This AOP is licensed under the BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
AOP: 277
Title
Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response
Short name
Graphical Representation
Additional AOP Exploration Options
Click links below to explore AOP 277, Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response in tools offered by third parties.
Point of Contact
Contributors
- Yutaka Kimura
- Takao Ashikaga
- Takumi Ohishi
- Kiyoshi Kushima
- Cataia Ives
Coaches
OECD Information Table
| OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
|---|---|---|---|---|
| 1.48 | WPHA/WNT Endorsed |
This AOP was last modified on May 26, 2024 20:39
Revision dates for related pages
| Page | Revision Date/Time |
|---|---|
| Impaired IL-1R1 signaling in T cell | March 02, 2023 04:26 |
| Suppression of T cell activation | March 06, 2023 01:23 |
| Inhibition, Nuclear factor kappa B (NF-kB) | March 02, 2023 01:58 |
| Impairment, T-cell dependent antibody response | February 19, 2023 21:49 |
| Impaired IL-1R1 signaling leads to Inhibition, Nuclear factor kappa B (NF-kB) | September 29, 2022 06:18 |
| Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation | March 02, 2023 03:13 |
| Suppression of T cell activation leads to Impairment, T-cell dependent antibody response | May 25, 2023 20:51 |
| 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. In addition to the NF-κB pathway, IL-1 receptor-associated kinase (IRAK) , which is one of the kinase consisting of the cascade, activates a variety of transcription factors, including Adaptor protein-1 (AP-1). The activation of NF-κB plays a principal role in the immunological function of IL-1. Namely, it stimulates innate immunity such as activation of dendritic cells and macrophages. It also stimulates T cells via activated dendritic function or directly. The activation of T cells is crucial for B cell proliferation and their antibody production. The cooperation by T cells and B cells constitutes a main part of host defense against infection. Therefore, the impaired IL-1R1 signaling either by the decreased IL-1 production or the inhibition of IL-1β binding to IL-1R1 by IL-1 receptor antagonist（IL-1Ra）or anti-IL-1β antibody) results in the blockade of the effects of the pleiotropic cytokine IL-1β leading to suppressed T cell dependent antibody response (TDAR).
In this AOP, we selected the impaired IL-1R signaling as a molecular initiating event (MIE) in T cell, and suppression of NF-κB (and/or AP-1), suppression of T cell activation, and suppression of TDAR as key events (KE).
Although the purpose of this AOP is to elucidate biological pathways that lead to immune suppression caused by impaired IL-1R signaling by chemicals, most of the stressors presented in this AOP were limited to pharmaceuticals because of the lack of information on chemicals.
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, and sometimes, mediation of autoinflammatory, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. The trimeric complex consists of IL-1, IL-1R1 and IL-1R3 (a coreceptor, formerly IL-1R accessory protein) allows for the approximation of the Toll-IL-1-Receptor (TIR) domains of each receptor chain. MyD88 then binds to the TIR domains. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB and/or AP-1 and fundamental inflammatory responses such as the induction of cyclooxygenase type 2, production of multiple cytokines and chemokines, increased expression of adhesion molecules, or synthesis of nitric oxide. (Dinarello, 2018; Weber et al., 2010a, b; Jain et al., 2014).
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 and/or AP-1 or the inhibition of posttranscriptional regulation of pro-IL-1β cause impaired IL-1R1 signaling. In addition, since IL-1 also mediates autoinflammatory syndromes, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever, several inhibitors against IL-1R1 have been developed. They are IL-1 receptor antagonist（IL-1Ra）, anakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R). Several reports described that the administration of these drugs led to increased susceptibility to infection(De Benedetti et al., 2018; Fleischmann et al., 2003; Genovese et al., 2004; Imagawa et al., 2013; Kullenberg et al., 2016; Lachmann et al., 2009; Lequerre et al., 2008; Migkos et al., 2015; Schlesinger et al., 2012; Yokota et al., 2017). In addition to these human data, the experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection(Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000).
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 in T cell | 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 | 984 | Impairment, T-cell dependent antibody response | Impairment, T-cell dependent antibody response |
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 Impairment, T-cell dependent antibody response | 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 human, 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 immunosuppression or increased susceptibility to infection (De Benedetti et al., 2018; Imagawa et al., 2013; Lachmann et al., 2009; Schlesinger et al., 2012).
In a similar way, defect of MyD88 signaling caused by knockout of mice gene or deficiency in human patient leads to the increased susceptibility to bacterial or tuberculosis infection (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 supression of TDAR
T cell-derived cytokines play important roles in TDAR. Among them, IL-2 promotes proliferation of B cells, and IL-4 affects maturation and class switching of B cells as well as proliferation.
