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Aop: 277
Title
Impaired IL-1R1 signaling leading to increased susceptibility to infection
Short name
Graphical Representation
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Point of Contact
Contributors
- Yutaka Kimura
Status
| Author status | OECD status | OECD project | SAAOP status |
|---|---|---|---|
| Open for citation & comment | EAGMST Under Review | 1.48 | Included in OECD Work Plan |
This AOP was last modified on June 04, 2021 15:16
Revision dates for related pages
| Page | Revision Date/Time |
|---|---|
| Impaired IL-1R1 signaling | May 23, 2021 00:45 |
| Suppression of T cell activation | May 03, 2021 03:02 |
| Inhibition, Nuclear factor kappa B (NF-kB) | May 03, 2021 02:57 |
| Increase, Increased susceptibility to infection | May 23, 2021 02:22 |
| Impaired IL-1R1 signaling leads to Inhibition, Nuclear factor kappa B (NF-kB) | May 03, 2021 04:09 |
| Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation | May 03, 2021 05:20 |
| Suppression of T cell activation leads to Increase, Increased susceptibility to infection | May 22, 2021 23:44 |
| IL-1 receptor antagonist（IL-1Ra）(Anakinra) | June 01, 2019 00:37 |
| anti-IL-1b antibody (Canakinumab) | June 01, 2019 00:38 |
| soluble IL-1R (Rilonacept) | June 01, 2019 00:38 |
| anti-IL-1b antibody (Gevokizumab) | December 15, 2019 20:41 |
| Dexamethasone | June 01, 2019 00:56 |
| minocycline | June 01, 2019 00:32 |
| Belnacasan (VX-765) | December 21, 2020 19:49 |
| Pralnacasan (VX-740, HMR3480) | December 21, 2020 19:57 |
| cinnamic aldehyde | June 01, 2019 00:37 |
| Dimethyl fumarate | May 01, 2021 00:17 |
| curcumin | December 21, 2020 20:39 |
| iguratimod | December 21, 2020 20:41 |
| (-)-Epigallocatechin gallate | May 01, 2021 00:25 |
| TAK-242 | December 21, 2020 20:44 |
| IRAK4 inhibitors | December 21, 2020 20:44 |
| Dehydroxymethylepoxyquinomicin (DHMEQ) | May 01, 2021 00:09 |
Abstract
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.
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).
Although the purpose of this AOP is to elucidate biological pathways that lead to increased susceptibility to infections 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.
AOP Development Strategy
Context
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).
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-1β 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).
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 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).
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
| Type | Event ID | Title | Short name |
|---|
| MIE | 1700 | Impaired IL-1R1 signaling | Impaired IL-1R1 signaling |
| KE | 202 | Inhibition, Nuclear factor kappa B (NF-kB) | Inhibition, Nuclear factor kappa B (NF-kB) |
| KE | 1702 | Suppression of T cell activation | Suppression of T cell activation |
| AO | 986 | Increase, Increased susceptibility to infection | Increase, Increased susceptibility to infection |
Relationships Between Two Key Events (Including MIEs and AOs)
| Title | Adjacency | Evidence | Quantitative Understanding |
|---|
| Impaired IL-1R1 signaling leads to Inhibition, Nuclear factor kappa B (NF-kB) | adjacent | High | Moderate |
| Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation | adjacent | High | Moderate |
| Suppression of T cell activation leads to Increase, Increased susceptibility to infection | adjacent | High | High |
Network View
Prototypical Stressors
Life Stage Applicability
| Life stage | Evidence |
|---|---|
| Not Otherwise Specified | High |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Mixed | High |
Overall Assessment of the AOP
Domain of Applicability
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 (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849).
The NFKB1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, and frog.
275 organisms have orthologs with human gene NFKB1.
(https://www.ncbi.nlm.nih.gov/gene/4790)
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).
Essentiality of the Key Events
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). 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 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 (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).
Evidence Assessment
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).
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
Inhibition of IL-1 binding to IL-1 receptor leads to Inhibition, Nuclear factor kappa B (NF-kB)
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.
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).
Inhibition, Nuclear factor kappa B (NF-κB) leads to Suppression of T cell activation
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).
Suppression of T cell activation leads to Increase, Increased susceptibility to infection
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.
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.
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, Teixeira and Moita, 2017).
Based on these evidences, the insufficient T cell or B cell function causes impaired resistance to infection
Empirical support
- Impaired IL-1R signaling.
Decreased production of IL-1 or inhibition of the binding of IL-1 to IL-1R impair IL-1R signaling.
-
- Decreased IL-1 production
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).
-
- Blocking of binding of IL-1 to IL-1R1
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).
- Reduction of host resistance to various infection by impaired IL-1 receptor signaling
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).
Known Modulating Factors
Quantitative Understanding
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 ∼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 = ∼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).
Considerations for Potential Applications of the AOP (optional)
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.
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