API XML

Aop: 277

AOP Title

?

---

Short name:

?

IL-1 inhibition

Graphical Representation

?

Click to download graphical representation template

Authors

?

---

Yutaka Kimura (1) Setsuya Aiba (1) 

(1) Depertment of Dermatology, Tohoku University Graduate School of Medicine

Corresponding author: Setsuya Aiba

Point of Contact

?

---

Yutaka Kimura   (email point of contact)

Contributors

?

---

• Yutaka Kimura

Status

?

---

This AOP was last modified on March 16, 2020 21:59

?

Revision dates for related pages

Page	Revision Date/Time
Inhibition of IL-1 binding to IL-1 receptor	November 18, 2019 00:38
Suppression of T cell activation	November 18, 2019 01:08
Inhibition, Nuclear factor kappa B (NF-kB)	March 12, 2020 22:10
Increase, Increased susceptibility to infection	March 12, 2020 22:32
Inhibition of IL-1 binding to IL-1 receptor leads to Inhibition, Nuclear factor kappa B (NF-kB)	March 13, 2020 02:27
Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation	March 13, 2020 03:08
Suppression of T cell activation leads to Increase, Increased susceptibility to infection	March 13, 2020 03:21
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

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 principle 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. 

 

In this AOP, we considered 2 MIEs, such as blocking IL-1 R and decreased IL-1 production. Either MIE leads to reduced IL-1 signaling. The biological plausibility of the signaling cascade from the activation of IL-1R to the activation of NF-kB is already confirmed. In addition, the biological plausibility that suppressed NF-kB activation leads to impaired T cell activation and antibody production lead to increased susceptibility to infection is supported by quite a few published works.

 

IL-1 also mediates several autoinflammatory syndromes. Therefore, several inhibitors against IL-1 signaling such as IL-1Ra (generic anakinra) , canakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R) have been developed. After these inhibitors became available to treat these disorders, it became clear that these inhibitors increased the frequency of serious bacterial infection. Similarly, the experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection. These data suggest that chemicals as well as drugs can suppress IL-1 signaling through their inhibitory effects on IL-1β. Taken together, developing the AOP for inhibition of IL-1 signaling is mandatory.

Background (optional)

?

---

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).

 

IL-1 also mediates autoinflammatory, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. Consequently, IL-1 family cytokines have sophisticated regulatory mechanisms to control their activities including proteolytic processing for their activation and the deployment of soluble receptors and receptor antagonists to limit their activities. Therefore, several inhibitors against IL-1 signaling have been developed. IL-1 receptor antagonist（IL-1Ra）was purified in 1990, and the cDNA was 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 was 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. 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 also 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). As IL-1 signaling antagonists, two drugs went up to the market, canakinumab (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; Imagawa et al., 2013; Lachmann et al., 2009; 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). 

 

In this AOP, we considered inhibition of IL-1R activation as a MIE. The biological plausibility of the signaling cascade from the activation of IL-1R to the activation of NF-kB is already accepted. In addition, the biological plausibility that suppressed NF-kB activation leads to impaired T cell activation, resulting in impaired antibody production and impaired T cell and antibody production lead to increased susceptibility to infection is confirmed.

     

Summary of the AOP

?

---

Events: Molecular Initiating Events (MIE)

?

Key Events (KE)

?

Adverse Outcomes (AO)

?

Sequence	Type	Event ID	Title	Short name

1

MIE

1700

Inhibition of IL-1 binding to IL-1 receptor

Inhibition of IL-1 binding to IL-1 receptor

2	KE	202	Inhibition, Nuclear factor kappa B (NF-kB)	Inhibition, Nuclear factor kappa B (NF-kB)
3	KE	1702	Suppression of T cell activation	Suppression of T cell activation

4

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

Inhibition of IL-1 binding to IL-1 receptor 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	Not Specified

Network View

?

Stressors

?

Life Stage Applicability

?

Taxonomic Applicability

?

Sex Applicability

?

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 RELB gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog.

216 organisms have orthologs with human gene RELB.

(https://www.ncbi.nlm.nih.gov/gene/5971)

These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.

