:369pt">Proteasome inhibition,stabilization of IKB, mitochondrial dysfunction and apoptosis</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:41.0pt; width:309pt">SDX-308 (CEP-180802)</td>~~
~~<td style="width:369pt">Caspase activation, poly (ADP-ribose) polymerase cleavage and apoptosis</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">SN50 (cell-permeable inhibitor peptide)</td>~~
~~<td style="width:369pt">NF-KB nuclear translocation inhibitor</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">Triptolide</td>~~
~~<td style="width:369pt">ROS generation,caspase activation and apoptosis</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:20.0pt; width:309pt">Xanthohumol</td>~~
~~<td style="width:369pt">AKT/NF-KB inhibitor</td>~~
~~</tr>~~
~~<tr>~~
~~<td style="height:45.0pt; width:309pt">4-hydroxy-2-nonenal</td>~~
~~<td style="width:369pt">Reduction of IKBa mRNA levels and decrease in phosphorylated IKBa</td>~~
~~</tr>~~
~~</tbody>~~
~~</table>~~
~~</td>~~
~~<td> </td>~~
~~</tr>~~
~~</tbody>~~
~~</table>~~
 
<span style="font-family:"Times New Roman",serif">Various concentrations of kinase-active or kinase-inactive IRAK-4 were transiently overexpressed in IRAK-4-deficient cells that were also transiently transfected with an NF-κB-dependent luciferase reporter and α-galactosidase expression vector.  IRAK-4 is recruited to the IL-1R-associated complex 1 min after IL-1β treatment (10 ng/mL). Transfected cells were left untreated or treated with IL-1β (10 ng/ml) for 6 h before luciferase and α-galactosidase activities were measured. The luciferase activity was divided by the α-galactosidase activity, and fold activation was calculated compared with the activity of untreated cells carrying an empty α-vector (normalized as 1). The results demonstrated that kinase-active IRAK-4 dose dependently activates IL-1-mediated NF-κB. Kinase-inactive IRAK-4 expression resulted in severely reduced IL-1 responses and defective NF-κB and JNK activation induced by IL-1 (Lye et al., 2004).
<h4>Quantitative Understanding of the Linkage</h4>
See Empirical Evidence.
Response-response relationship
IL-1Ra blocks IL-1 signaling:
Suppression of IL-1-induced IL-1, TNFa, or IL-6 synthesis was dose-dependent (P ≦ .0001). At a twofold molar excess, IL-lra inhibited IL-1-induced IL-1 or TNFa synthesis by 50% (P < .01); an equimolar concentration of IL-lra inhibited synthesis of these two cytokines by over 20% (P < .05). A 10-fold molar excess of IL-lra over IL-lb reduced IL-lb-induced IL-la by 95% (P = .01) and IL-la-induced IL-1b by 73% (P < .01). In elutriated monocytes, a 10-fold molar excess of IL-lra reduced IL-lb-induced IL-la by 82% (P < .05), TNFa by 64% (P = .05), and IL-6 by 47% (P < .05). (Granowitz et al., 1992)
Rilonacept (IL-1 Trap, Arcalyst) blocks IL-1 signaling:
The titration curve of IL-1 trap in the presence of 10 pM IL-1β shows an IC50 of 6.5 pM, which corresponds to a calculated KD of 1.5 pM (This affinity is 100 times higher than that of the soluble single component receptor IL-1RI (Economides et al., 2003).
<h4>References</h4>
Alten, R., Gram, H., Joosten, L.A., et al., 2008. The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res Ther 10, R67.
Arend, W.P., Welgus, H.G., Thompson, R.C., et al., 1990. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest 85, 1694-1697.
Brikos, C., Wait, R., Begum, S., et al., 2007. Mass spectrometric analysis of the endogenous type I interleukin-1 (IL-1) receptor signaling complex formed after IL-1 binding identifies IL-1RAcP, MyD88, and IRAK-4 as the stable components. Mol Cell Proteomics 6, 1551-1559.
De Benedetti, F., Gattorno, M., Anton, J., et al., 2018. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med 378, 1908-1919.
Dhimolea, E., 2010. Canakinumab. MAbs 2, 3-13.
<span style="font-family:times">Dripps, D.J., Brandhuber, B.J., Thompson, R.C., et al., 1991. Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266, 10331-10336.
Adachi, O., Kawai, T., Takeda, K., et al. (1998), Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9: 143-150,
Economides, A.N., Carpenter, L.R., Rudge, J.S., et al., 2003. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med 9, 47-52.
Alten, R., Gram, H., Joosten, L.A., et al. (2008), The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res Ther 10: R67, 10.1186/ar2438
Fleischmann, R.M., Schechtman, J., Bennett, R., et al., 2003. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis Rheum 48, 927-934.
Arend, W.P., Welgus, H.G., Thompson, R.C., et al. (1990), Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest 85: 1694-1697, 10.1172/jci114622
Genovese, M.C., Cohen, S., Moreland, L., et al., 2004. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50, 1412-1419.
Dhimolea, E. (2010), Canakinumab. MAbs 2: 3-13,
Granowitz, E.V., Clark, B.D., Vannier, E., et al., 1992. Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes. Blood 79, 2356-2363.
Dripps, D.J., Brandhuber, B.J., Thompson, R.C., et al. (1991), Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266: 10331-10336, 
Imagawa, T., Nishikomori, R., Takada, H., et al., 2013. Safety and efficacy of canakinumab in Japanese patients with phenotypes of cryopyrin-associated periodic syndrome as established in the first open-label, phase-3 pivotal study (24-week results). Clin Exp Rheumatol 31, 302-309.
Economides, A.N., Carpenter, L.R., Rudge, J.S., et al. (2003), Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med 9: 47-52, 10.1038/nm811
Kullenberg, T., Lofqvist, M., Leinonen, M., et al., 2016. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford) 55, 1499-1506.
Granowitz, E.V., Clark, B.D., Vannier, E., et al. (1992), Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes. Blood 79: 2356-2363,
Lachmann, H.J., Kone-Paut, I., Kuemmerle-Deschner, J.B., et al., 2009. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360, 2416-2425.
Lye, E., Dhanji, S., Calzascia, T., et al. (2008), IRAK-4 kinase activity is required for IRAK-4-dependent innate and adaptive immune responses. Eur J Immunol 38: 870-876, 10.1002/eji.200737429
Lequerre, T., Quartier, P., Rosellini, D., </span><em>et al.<span style="font-family:times">, 2008. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 67, 302-308.
