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Aop: 277

AOP Title

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Short name:

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IL-1 inhibition

Graphical Representation

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Authors

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Yutaka Kimura (1) Setsuya Aiba (1) 

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

Corresponding author: Setsuya Aiba

Point of Contact

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Yutaka Kimura   (email point of contact)

Contributors

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• Yutaka Kimura

Status

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This AOP was last modified on January 07, 2020 10:33

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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)	November 18, 2019 00:47
Increase, Increased susceptibility to infection	November 18, 2019 22:54
Inhibition of IL-1 binding to IL-1 receptor leads to Inhibition, Nuclear factor kappa B (NF-kB)	December 29, 2019 21:42
Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation	November 18, 2019 07:00
Suppression of T cell activation leads to Increase, Increased susceptibility to infection	November 18, 2019 02:06
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

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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 the inhibition of IL-1 binding to IL-1 receptor as a MIE. The biological plausibility of the signaling cascade from IL-1 receptor activation 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, resulting in impaired antibody production and increased susceptibility to infection is supported by quite a few published works.

 

IL-1 also mediates several autoinflammatory syndromes. Therefore, several inhibitors against IL-1R stimulation such as IL-1Ra (generic anakinra), canakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R) have been developed. Indeed, after these inhibitors became available to treat these disorders, it became clear that these inhibitors increased the frequency of serious bacterial infection. Taken together, developing the AOP for “inhibition of IL-1 binding to IL-1 receptor leading to increased susceptibility to infection” is mandatory.

Background (optional)

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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. Therefore, several inhibitors against IL-1 signaling have been developed. Recombinant IL-1Ra (generic anakinra) is fully active in blocking the IL-1R1, and therefore, the activities of IL-1α and IL-1β. (Dripps et al., 1991) Anakinra was approved for the treatment of rheumatoid arthritis and cryopyrin-associated periodic syndrome (CAPS). Although anakinra is a safe drug in general, several papers reported that anakinra increased susceptibility to bacterial and tuberculosis infection (Genovese et al., 2004; Kullenberg et al., 2016; Lequerre et al., 2008; Migkos et al., 2015). Similarly, other IL-1 signaling antagonists, canakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R) have been reported increase 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

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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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

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AO

986

Increase, Increased susceptibility to infection

Increase, Increased susceptibility to infection

Relationships Between Two Key Events
(Including MIEs and AOs)

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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	Not Specified
Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation	adjacent	High	Not Specified
Suppression of T cell activation leads to Increase, Increased susceptibility to infection	adjacent	High	Not Specified

Network View

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Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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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

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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） (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, there are several reports indicating that serious infectious episodes were observed more frequently in the anakinra group (Fleischmann et al., 2003)(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, Hoffman et al. 2008). 

Evidence Assessment

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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. The sequentiality and essentiality of each signaling molecule have been demonstrated by mice lacking relevant molecules (Weber et al., 2010a, b).

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. 2010)

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

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So far, we could find only a few appropriate reports that speak the quantitative aspects of three KERs. 

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

MG132 suppresses NF-kB activity at 10-40 mM. MG132 also suppresses IL-2-induced activation of phosphorylated STAT5, (CMV-specific cytotoxicity of CD8(+) T cells), at 50 mM or . (Yu and Malek 2001, (Wang et al. 2011))

DHMEQ (1microg/mL) blocked PHA-induced nuclear translocation of NF-kB in Jurkat cells via inhibition of degradation of IkBa. In the same report, exposure of PBMC to PHA greatly stimulated expression of IFN-g, IL-2 and TNF-a. Preincubation of these cells with DHMEQ (1 microg/ml, 3 hr) greatly reduced PHA-stimulated expression of these cytokine genes. Similarly, PHA increased expression of IL-2 and IFN-g in Jurkat cells and pre-incubation of these cells with DHMEQ (1 microg/ml) decreased these levels by approximately half.(Nishioka et al. 2008)

Considerations for Potential Applications of the AOP (optional)

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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

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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.

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.

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.

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.

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.

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