 

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 (Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 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). 

 

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.

 

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. 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).

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).

 

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 et al., 2010a, b)

Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation

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)

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 et al., 2017).

Based on these evidences, the insufficient T cell or B cell function causes impaired resistance to infection.

Empirical support

This table summarizes the empirical support obtained from the experiment using several inhibitor or gene targeting mice.  

concordance table empirical data               Reference Chmical Initiator or deleted gene dose Species MIE KE1 KE2 AO Inhibition of IL-1 binding to IL-1 receptor Inhibition, Nuclear factor kappa B (NF-kB) Suppression of T cell activation Increase, Increased susceptibility to infection Dripps et al. 1991 IL-1Ra (anakinra)     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       Sigma-Aldrich Specification Sheet IL-1Ra (anakinra)     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.       Fleischmann et al. 2003 IL-1Ra (anakinra) 100 mg of anakinra or placebo, administered daily by subcutaneous injection human       Serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group).  Genovese et al. 2004 IL-1Ra (anakinra) 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 human       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. Kullenberg et al. 2016 IL-1Ra (anakinra) administered as daily s.c. injections human       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.  Lequerre et al. 2008 IL-1Ra (anakinra) treated with anakinra (1–2 mg/kg/day in children, 100 mg/day in adults) human       Two patients stopped anakinra due to severe skin reaction, and two patients due to infection: one visceral leishmaniasis and one varicella. Migkos et al. 2015 IL-1Ra (anakinra)   human       a case of tuberculous pyomyositis in a 85-year-old Caucasian patient with rheumatoid arthritis (RA) treated with steroids and anakinra. Settas et al. 2007 IL-1Ra (anakinra)   human       reactivation of previous pulmonary tuberculosis (TBC) after 23 months of treatment with the IL-1 receptor antagonist anakinra. Lee et al. 2004 IL-1Ra (anakinra)   intrathecal administration of IL-1ra (6 mg)   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.     Vallejo et al. 2014 IL-1Ra (anakinra) In diabetic rats treated with anakinra (100 or 160 mg/Kg/day for 3 or 7 days before sacrifice) rat   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.     Dhimolea et al. 2010 canakinumab     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.       De Benedetti et al. 2018 canakinumab 150 mg subcutaneously every 4 weeks human       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). Imagawa et al. 2013 canakinumab either 150 mg s.c. or 2 mg/kg for patients with a body weight ≤ 40 kg every 8 weeks for 24 weeks human       Two patients had serious adverse events, which resolved with standard treatment.  Lachmann et al. 2009 canakinumab received 150 mg of canakinumab subcutaneously every 8 weeks for up to 24 weeks human       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. Schlesinger et al. 2012 canakinumab one dose of canakinumab 150 mg human       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. Textbook of Pediatric Rheumatology (Sixth Edition), 2011 rilonacept   human Rilonacept has a very high binding affinity for IL-1 (dissociation constant ~1 pM), and it is specific for IL-1β and IL-1α.       Hoffman et al. 2008 rilonacept weekly subcutaneous injections (160 mg) human       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 Roell et al. 2010 gevokizumab (XOMA 052)   human   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).     Mansouri et al. 2015 gevokizumab (XOMA 052) receive gevokizumab 60 mg subcutaneously every 4 weeks for a total of three injections (12 weeks) with a 4-week follow-up period human       There were no significant adverse events related to the study medication, although one patient developed an abscess in a haematoma secondary to an injury. Issafras et al. 2014 gevokizumab (XOMA 052)   human (HeLa cells stably transfected with a nuclear factor-kB (NF-kB) luciferase reporter plasmid)   an average KB value (mean±S.D., n=3) of 4.8±4.4 pM     Palombella et al. 1994 MG-132   human (in vitro)   Both MG115 and MG132 (at 20-40 mM) markedly inhibited the formation of p50 in HeLa S100 extracts (Figure 4A, lanes 8-13).     Hellerbrand et al. 1998 MG-132   rat (in vitro)   ALLN (Fig. 3A) and MG132 (Fig. 3B) (10 mg/mL = 21mM) reduced the cytokine-mediated NFkB activation.     Arlt et al. 2001 MG-132   human (in vitro)   In all cell lines, gliotoxin, MG132 (10 mM) or sulfasalazine strongly reduced VP16-induced NF-kB-driven luciferase expression.     Ortiz-Lazareno et al. 2008 MG-132   human (in vitro)   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.     Yu and Malek 2001 MG-132   mice (in vitro)     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).   Wang et al. 2011 MG-132   human (in vitro)     CMV-specific cytotoxicity of CD8(+) T cells was decreased in the presence of MG132.   Ohkusu-Tsukada et al. 2018 MG-132 repeatedly i.p. injected 200 nmol of MG132 on days 0, 3, 5, 7, 9, 11, 13, 15, 17, and 19. mice (in vivo)     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.   Satou et al. 2004 bortezomib   human (in vitro, in vivo)     potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro   Orciuolo et al. 2007 bortezomib 0.1 mM, 1 mM, 10 mM human (in vitro)     the percentage of CD69/TNFa positive T-cell reduces with the increment of bortezomib concentration.   Matsumoto et al. 2005 dehydroxymethylepoxyquinomicin (DHMEQ)   human   The addition of DHMEQ (10 mg/mL) completely inhibited the activated NF-KB for at least 8 hours.     Nishioka et al. 2008 dehydroxymethylepoxyquinomicin (DHMEQ)   human (in vitro)   DHMEQ (1mg/mL) blocked PHA-induced nuclear translocation of NF-kB in Jurkat cells via inhibition of degradation of IkBa. 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).   Alessiani et al. 1991 FK 506   human     Five of eight deaths were due to infection (62.5%). Overall, 50% of patients developed infection of which 38% suffered severe ones.   Fung et al. 1991 FK 506   human     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.   Ekberg et al. 2007 cyclosporine   human     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).                   Guler et al. 2011 i) IL-1RI-/- ii) Autologous Qb virus-like particle-based vaccines against IL-1a and IL-1b ii) immunized s.c. three times before (at week: −5, −3 and −1) and once at week 10 post-infection mice       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. Parnet et al. 2003 IL-1RI-/-       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,      Yamada et al. 2001 NF-kB p50-/- knockout mice mice       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).  Weih et al. 1995 RelB-/- knockout mice mice     RelB-deficient animals also had an impaired cellular immunity, as observed in contact sensitivity experiments.   Lin et al. 2015 Secreted IL-1α expression   mice     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   Nambu et al. 2006 IL-1a-/-, IL-1b-/-, IL-1a/b-/- knockout mice mice     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