Lye, E., Mirtsos, C., Suzuki, N., et al. (2004), The role of interleukin 1 receptor-associated kinase-4 (IRAK-4) kinase activity in IRAK-4-mediated signaling. J Biol Chem 279: 40653-40658, 10.1074/jbc.M402666200
Lye, E., Dhanji, S., Calzascia, T., Elford, AR., Ohashi, PA.. 2008. IRAK-4 kinase activity is required for IRAK-4-dependent innate and adaptive immune responses. Eur J Immunol. 38: 870-876/
McIntyre, K.W., Stepan, G.J., Kolinsky, K.D., et al. (1991), Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med 173: 931-939,
Lye, E., Mirtos, C., Suzuki, N., Suzuki, S., Yeh, W-C. 2004. The role of interleukin 1 receptor-associated kinase-4 (IRAK-4) kinase activity in IRAK-4-mediated signaling. J Biol Chem. 279: 40653-40658.
Medzhitov, R., Preston-Hurlburt, P., Kopp, E., et al. (1998), MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 2: 253-258,
McIntyre, K.W., Stepan, G.J., Kolinsky, K.D., et al., 1991. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med 173, 931-939.
Picard, C., Puel, A., Bonnet, M., et al. (2003), Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299: 2076-2079, 10.1126/science.1081902
Migkos, M.P., Somarakis, G.A., Markatseli, T.E., et al., 2015. Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra. Clin Exp Rheumatol 33, 734-736.
Shuck, M.E., Eessalu, T.E., Tracey, D.E., et al. (1991), Cloning, heterologous expression and characterization of murine interleukin 1 receptor antagonist protein. Eur J Immunol 21: 2775-2780, 10.1002/eji.1830211119
Schlesinger, N., Alten, R.E., Bardin, T., et al., 2012. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis 71, 1839-1848.
Shuck, M.E., Eessalu, T.E., Tracey, D.E., et al., 1991. Cloning, heterologous expression and characterization of murine interleukin 1 receptor antagonist protein. Eur J Immunol 21, 2775-2780.
<span style="font-family:times">Weber, A., Wasiliew, P., Kracht, M., 2010. Interleukin-1 (IL-1) pathway. Sci Signal 3, cm1.
Suzuki, N., Suzuki, S., Duncan, G.S., et al. (2002), Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416: 750-756, 10.1038/nature736
</div>
<div>
<h4><a href="/relationships/2003">Relationship: 2003: Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
~~<td><a href="/aops/277">Impaired IL-1R1 signaling leading to increased susceptibility to infection</a></td>~~
<td><a href="/aops/277">Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response</a></td>
<td>adjacent</td>
<td>High</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Mus musculus</td>
<td>Mus musculus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Rattus norvegicus</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<h4>Key Event Relationship Description</h4>
In T cells, NF-kB can be activated by several pathways of signal transduction. The engagement of the TCR by major histocompatibility complex (MHC) plus antigen initiates downstream CD3 immunotyrosine activation motif (ITAM) phosphorylation by the Src family kinases, FYN and leukocyte C-terminal src kinase (LCK). Phosphorylated CD3 activates the T cell specific tyrosine kinase, zeta-chain associated protein kinase (ZAP-70), which ultimately trigger calcium release and protein kinase (PK)C activation, respectively. Activation of a specific PKC isoform, PKC<em>u</em>, connects the above described TCR proximal signaling events to distal events that ultimately lead to NF-kB activation. Importantly, PKC<em>u activation is also driven by engagement of the T cell co-stimulatory receptor CD28 by B7 ligands on antigen presenting cells (APCs). In addition, the stimulation of T cells by IL-1 activates NF-kB as already described before. Once in the nucleus, NF-kB governs the transcription of numerous genes involved in T cell survival, proliferation, and effector functions (Paul and Schaefer, 2013).
NF-kB plays a crucial role in the activation of dendritic cells as well as T cells. In dendritic cells,  the activation of the canonical NF-kB pathway in response to pro-inflammatory stimuli, such as cytokines including IL-1a or IL-1b and TLR ligands, stimulate the maturation of dendritic cells with enhanced antigen presenting function.  The inhibition of NF-kB suppress antigen presenting function of dendritic cells, resulting in suppression of T cell activation (reviewed by Reinhard et al (Reinhard et al., 2012) and van Delft et al (van Delft, Huitema and Tas, 2015).
In T cells, NF-kB can be activated by several pathways of signal transduction. The engagement of the TCR by major histocompatibility complex (MHC) plus antigen initiates downstream CD3 immunotyrosine activation motif (ITAM) phosphorylation by the Src family kinases, FYN and leukocyte C-terminal src kinase (LCK). Phosphorylated CD3 activates the T cell specific tyrosine kinase, zeta-chain associated protein kinase (ZAP-70), which ultimately trigger calcium release and protein kinase (PK)C activation, respectively. Activation of a specific PKC isoform, PKCμ, connects the above described TCR proximal signaling events to distal events that ultimately lead to NF-</span>k</span>B activation. Importantly, PKC</span>m activation is also driven by engagement of the T cell co-stimulatory receptor CD28 by B7 ligands on antigen presenting cells (APCs). In addition, the stimulation of T cells by IL-1 activates NF-kB as already described before. Once in the nucleus, NF-</span>k</span>B governs the transcription of numerous genes involved in T cell survival, proliferation, and effector functions (Paul and Schaefer, 2013).</span></p>
<h4>Evidence Supporting this KER</h4>
Mice lacking NF-kB p50 are unable to effectively clear L. monocytogenes and are more susceptible to infection with S. peumoniae (Sha et al., 1995).
Biological Plausibility
Although CD4 T cells are able to commit to Th1, Th2 and Th17 lineages in the absence of IL-1R signaling at steady state, these committed CD4 T cells are unable to effectively secrete their cytokines upon TCR ligation. Namely, IL-1 is indispensable for CD4 T cell effector function. (Lin et al, 2015)
RelB deficient mice had an impaired cellular immunity, as observed in contact sensitivity reaction (Weih et al., 1995).
