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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
Yutaka Kimura (email point of contact)
- Yutaka Kimura
|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 January 07, 2020 10:33
|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|
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.
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
Events: Molecular Initiating Events (MIE)
|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)
|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|
|IL-1 receptor antagonist（IL-1Ra）(Anakinra)||High|
|anti-IL-1b antibody (Canakinumab)||High|
|soluble IL-1R (Rilonacept)||High|
|anti-IL-1b antibody (Gevokizumab)||High|
Life Stage Applicability
|Not Otherwise Specified||High|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
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.
The RELB gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog.
216 organisms have orthologs with human gene RELB.
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） (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).
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).
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.
This table summarizes the empirical support obtained from the experiment using several inhibitor or gene targeting mice.
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)
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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