 

 

Quantitative Understanding

?

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.

References

?

---

Alessiani, M., Kusne, S., Martin, M., Jain, A., Abu-Elmagd, K., Moser, J., Todo, S., Fung, J., Starzl, T., 1991. Infections in adult liver transplant patients under FK 506 immunosuppression. Transplant Proc 23, 1501-1503.

Arlt, A., Vorndamm, J., Breitenbroich, M., Folsch, U.R., Kalthoff, H., Schmidt, W.E., Schafer, H., 2001. Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin. Oncogene 20, 859-868.

Cassidy, J.P., R.: Laxer, R.; Lindsley, C, 2010. Textbook of Pediatric Rheumatology

6th Edition. Saunders.

De Benedetti, F., Gattorno, M., Anton, J., Ben-Chetrit, E., Frenkel, J., Hoffman, H.M., Kone-Paut, I., Lachmann, H.J., Ozen, S., Simon, A., Zeft, A., Calvo Penades, I., Moutschen, M., Quartier, P., Kasapcopur, O., Shcherbina, A., Hofer, M., Hashkes, P.J., Van der Hilst, J., Hara, R., Bujan-Rivas, S., Constantin, T., Gul, A., Livneh, A., Brogan, P., Cattalini, M., Obici, L., Lheritier, K., Speziale, A., Junge, G., 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.

Dinarello, C.A., 2018. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 281, 8-27.