Delayed-type hypersensitivity (DTH) responses were significantly suppressed in IL-1b-deficient and IL-1a/b-deficient mice. Lymph node cells derived from antigen-sensitized IL-1b-deficient and IL-1a/b-deficient mice and IL-1R type I-deficient mice, exhibited reduced proliferative responses against antigen. (Nambu et al., 2006).
Delayed-type hypersensitivity (DTH) responses were significantly suppressed in IL-1b-deficient and IL-1a/b-deficient mice. Lymph node cells derived from antigen-sensitized IL-1b-deficient and IL-1a/b-deficient mice and IL-1R type I-deficient mice, exhibited reduced proliferative responses against antigen. Antigen-specific CD4+ T cell proliferative responses were significantly reduced following co-culture with IL-1RI−/− dendritic cells (DCs) (Nambu et al., 2006).
Empirical Evidence
RelB deficient mice had an impaired cellular immunity, as observed in contact sensitivity reaction (Weih et al., 1995).
Quite a few NF-kB inhibitors have been reported. MG132, bortezomib, curcumin, DHMEQ(Dehydroxymethylepoxyquinomicin), naringin, sorafenib, genistein and parthenolide are some of representatives (Pordanjani and Hosseinimehr, 2016).
Interferon-γ (IFN-γ) production in response to CMV-infected fibroblasts was reduced under the influence of MG132 in a dose-dependent manner. A marked reduction was observed at 0.5 μM. Likewise, CMV-specific cytotoxicity of CD8(+) T cells was decreased in the presence of MG132 (Wang et al., 2011).
Interferon-γ (IFN-γ) production in response to CMV-infected fibroblasts was reduced under the influence of MG132, a proteosome inhibitor as  well as a NF-kB inhibitor,  in a dose-dependent manner. A marked reduction was observed at 0.5 μM. Likewise, CMV-specific cytotoxicity of CD8(+) T cells was decreased in the presence of MG132 (Wang et al., 2011).
In vivo MG132 administration to NC/Nga mice with DNFB-induced dermatitis reduced Th17 cells but maintained the level of Th1 cells, resulting in the alleviation of dermatitis lesions by decreasing both serum IgE hyperproduction and mast cell migration (Ohkusu-Tsukada et al., 2018).
Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro (Satou et al., 2004). Bortezomib inhibits T-cell function versus infective antigenic stimuli in a dose-dependent manner in vitro (Orciuolo et al., 2007).
DHMEQ, a novel nuclear factor-kappaB inhibitor, induces selective depletion of alloreactive or phytohaemagglutinin-stimulated peripheral blood mononuclear cells, decreases production of T helper type 1 cytokines, and blocks maturation of dendritic cells (Nishioka et al., 2008).
Dehydroxymethylepoxyquinomicin (DHMEQ), a novel nuclear factor-kappaB inhibitor, induces selective depletion of alloreactive or phytohaemagglutinin-stimulated peripheral blood mononuclear cells, decreases production of T helper type 1 cytokines, and blocks maturation of dendritic cells (Nishioka et al., 2008).
Regarding the suppression of NF-kB by impaired IL-1 signaling, it was reported that delayed-type hypersensitivity (DTH) responses were significantly suppressed in IL-1b-deficient and IL-1a/b-deficient mice. Lymph node cells derived from antigen-sensitized IL-1b-deficient and IL-1a/b-deficient mice and IL-1R type I-deficient mice, exhibited reduced proliferative responses against antigen. These data suggest that IL-1b is necessary for the efficient priming of T cells. In addition, CD4+ T cell-derived IL-1 plays an important role in the activation of DCs during the elicitation phase, resulting in the production of TNF, that activate allergen-specific T cells (Nambu et al., 2006).
Regarding the suppression of NF-kB by impaired IL-1 signaling, it was reported that delayed-type hypersensitivity (DTH) responses were significantly suppressed in IL-1β-deficient and IL-1α/β-deficient mice. Lymph node cells derived from antigen-sensitized IL-1β-deficient and IL-1α/β-deficient mice and IL-1R type I-deficient mice, exhibited reduced proliferative responses against antigen. These data suggest that IL-1β is necessary for the efficient priming of T cells. In addition, CD4+ T cell-derived IL-1 plays an important role in the activation of DCs during the elicitation phase, resulting in the production of TNF, that activate allergen-specific T cells (Nambu et al., 2006).
<h4>Quantitative Understanding of the Linkage</h4>
A representative NF-kB inhibitor, MG132 that suppresses NF-kB activity at more than 10 mM (Fiedler et al. 1998) suppresses IL-2-induced activation of STAT5 at 50 mM. (Yu and Malek 2001) 
A representative NF-kB inhibitor, DHMEQ (1mg/mL) blocked PHA-induced nuclear translocation of NF-kB in Jurkat cells via inhibition of degradation of IkBa. Preincubation of peripheral blood mononuclear cells with DHMEQ (1 mg/ml, 3 hr) greatly reduced PHA-stimulated expression of IFN-g, IL-2 and TNF-a genes.
A representative NF-kB inhibitor, MG132 that suppresses NF-kB activity at more than 10 mM (Fiedler et al. 1998) suppresses IL-2-induced activation of STAT5 at 50 mM. (Yu and Malek., 2001). However, MG-132 did not decrease the effect of TNF-α on AP-1 activation (Fiedler, Wernke-Dollries and Stark, 1998).</p>
A representative NF-kB inhibitor, DHMEQ (1μg/mL) blocked phytohaemagglutinin (PHA-)-induced nuclear translocation of NF-kB in Jurkat cells via inhibition of degradation of IkBa. Preincubation of peripheral blood mononuclear cells and Jurkat cells with DHMEQ (1 μg/ml, 3 hr) greatly reduced PHA-stimulated expression of IFN-, IL-2 and TNF- genes although DHMEQ alone without PHA-stimulation did not affect cytokine production in unstimulated PBMC. DHMEQ (0·5–3 μg/mL, 3 days) inhibited PHA-stimulated proliferation of peripheral blood mononuclear cells (PBMC) in a dose-dependent manner although did not affect the viability of resting PBMC under identical culture conditions. DHMEQ (3 μg/mL, 24 hr) induced apoptosis of PHA-stimulated PBMC. DHMEQ (0·5 μg/mL) decreased levels of TNF-α-stimulated expression of CD40 in monocyte-derived dendritic cells (DCs). Exposure of DCs to DHMEQ (0·5 or 1 μg/ml) reduced their endocytic ability (Nishioka et al., 2008).
Response-response relationship
Interferon-γ (IFN-γ) production in response to CMV-infected fibroblasts was reduced under the influence of MG132 in a dose-dependent manner. A marked reduction was observed at 0.5 μM. Likewise, CMV-specific cytotoxicity of CD8(+) T cells was decreased in the presence of MG132 (Wang et al., 2011).
~~Bortezomib inhibits T-cell function versus infective antigenic stimuli in a dose-dependent manner in vitro (Orciuolo et al., 2007).~~
Bortezomib (1 mg/kg) inhibits T-cell function versus infective antigenic stimuli in vitro (Orciuolo et al., 2007).
<h4>References</h4>
Ahmad, S.F., Zoheir, K.M., Abdel-Hamied, H.E., Ashour, A.E., Bakheet, S.A., Attia, S.M., Abd-Allah, A.R., 2014. Amelioration of autoimmune arthritis by naringin through modulation of T regulatory cells and Th1/Th2 cytokines. Cell Immunol 287, 112-120.
Fiedler, M.A., Wernke-Dollries, K., Stark, J.M. (1998), Inhibition of TNF-alpha-induced NF-kappaB activation and IL-8 release in A549 cells with the proteasome inhibitor MG-132. Am J Respir Cell Mol Biol 19: 259-268, 10.1165/ajrcmb.19.2.3149
Nambu, A., Nakae, S., Iwakura, Y., 2006. IL-1beta, but not IL-1alpha, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses. Int Immunol 18, 701-712.
Lin, D., Lei, L., Zhang, Y., et al. (2015), Secreted IL-1alpha promotes T-cell activation and expansion of CD11b(+) Gr1(+) cells in carbon tetrachloride-induced liver injury in mice. Eur J Immunol 45: 2084-2098, 10.1002/eji.201445195
Nishioka, C., Ikezoe, T., Jing, Y., Umezawa, K., Yokoyama, A., 2008. DHMEQ, a novel nuclear factor-kappaB inhibitor, induces selective depletion of alloreactive or phytohaemagglutinin-stimulated peripheral blood mononuclear cells, decreases production of T helper type 1 cytokines, and blocks maturation of dendritic cells. Immunology 124, 198-205.
Nambu, A., Nakae, S., Iwakura, Y. (2006), IL-1beta, but not IL-1alpha, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses. Int Immunol 18: 701-712, 10.1093/intimm/dxl007
Ohkusu-Tsukada, K., Ito, D., Takahashi, K., 2018. The Role of Proteasome Inhibitor MG132 in 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis in NC/Nga Mice. Int Arch Allergy Immunol 176, 91-100.
Nishioka, C., Ikezoe, T., Jing, Y., et al. (2008), DHMEQ, a novel nuclear factor-kappaB inhibitor, induces selective depletion of alloreactive or phytohaemagglutinin-stimulated peripheral blood mononuclear cells, decreases production of T helper type 1 cytokines, and blocks maturation of dendritic cells. Immunology 124: 198-205, 10.1111/j.1365-2567.2007.02755.x
Orciuolo, E., Galimberti, S., Petrini, M., 2007. Bortezomib inhibits T-cell function versus infective antigenic stimuli in a dose-dependent manner in vitro. Leuk Res 31, 1026-1027.
Ohkusu-Tsukada, K., Ito, D., Takahashi, K. (2018), The Role of Proteasome Inhibitor MG132 in 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis in NC/Nga Mice. Int Arch Allergy Immunol 176: 91-100, 10.1159/000488155
~~Paul, S., Schaefer, B.C., 2013. A new look at T cell receptor signaling to nuclear factor-kappaB. Trends Immunol 34, 269-281.~~
Orciuolo, E., Galimberti, S., Petrini, M. (2007), Bortezomib inhibits T-cell function versus infective antigenic stimuli in a dose-dependent manner in vitro. Leuk Res 31: 1026-1027, 10.1016/j.leukres.2006.09.002
Pordanjani, S.M., Hosseinimehr, S.J., 2016. The Role of NF-kB Inhibitors in Cell Response to Radiation. Curr Med Chem 23, 3951-3963.
Reinhard, K., Huber, M., Lohoff, M., et al. (2012), The role of NF-kappaB activation during protection against Leishmania infection. Int J Med Microbiol 302: 230-235, 10.1016/j.ijmm.2012.07.006
Satou, Y., Nosaka, K., Koya, Y., Yasunaga, J.I., Toyokuni, S., Matsuoka, M., 2004. Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro. Leukemia 18, 1357-1363.
Sha, W.C., Liou, H.C., Tuomanen, E.I., et al. (1995), Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 80: 321-330, 
Wang, Y., Sun, B., Volk, H.D., Proesch, S., Kern, F., 2011. </span>Comparative study of the influence of proteasome inhibitor MG132 and ganciclovir on the cytomegalovirus-specific CD8(+) T-cell immune response. Viral Immunol 24, 455-461.
van Delft, M.A., Huitema, L.F., Tas, S.W. (2015), The contribution of NF-kappaB signalling to immune regulation and tolerance. Eur J Clin Invest 45: 529-539, 10.1111/eci.12430
Weih, F., Carrasco, D., Durham, S.K., Barton, D.S., Rizzo, C.A., Ryseck, R.P., Lira, S.A., Bravo, R., 1995. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80, 331-340.
Wang, Y., Sun, B., Volk, H.D., et al. (2011), Comparative study of the influence of proteasome inhibitor MG132 and ganciclovir on the cytomegalovirus-specific CD8(+) T-cell immune response. Viral Immunol 24: 455-461, 10.1089/vim.2011.0038
Weih, F., Carrasco, D., Durham, S.K., et al. (1995), Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80: 331-340,
Yu, A., Malek, T.R. (2001), The proteasome regulates receptor-mediated endocytosis of interleukin-2. J Biol Chem 276: 381-385, 10.1074/jbc.M007991200
</div>
<div>
~~<h4><a href="/relationships/2004">Relationship: 2004: Suppression of T cell activation leads to Increase, Increased susceptibility to infection</a></h4>~~
<h4><a href="/relationships/2928">Relationship: 2928: Suppression of T cell activation leads to Impairment, T-cell dependent antibody response</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
~~<td><a href="/aops/277">Impaired IL-1R1 signaling leading to increased susceptibility to infection</a></td>~~
<td><a href="/aops/277">Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response</a></td>
<td>adjacent</td>
<td>High</td>
~~<td>Not Specified</td>~~
<td>High</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Mus musculus</td>
<td>Mus musculus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Rattus norvegicus</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms.