Dripps, D.J., Brandhuber, B.J., Thompson, R.C., Eisenberg, S.P., 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.

Ekberg, H., Grinyo, J., Nashan, B., Vanrenterghem, Y., Vincenti, F., Voulgari, A., Truman, M., Nasmyth-Miller, C., Rashford, M., 2007. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study. Am J Transplant 7, 560-570.

Fleischmann, R.M., Schechtman, J., Bennett, R., Handel, M.L., Burmester, G.R., Tesser, J., Modafferi, D., Poulakos, J., Sun, G., 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.

Fremond, C.M., Yeremeev, V., Nicolle, D.M., Jacobs, M., Quesniaux, V.F., Ryffel, B., 2004. Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88. J Clin Invest 114, 1790-1799.

Fung, J.J., Todo, S., Tzakis, A., Alessiani, M., Abu-Elmagd, K., Jain, A., Bronster, O., Martin, M., Gordon, R., Starzl, T.E., 1991. Current status of FK 506 in liver transplantation. Transplant Proc 23, 1902-1905.

Genovese, M.C., Cohen, S., Moreland, L., Lium, D., Robbins, S., Newmark, R., Bekker, P., 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.

Gerondakis, S., Fulford, T.S., Messina, N.L., Grumont, R.J., 2014. NF-kappaB control of T cell development. Nat Immunol 15, 15-25.

Goh, A.X., Bertin-Maghit, S., Ping Yeo, S., Ho, A.W., Derks, H., Mortellaro, A., Wang, C.I., 2014. A novel human anti-interleukin-1beta neutralizing monoclonal antibody showing in vivo efficacy. MAbs 6, 765-773.

Guler, R., Parihar, S.P., Spohn, G., Johansen, P., Brombacher, F., Bachmann, M.F., 2011. Blocking IL-1alpha but not IL-1beta increases susceptibility to chronic Mycobacterium tuberculosis infection in mice. Vaccine 29, 1339-1346.

Hannum, C.H., Wilcox, C.J., Arend, W.P., Joslin, F.G., Dripps, D.J., Heimdal, P.L., Armes, L.G., Sommer, A., Eisenberg, S.P., Thompson, R.C., 1990. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343, 336-340.

Hellerbrand, C., Jobin, C., Iimuro, Y., Licato, L., Sartor, R.B., Brenner, D.A., 1998. Inhibition of NFkappaB in activated rat hepatic stellate cells by proteasome inhibitors and an IkappaB super-repressor. Hepatology 27, 1285-1295.

Hoffman, H.M., Throne, M.L., Amar, N.J., Sebai, M., Kivitz, A.J., Kavanaugh, A., Weinstein, S.P., Belomestnov, P., Yancopoulos, G.D., Stahl, N., Mellis, S.J., 2008. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum 58, 2443-2452.

Horino, T., Matsumoto, T., Ishikawa, H., Kimura, S., Uramatsu, M., Tanabe, M., Tateda, K., Miyazaki, S., Aramaki, Y., Iwakura, Y., Yoshida, M., Onodera, S., Yamaguchi, K., 2009. Interleukin-1 deficiency in combination with macrophage depletion increases susceptibility to Pseudomonas aeruginosa bacteremia. Microbiol Immunol 53, 502-511.

Imagawa, T., Nishikomori, R., Takada, H., Takeshita, S., Patel, N., Kim, D., Lheritier, K., Heike, T., Hara, T., Yokota, S., 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.

Issafras, H., Corbin, J.A., Goldfine, I.D., Roell, M.K., 2014. Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1beta antibody with differential receptor-modulating properties. J Pharmacol Exp Ther 348, 202-215.

Juffermans, N.P., Florquin, S., Camoglio, L., Verbon, A., Kolk, A.H., Speelman, P., van Deventer, S.J., van Der Poll, T., 2000. Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis 182, 902-908.

Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.

Kullenberg, T., Lofqvist, M., Leinonen, M., Goldbach-Mansky, R., Olivecrona, H., 2016. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford) 55, 1499-1506.