<h4>Key Event Relationship Description</h4>
~~Normal T cell and B cell function is indispensable for host defense mechanism.~~
Normal T cell and B cell function is indispensable for host defense mechanism. T cells are activated when they recognize antigens and induce T-cell dependent antibody response (TDAR) by secreting various cytokines as described below (Abbas et al. 2020). Therefore, suppression of T cell activation leads to impairment of TDAR. Various Interleukins (ILs) such as IL-2 and IL-4 are produced and secreted by activated helper T cells and play important roles in the development of TDAR. IL-4 affects maturation and class switching of B cells as well as proliferation, IL-2 promotes differentiation of B cells through IL-2 receptors and stimulates the activated T cell into T cell called Th2 cell. Therefore, suppressed production of IL-2 and IL-4 impairs T cell dependent antibody production (Alberts et al. 2008).
 
T cells, B cells, and antigen-presenting cells such as dendritic cells are involved in inducing and developing of TDAR. Thus, changes in any of these immune cell populations can influence TDAR. Activated T cell-derived cytokines play important roles in the development of TDAR. Among them, IL-2 promotes proliferation of B cells, and IL-4 affects maturation and class switching of B cells as well as proliferation, both of which induces/enhances T cell dependent antibody production.
 
Thus, suppressing the production of IL-2, IL-4, and other cytokines in T cells reduces stimulation of B cells including proliferation, activation, and class switching, and leading to impairment of TDAR. Therefore, suppressing the production of these B-cell-related cytokines appears to be the main factor in impairment of TDAR by inhibitors of T-cell–dependent-antibody production.
<h4>Evidence Supporting this KER</h4>
The experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection (Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000).
In cynomolgus monkeys, the effects of CsA on production of IL-2 and IL-4, and antigen-specific IgM and IgG in TDAR were demonstrated (Gaida K. 2015).
Suppressed IgE and antigen specific IgG1 productions by the blocking of IL-4 receptor were reported in mice using dupilumab (antiIL-4/13R antibody) (Sanofi K.K. 2018).
Suppressed antigen specific IgE production by the inhibition of IL-4 production was reported in mice using suplatast tosilate (Taiho Pharmaceutical 2013). Suppressed antigen specific IgE and IL-4 productions by the inhibition of IL-4 production were reported in human cell culture using suplatast tosilate(Taiho Pharmaceutical 2013).
The effects of FK506 on serum concentration of anti-KLH antibodies IgM and IgG have been demonstrated in rats treated with FK506 for over four weeks and immunized with KLH (Ulrich et al. 2004).
The effects of FK506 and CsA on antigen-specific plaque-forming splenocytes have been demonstrated in mice treated with FK506 or CsA for 4 days and immunized with SRBC (Kino et al. 1987b).
The effects of FK506 and CsA on the levels of IgM and IgG in the culture supernatant have been demonstrated in human cells (Heidt et al, 2009, Sakuma et al, 2001). The effects of FK506 and CsA on production of IL-2 and IL-4 have been demonstrated using mice and human cells (Kino et al. 1987a, Dumont et al. 1998).
These facts suggest that there are no species differences between humans, monkeys and rodents in inhibitions of IL-2 and IL-4 production and TDAR induction.
Biological Plausibility
~~To protect the infection from different pathogens, different types of immune response depending on the pathogens are required. ~~
Cyclosporin A (CsA) is known to be one of the calcineurin inhibitiors. CsA-treatment is reported to suppress the productions of IL-2 and IL-4 and result in the reduction of the productions of antigen-specific IgM and IgG in cynomolgus monkeys (Gaida K. 2015).
1). Type 1 immunity drives resistance to viruses and intracellular bacteria, such as Listeria monocytogenes, Salmonella spp. and Mycobacteria spp., as well as to intracellular protozoan parasites such as Leishmania spp. The T helper 1 (TH1) signature cytokine interferon-γ (IFNγ) has a central role in triggering cytotoxic mechanisms including macrophage polarization towards an antimicrobial response associated with the production of high levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), activation of CD8+ cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to kill infected cells via the perforin and/or granzyme B-dependent lytic pathway or via the ligation of surface death receptors; and B cell activation towards the production of cytolytic antibodies that target infected cells for complement and Fc receptor-mediated cellular cytotoxicity.
It is established that IL-2 stimulates B cells to proliferate through the surface IL-2 receptors and that IL-4 stimulates B cells to proliferate, to induce class switch, and to differentiate into plasma and memory cells.
2) Resistance to extracellular metazoan parasites and other large parasites is mediated and/or involves type 2 immunit. Pathogen neutralization is achieved via different mechanisms controlled by TH2 signature cytokines, including interleukin-4 (IL-4), IL-5 and IL-13, and by additional type 2 cytokines such as thymic stromal lymphopoietin (TSLP), IL-25 or IL-33, secreted by damaged cell. TH2 signature cytokines drive B cell activation towards the production of high-affinity pathogen-specific IgG1 and IgE antibodies that function via Fc-dependent mechanisms to trigger the activation of eosinophils, mast cells and basophils, expelling pathogens across epithelia.
Dupilumab is known as anti-IL-4/13 receptor (IL-4/13R) antibody. Dupilumab (Dupixent) reduces productions of immunoglobulin (Ig)E and antigen specific IgG1 in mice (Sanofi K.K. 2018). It suggests that the blocking of IL-4 signaling by anti-IL-4/13R antibody results in the decrease in T cell dependent antibody production.
3) TH17 immunity confers resistance to extracellular bacteria such as Klebsiella pneumoniae, Escherichia coli, Citrobacter rodentium, Bordetella pertussis, Porphyromonas gingivalis and Streptococcus pneumoniae, and also to fungi such as Candida albicans, Coccidioides posadasii, Histoplasma capsulatum and Blastomyces dermatitidis. Activation of TH17 cells by cognate T cell receptor (TCR–MHC class II interactions and activation of group 3 innate lymphoid cells (ILC3s) via engagement of IL-1 receptor (IL-1R) by IL-1β secreted from damaged cells lead to the recruitment and activation of neutrophils. TH17 immunopathology is driven to a large extent by products of neutrophil activation, such as ROS and elastase (reviewed by Soares et al. (Soares et al., 2017)).
Th2 cell produces cytokines including IL-4. Suplatast tosilate (IPD) is known as an inhibitor of the production of IL-4 and IL-5 from Th2 cells and reduces the production of antigen specific IgE in human cell culture and mice (Taiho Pharmaceutical 2013). These findings suggests that the reduction of IL-4 production by the inhibitor of Th2 cell cytokines results in reduced production of IgE and/or IgG1 through inhibitions of maturation, proliferation and class switching of B cells.
~~Based on these evidences, the insufficient T cell or B cell function causes impaired resistance to infection. ~~
IL-2 binds to IL-2 receptor (IL-2R) and acts on T cell. CD25 is one of IL-2R. Basiliximab (Simulect) is known as anti-CD25 antibody. Basiliximab binds to IL-2R and blocks IL-2 signaling. Clinical transplantation study of basiliximab reveals decreases in rejections. On the other hand, basiliximab inhibits the activation of antigen specific T cells (Novartis Pharma 2016). They suggest that the blocking of IL-2 signaling by anti-IL-2R antibody results in decreased rejection through the inhibition of the activation of antigen specific T cell with reduced antibody production.
FK506 and CsA suppress mRNA expression levels of cytokines in T cells including IL-2 and IL-4 that stimulate proliferation of B cells as well as B cell activation and class switching (Heidt et al, 2010).
Several in vivo studies in rodents showed decreased TDAR by the treatment of FK506 (Kino et al. 1987b, Ulrich et al. 2004). In in vitro tests examining antibody production in blood samples obtained from blood-bank donors, peripheral blood mononuclear cells (PBMC) treated with FK506 and CsA suppressed the production of IgM and IgG antibodies to T-cell dependent antigens (Heidt et al, 2009).
T cells, B cells, and antigen-presenting cells such as dendritic cells are involved in inducing and developing of TDAR. Thus, changes in any of these immune cell populations can influence TDAR. However, as for the suppression of humoral immunity induced by the inhibition of calcineurin (CN) phosphatase activity, calcineurin inhibitors (CNIs) do not affect B cells directly but rather indirectly through T cells. That is, FK506 and CsA are capable of inhibiting immunoglobulin production when B cells are cultured with non-pre-activated T cells, but FK506 and CsA fail to inhibit immunoglobulin levels when pre-activated T cells are used to stimulate B cells. Hence, the inhibition of B cell response by FK506 and CsA appears due solely to inhibition of T helper cells (Heidt et al, 2010).
Therefore, it is concluded that decreased amounts of IL-2 and IL-4 secreted from helper T cells is the main factor for suppression of TDAR induced by CN phosphatase inhibition.
Empirical Evidence
Administration of IL-1R antagonist or neutralizing antibody such as IL-1Ra (generic anakinra), canakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R) led to the suppression of downstream phenomena, which included internalization of IL-1 (Dripps et al., 1991), production of PGE2 (Hannum et al., 1990; Seckinger et al., 1990), IL-6 (Goh et al., 2014), and T cell proliferation (Seckinger et al., 1990).
Empirical support of the suppression, IL-2 and IL-4 production leads to impairment, T-cell dependent antibody response is strong.
Rationale
<p>Since these inhibitors became available to treat some of autoinflammatory syndromes, it became clear that these inhibitors increased the frequency of serious bacterial infection (De Benedetti et al., 2018; Genovese et al., 2004; Imagawa et al., 2013; Kullenberg et al., 2016; Lachmann et al., 2009; Lequerre et al., 2008; Migkos et al., 2015; Schlesinger et al., 2012; Yokota et al., 2017).
<ul>
<li>Cynomolgus monkeys treated wth CsA at 50 mg/kg BID for 24 days suppression of IL-2, IL-4 and sheep red blood cell (SRBC)-specific IgM and IgG (Gaida K. 2015).</li>
<li>In the allergen-induced pneumonia model in mice, dupilumab (anti-IL-4/13R antibody) reduced productions of IgE and antigen specific IgG1 at 25 mg/kg of twice weekly subcutaneous administration for 4weeks (Sanofi K.K. 2018).</li>
<li>In mice immunized with dinitrophenyl antigen by i.p. injection, suplatast tosilate (an inhibitor of the production of cytokines on Th2 cell) reduced productions of antigen specific IgE at 10, 20, 50 and 100 mg/kg of oral administration for 5 days (Yanagihara, 2013). In human cell culture immunized with Japanese cedar antigen, suplatast tosilate reduced productions of antigen specific IgE at the concentration of 10 µg/mL for 10 days (Yanagihara, 2013).</li>
<li>In the clinical study of renal transplantation, basiliximab decreased incidence of acute rejection at 20 mg/kg (Kircher, 2003). In human T cell culture immunized with PPD, basiliximab reduced activation of antigen specific T cell at the concentration of 300 ng/mL (Kircher, 2003).</li>
<li>In CD3/phorbol 12-myristate-13-acetate-activated human T cells, FK506 suppressed production of IL-2, IL-4 and Interferon (IFN)-γ at the concentrations of 1.2 to 12.5 nM as well as inhibited expression of IL-2, IL-4 and IFN-γ mRNA at the concentrations of 10 nM. (Dumont et al. 1998).</li>
<li>FK506 or CsA suppressed production of IL-2 in mouse mixed lymphocyte reaction (MLR) at 0.1 to 10 nM of FK506 and 10 to 100 nM of CsA as well as in human MLR at 0.1 to 10 nM of FK506 and 10 to 100 nM of CsA (Kino et al. 1987a).</li>
<li>After 9-day culture of B cells and non-pre-activated T cell stimulationwith FK506 or CsA, the levels of IgM and IgG in the culture supernatant were reduced at 0.3 and 1.0 ng/mL (0.37 and 1.24 nM) of FK506 or 50 and 100 ng/mL (41 and 83nM) of CsA (Heidt et al, 2009).</li>
<li>After 4-day culture of SKW6.4 cells (IL-6-dependent IgM-secreting human B-cell line) and anti-CD3/CD28 stimulated PBMC culture supernatant with FK506 or CsA, the level of IgM in the culture supernatant was reduced at the concentrations of 0.01 to 100 ng/mL (0.01 to 124 nM) of FK506 or 0.1 to 1000 ng/mL (0.08 to 832 nM) of CsA (Sakuma et al, 2001).</li>
<li>Rats were treated with FK506 for over four weeks and immunized with keyhole limpet hemocyanine (KLH), after which serum concentration of anti-KLH IgM and IgG reduced at the dose levels of 3 mg/kg/day (Ulrich et al. 2004).</li>
<li>Mice were treated with FK506 or CsA for 4 days, and immunized with sheep red blood cells (SRBC), after which antigenspecific plaque-forming splenocytes reduced at the dose levels of 3.2, 10, 32 and 100 mg/kg of FK506 or 32 and 100 mg/kg of CsA (Kino et al. 1987b).</li>
<li>1,2:5,6-dibenzanthracene single administration suppressed production of IL-2 and total IgG antibody in mice at the dose levels of 3 and 30 mg/kg(Donna, C. et al. 2010).</li>
<li>In male CD-1 mice, chronic psychosocial stress (types of social outcome occurred: residents becoming subordinates) for 21 days reduced IL-2 release in response to KLH and decrease in anti-KLH IgG (Alessandro, B. et al. 2003).</li>
</ul>
~~<h4>References</h4>~~
Auphan, N., DiDonato, J.A., Rosette, C., et al., 1995. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 270, 286-290.