Lachmann, H.J., Kone-Paut, I., Kuemmerle-Deschner, J.B., Leslie, K.S., Hachulla, E., Quartier, P., Gitton, X., Widmer, A., Patel, N., Hawkins, P.N., 2009. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360, 2416-2425.

Lee, K.M., Kang, B.S., Lee, H.L., Son, S.J., Hwang, S.H., Kim, D.S., Park, J.S., Cho, H.J., 2004. Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity. Eur J Neurosci 19, 3375-3381.

Lequerre, T., Quartier, P., Rosellini, D., Alaoui, F., De Bandt, M., Mejjad, O., Kone-Paut, I., Michel, M., Dernis, E., Khellaf, M., Limal, N., Job-Deslandre, C., Fautrel, B., Le Loet, X., Sibilia, J., 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.

Lin, D., Lei, L., Zhang, Y., Hu, B., Bao, G., Liu, Y., Song, Y., Liu, C., Wu, Y., Zhao, L., Yu, X., Liu, H., 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.

Mansouri, B., Richards, L., Menter, A., 2015. Treatment of two patients with generalized pustular psoriasis with the interleukin-1beta inhibitor gevokizumab. Br J Dermatol 173, 239-241.

Matsumoto, G., Namekawa, J., Muta, M., Nakamura, T., Bando, H., Tohyama, K., Toi, M., Umezawa, K., 2005. Targeting of nuclear factor kappaB Pathways by dehydroxymethylepoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo. Clin Cancer Res 11, 1287-1293.

Migkos, M.P., Somarakis, G.A., Markatseli, T.E., Matthaiou, M., Kosta, P., Voulgari, P.V., Drosos, A.A., 2015. Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra. Clin Exp Rheumatol 33, 734-736.

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.

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.

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.

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.

Ortiz-Lazareno, P.C., Hernandez-Flores, G., Dominguez-Rodriguez, J.R., Lerma-Diaz, J.M., Jave-Suarez, L.F., Aguilar-Lemarroy, A., Gomez-Contreras, P.C., Scott-Algara, D., Bravo-Cuellar, A., 2008. MG132 proteasome inhibitor modulates proinflammatory cytokines production and expression of their receptors in U937 cells: involvement of nuclear factor-kappaB and activator protein-1. Immunology 124, 534-541.

Palombella, V.J., Rando, O.J., Goldberg, A.L., Maniatis, T., 1994. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 78, 773-785.

Parnet, P., Pousset, F., Laye, S., 2003. NF kappa B activation in mouse pituitary: comparison of response to interleukin-1 beta and lipopolysaccharide. J Neuroendocrinol 15, 304-314.

Picard, C., von Bernuth, H., Ghandil, P., Chrabieh, M., Levy, O., Arkwright, P.D., McDonald, D., Geha, R.S., Takada, H., Krause, J.C., Creech, C.B., Ku, C.L., Ehl, S., Marodi, L., Al-Muhsen, S., Al-Hajjar, S., Al-Ghonaium, A., Day-Good, N.K., Holland, S.M., Gallin, J.I., Chapel, H., Speert, D.P., Rodriguez-Gallego, C., Colino, E., Garty, B.Z., Roifman, C., Hara, T., Yoshikawa, H., Nonoyama, S., Domachowske, J., Issekutz, A.C., Tang, M., Smart, J., Zitnik, S.E., Hoarau, C., Kumararatne, D.S., Thrasher, A.J., Davies, E.G., Bethune, C., Sirvent, N., de Ricaud, D., Camcioglu, Y., Vasconcelos, J., Guedes, M., Vitor, A.B., Rodrigo, C., Almazan, F., Mendez, M., Arostegui, J.I., Alsina, L., Fortuny, C., Reichenbach, J., Verbsky, J.W., Bossuyt, X., Doffinger, R., Abel, L., Puel, A., Casanova, J.L., 2010. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore) 89, 403-425.

Roell, M.K., Issafras, H., Bauer, R.J., Michelson, K.S., Mendoza, N., Vanegas, S.I., Gross, L.M., Larsen, P.D., Bedinger, D.H., Bohmann, D.J., Nonet, G.H., Liu, N., Lee, S.R., Handa, M., Kantak, S.S., Horwitz, A.H., Hunter, J.J., Owyang, A.M., Mirza, A.M., Corbin, J.A., White, M.L., 2010. Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity. J Biol Chem 285, 20607-20614.