<strong>Uncertainties and Inconsistencies</strong>
IL-2 affects multiple populations of immune cells expressing IL-2 receptors, while IL-4 mainly acts on B cells. Therefore, reduced production of both IL-2 and IL-4 might certainly induce suppression of TDAR; however, there remains some possibility of additional suppression of other immune functions.
<h4>Quantitative Understanding of the Linkage</h4>
Luster et al  (1993) demonstrated that Concanavalin A response of splenocytes showed the linear dose-response relationship with the host resistnace to Listeria monocytogenes or Streptococcus pneumoniae.
Response-response relationship
Cynomolgus monkeys treated wth CsA at 50 mg/kg BID showed suppression of IL-2 and IL-4 production and inhibition of SRBC-specific IgM and IgG in TDAR (Gaida K. 2015).
In the blocking of IL-4 receptor in mice by dupilumab (anti-IL-4/13R antibody) at 25 mg/kg of twice weekly subcutaneous administration for 4weeks, IgE production was suppressed to about 1/100 and antigen specific IgG1 production was suppressed to
~~Chatham, W.W., 2019. Glucocorticoid effects on the immune system.~~
about 1/200 (Sanofi K.K. 2018).
De Benedetti, F., Gattorno, M., Anton, J., et al., 2018. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med 378, 1908-1919.
In the inhibition of IL-4 production in mice by suplatast tosilate at 10, 20, 50 and 100 mg/kg of oral administration for 5 days, antigen specific IgE production was suppressed from about 1/10 to 1/100 (Taiho Pharmaceutical 2013). In human T cell culture by suplatast tosilate at the concentration of 10 µg/mL, antigen specific IgE production after 10 days was suppressed from 56 to 72% and IL-4 production after 3 days was suppressed from 58 to 76% (Taiho Pharmaceutical 2013).
Dripps, D.J., Brandhuber, B.J., Thompson, R.C., et al., 1991. Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266, 10331-10336.
As for IL-2 and antibody production, in vitro T-cell-induced polyclonal B cell activation to produce antibody was inhibited with anti-IL-2 and anti-IL-2R antibodies. That is, murine small resting B cells, cultured with irradiated hapten-specific TH1 clone, were induced to enter cell cycle at 2 days and to secret antibody at 5 days. An anti-IL-2 and anti-IL-2R antibodies completely inhibited this T-cell dependent antibody production (Owens T, 1991).
Genovese, M.C., Cohen, S., Moreland, L., et al., 2004. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50, 1412-1419.
In the human T-B cell co-culture stimulated with anti-CD3 monoclonal antibody, CNIs of FK506 and CsA lowered the m-RNA levels of T-cell cytokines at 8h post-stimulation including IL-2 and IL-4 at 1.0ng/mL (1.24nM) FK506 or 100ng/mL (90.7nM) CsA and
Goh, A.X., Bertin-Maghit, S., Ping Yeo, S., et al., 2014. A novel human anti-interleukin-1beta neutralizing monoclonal antibody showing in vivo efficacy. MAbs 6, 765-773.
inhibited IgM and IgG productions after 9 days at 0.3 and 1.0ng/mL FK506 and 50 and 100ng/mL CsA (Heidt S. 2010).
Time-scale
In CsA-treatment for 24 days at 50 mg/kg BID, cynomolgus monkeys showed suppression of IL-2 and IL-4 production and inhibition of SRBC-specific IgM and IgG in TDAR (Gaida K. 2015).</p>
Guler, R., Parihar, S.P., Spohn, G., et al., 2011. Blocking IL-1alpha but not IL-1beta increases susceptibility to chronic Mycobacterium tuberculosis infection in mice. Vaccine 29, 1339-1346.</p>
In human T cell culture, suplatast tosilate inhibits IL-4 production after 3 days and antigen specific IgE production after 10 days (Taiho Pharmaceutical 2013).</p>
Hannum, C.H., Wilcox, C.J., Arend, W.P., et al., 1990. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343, 336-340.
In the human T-B cell co-culture, CNIs of FK506 and CsA lowered the m-RNA levels of IL-2 and IL-4 at 8h post-stimulation and inhibited IgM and IgG productions after 9 days (Heidt S. 2010).
<h5> </h5>
Known modulating factors
<div>This table captures specific information on the MF, its properties, how it affects the KER and respective references. 1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet  2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...)  3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...)  4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  
<table class="table table-bordered table-fullwidth">
<thead>
<tr>
<th>Modulating Factor (MF)</th>
<th>MF Specification</th>
<th>Effect(s) on the KER</th>
<th>Reference(s)</th>
</tr>
</thead>
<tbody>
<tr>
<td> </td>
<td> </td>
<td> </td>
<td> </td>
</tr>
</tbody>
</table>
</div>
Known Feedforward/Feedback loops influencing this KER
At present, no evidence is found.