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.

Scanga, C.A., Bafica, A., Feng, C.G., Cheever, A.W., Hieny, S., Sher, A., 2004. MyD88-deficient mice display a profound loss in resistance to Mycobacterium tuberculosis associated with partially impaired Th1 cytokine and nitric oxide synthase 2 expression. Infect Immun 72, 2400-2404.

Schlesinger, N., Alten, R.E., Bardin, T., Schumacher, H.R., Bloch, M., Gimona, A., Krammer, G., Murphy, V., Richard, D., So, A.K., 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.

Seckinger, P., Kaufmann, M.T., Dayer, J.M., 1990a. 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.

Seckinger, P., Klein-Nulend, J., Alander, C., Thompson, R.C., Dayer, J.M., Raisz, L.G., 1990b. Natural and recombinant human IL-1 receptor antagonists block the effects of IL-1 on bone resorption and prostaglandin production. J Immunol 145, 4181-4184.

Settas, L.D., Tsimirikas, G., Vosvotekas, G., Triantafyllidou, E., Nicolaides, P., 2007. Reactivation of pulmonary tuberculosis in a patient with rheumatoid arthritis during treatment with IL-1 receptor antagonists (anakinra). J Clin Rheumatol 13, 219-220.

Sha, W.C., Liou, H.C., Tuomanen, E.I., Baltimore, D., 1995. Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 80, 321-330.

Sigma-Aldrich, IL-1Ra Specification Sheet.

Soares, M.P., Teixeira, L., Moita, L.F., 2017. Disease tolerance and immunity in host protection against infection. Nat Rev Immunol 17, 83-96.

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.

Vallejo, S., Palacios, E., Romacho, T., Villalobos, L., Peiro, C., Sanchez-Ferrer, C.F., 2014. The interleukin-1 receptor antagonist anakinra improves endothelial dysfunction in streptozotocin-induced diabetic rats. Cardiovasc Diabetol 13, 158.

von Bernuth, H., Picard, C., Jin, Z., Pankla, R., Xiao, H., Ku, C.L., Chrabieh, M., Mustapha, I.B., Ghandil, P., Camcioglu, Y., Vasconcelos, J., Sirvent, N., Guedes, M., Vitor, A.B., Herrero-Mata, M.J., Arostegui, J.I., Rodrigo, C., Alsina, L., Ruiz-Ortiz, E., Juan, M., Fortuny, C., Yague, J., Anton, J., Pascal, M., Chang, H.H., Janniere, L., Rose, Y., Garty, B.Z., Chapel, H., Issekutz, A., Marodi, L., Rodriguez-Gallego, C., Banchereau, J., Abel, L., Li, X., Chaussabel, D., Puel, A., Casanova, J.L., 2008. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321, 691-696.

Wang, Y., Sun, B., Volk, H.D., Proesch, S., Kern, F., 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.

Weber, A., Wasiliew, P., Kracht, M., 2010a. Interleukin-1 (IL-1) pathway. Sci Signal 3, cm1.

Weber, A., Wasiliew, P., Kracht, M., 2010b. Interleukin-1beta (IL-1beta) processing pathway. Sci Signal 3, cm2.

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.

Yamada, H., Mizumo, S., Horai, R., Iwakura, Y., Sugawara, I., 2000. Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice. Lab Invest 80, 759-767.

Yamada, H., Mizuno, S., Reza-Gholizadeh, M., Sugawara, I., 2001. Relative importance of NF-kappaB p50 in mycobacterial infection. Infect Immun 69, 7100-7105.

Yokota, S., Imagawa, T., Nishikomori, R., Takada, H., Abrams, K., Lheritier, K., Heike, T., Hara, T., 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.

Yu, A., Malek, T.R., 2001. The proteasome regulates receptor-mediated endocytosis of interleukin-2. J Biol Chem 276, 381-385.