<h4>References</h4>
Abbas, AK., Lichtman, AH. and Pillai, S. (2020). Basic Immunology: Functions and disorders of the immune system. 6th ed., Elsevier Inc., China
Horino, T., Matsumoto, T., Ishikawa, H., et al., 2009. Interleukin-1 deficiency in combination with macrophage depletion increases susceptibility to Pseudomonas aeruginosa bacteremia. Microbiol Immunol 53, 502-511.
Alberts, B., Johnson, A., Lewis, L., Raff, M., Roberts, K. and Walter, P. (2008). Molecular Biology of the Cell. 5th ed., Garland Science, New York. 1539-1601
Imagawa, T., Nishikomori, R., Takada, H., et al., 2013. Safety and efficacy of canakinumab in Japanese patients with phenotypes of cryopyrin-associated periodic syndrome as established in the first open-label, phase-3 pivotal study (24-week results). Clin Exp Rheumatol 31, 302-309.
Sanofi K.K. (2018) Drug interview form Dupixent subcutaneous injection 300 mg syringe. 2nd edition.
Juffermans, N.P., Florquin, S., Camoglio, L., et al., 2000. Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis 182, 902-908.
Dumont, F.J., Staruch, M.J., Fischer, P., DaSilva, C. and Camacho, R. (1998). Inhibition of T cell activation by pharmacologic disruption of the MEK1/ERK MAP kinase or calcineurin signaling pathways results in differential modulation of cytokine production. Journal of immunology 160 (6): 2579-89.
Kullenberg, T., Lofqvist, M., Leinonen, M., et al., 2016. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford) 55, 1499-1506.</p>
Heidt, S., Roelen, D. L., Eijsink, C., Eikmans, M., van Kooten, C., Claas, F. H. and Mulder, A. (2010). Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help. Clinical and experimental immunology. 159(2): 199- 207. Gaida K., Salimi-Moosavi H., Subramanian R., Almon V., Knize A., Zhang M., Lin F.F., Nguyen H.Q., Zhou L., Sullivan J.K., Wong M., McBride H.J. (2015). Inhibition of CRAC with a human anti-ORAI1 monoclonal antibody inhibits T-cell-derived cytokine production but fails to inhibit a T-cell-dependent antibody response in the cynomolgus monkey. J Immunotoxicol AOP154 38/39 12:164-173.
Lachmann, H.J., Kone-Paut, I., Kuemmerle-Deschner, J.B., et al., 2009. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360, 2416-2425.</span></p>
Kino, T., Hatanaka, H., Miyata, S., Inamura, N., Nishiyama, M., Yajima, T., Goto, T., Okuhara, M., Kohsaka, M. and Aoki, H. (1987a). FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. Journal of antibiotics. 40(9): 1256-1265.
Lequerre, T., Quartier, P., Rosellini, D., et al., 2008. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 67, 302-308.
Kino, T., Hatanaka, H., Hashimoto, M., Nishiyama, M., Goto, T., Okuhara, M., Kohsaka, M., Aoki, H. and Imanaka, H. (1987b). FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. Journal of antibiotics. 40(9): 1249-1255.
Migkos, M.P., Somarakis, G.A., Markatseli, T.E., et al., 2015. Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra. Clin Exp Rheumatol 33, 734-736.
Kircher, B., Latze, K., Gastl, G., Nachbaur, D. (2003), Comparative in vitro study of the immunomodulatory activity of humanized and chimeric anti-CD25 monoclonal antibodies. Clinical and Experimental Immunology,  134 (3),  426–430, 10.1111/j.1365-2249.2003.02324.x
Schlesinger, N., Alten, R.E., Bardin, T., et al., 2012. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis 71, 1839-1848.
Owens T.(1991). Requirement for noncognate interaction with T cells for the activation of B cell immunoglobulin secretion by IL-2. Cell Immunol 133:352-366.
Seckinger, P., Kaufmann, M.T., Dayer, J.M., 1990. An interleukin 1 inhibitor affects both cell-associated interleukin 1-induced T cell proliferation and PGE2/collagenase production by human dermal fibroblasts and synovial cells. Immunobiology 180, 316-327.</span></p>
Sakuma, S., Kato, Y., Nishigaki, F., Magari, K., Miyata, S., Ohkubo, Y., and Goto, T. (2001b). Effects of FK506 and other immunosuppressive anti-rheumatic agents on T cell activation mediated IL-6 and IgM production in vitro. International Immunopharmacology 1(4): 749-57.
~~Soares, M.P., Teixeira, L., Moita, L.F., 2017. Disease tolerance and immunity in host protection against infection. Nat Rev Immunol 17, 83-96.~~
Ulrich, P., Paul, G., Perentes, E., Mahl, A., and Roman D. (2004). Validation of immune function testing during a 4-week oral toxicity study with FK506. Toxicology Letters 149(1-3): 123-31.
Tian, T., Jin, M.Q., Dubin, K., 2017. IL-1R Type 1-Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection.  198, 4341-4351.
Alessandro B, Paola S, Alberto E. Paneraic, Tiziana P,Paola Palanzaa and Stefano P(2003). Chronic psychosocial stress-induced down-regulation of immunity depends upon individual factors Journal of Neuroimmunology 141: 58–64
Yamada, H., Mizumo, S., Horai, R., et al., 2000. Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice. Lab Invest 80, 759-767.
Donna C. S, Matthew J. S and Kimber L. W Jr. (2010) Systemic immunosuppression following a single pharyngeal aspiration of 1,2:5,6-dibenzanthracene in female B6C3F1 mice, Journal of Immunotoxicology, 7:3, 219-231
Yokota, S., Imagawa, T., Nishikomori, R., et al., 2017. Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndrome: results from an open-label, phase III pivotal study in Japanese patients. Clin Exp Rheumatol 35 Suppl 108, 19-26.
Yanagihara, Y., Kiniwa, M., Ikizawa K., Yamaya H., Shida, T., Matsuura, N., Koda A. (2013),  Suppression of IgE Production by IPD-1151 T (Suplatast Tosilate), a New Dimethylsulfonium Agent: (1)Regulation of Murine IgE Response. The Japanese Journal of Pharmacology 61 (1): 23-30,  10.1254/jjp.61.23
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