Th2 cells produce cytokines including IL-4. Suplatast tosilate (IPD) is known as an inhibitor of the production of IL-4 and IL-5 in Th2 cells and reduces the production of antigen specific IgE in human cell culture and mice (Yanagihara, 2013). These findings suggests that the reduction of IL-4 production by the inhibitor of
Th2 cell cytokines results in reduced production of IgE and/or IgG1 through inhibitions of maturation, proliferation and class switching of B cells.
IL-2 binds to IL-2 receptor (IL-2R) and acts on T cells. CD25 is one the of IL-2R. Basiliximab (Simulect) is known as anti-CD25antibody. Basiliximab binds to IL-2R and blocks IL-2 signaling. Clinical transplantation study of basiliximab reveals decreases in rejections. On the other hand, basiliximab inhibits the activation of antigen specific T cells (Kircher, 2003).
Based on these evidences, the insufficient T cell or B cell function causes suppression of TDAR
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).
- 1-2. 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).
- Immunosuppression 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
| Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
|---|---|---|
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 immunosuppression. Therefore, the test guideline to detect chemicals that decrease IL-1 signaling is required to support regulatory decision-making. This AOP can promote the understanding of the usefulness of the test guideline.
References
Alten, R., Gram, H., Joosten, L.A., et al. (2008), The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res Ther 10: R67, 10.1186/ar2438
Bent, R., Moll, L., Grabbe, S., et al. (2018), Interleukin-1 Beta-A Friend or Foe in Malignancies? Int J Mol Sci 19, 10.3390/ijms19082155
Bhaskaran, N., Faddoul, F., Paes da Silva, A., et al. (2020), IL-1beta-MyD88-mTOR Axis Promotes Immune-Protective IL-17A(+)Foxp3(+) Cells During Mucosal Infection and Is Dysregulated With Aging. Front Immunol 11: 595936, 10.3389/fimmu.2020.595936
Bohrer, A.C., Tocheny, C., Assmann, M., et al. (2018), Cutting Edge: IL-1R1 Mediates Host Resistance to Mycobacterium tuberculosis by Trans-Protection of Infected Cells. J Immunol 201: 1645-1650, 10.4049/jimmunol.1800438
Chaudhary, D., Robinson, S., Romero, D.L. (2015), Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders. J Med Chem 58: 96-110, 10.1021/jm5016044
Church, L.D., McDermott, M.F. (2009), Canakinumab, a fully-human mAb against IL-1beta for the potential treatment of inflammatory disorders. Curr Opin Mol Ther 11: 81-89,
De Benedetti, F., Gattorno, M., Anton, J., et al. (2018), Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med 378: 1908-1919, 10.1056/NEJMoa1706314
Dinarello, C.A. (2018), Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 281: 8-27, 10.1111/imr.12621
Dripps, D.J., Brandhuber, B.J., Thompson, R.C., et al. (1991), Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266: 10331-10336,
Economides, A.N., Carpenter, L.R., Rudge, J.S., et al. (2003), Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med 9: 47-52, 10.1038/nm811
Fang, X.M., Schroder, S., Hoeft, A., et al. (1999), Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis. Crit Care Med 27: 1330-1334, 10.1097/00003246-199907000-00024
Fenini, G., Contassot, E., French, L.E. (2017), Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases. Front Pharmacol 8: 278, 10.3389/fphar.2017.00278
Finch-Arietta, M.B., Cochran, F.R. (1991), Cytokine production in whole blood ex vivo. Agents Actions 34: 49-52, 10.1007/BF01993235
Fleischmann, R.M., Schechtman, J., Bennett, R., et al. (2003), Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis Rheum 48: 927-934, 10.1002/art.10870
Fuchs, O. (2010), Transcription factor NF-kappaB inhibitors as single therapeutic agents or in combination with classical chemotherapeutic agents for the treatment of hematologic malignancies. Curr Mol Pharmacol 3: 98-122, 10.2174/1874467211003030098
Genovese, M.C., Cohen, S., Moreland, L., et al. (2004), Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50: 1412-1419, 10.1002/art.20221
Gerondakis, S., Fulford, T.S., Messina, N.L., et al. (2014), NF-kappaB control of T cell development. Nat Immunol 15: 15-25, 10.1038/ni.2785
Goh, A.X., Bertin-Maghit, S., Ping Yeo, S., et al. (2014), A novel human anti-interleukin-1beta neutralizing monoclonal antibody showing in vivo efficacy. MAbs 6: 765-773, 10.4161/mabs.28614
Granowitz, E.V., Clark, B.D., Vannier, E., et al. (1992), Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes. Blood 79: 2356-2363,
Guler, R., Parihar, S.P., Spohn, G., et al. (2011), Blocking IL-1alpha but not IL-1beta increases susceptibility to chronic Mycobacterium tuberculosis infection in mice. Vaccine 29: 1339-1346, 10.1016/j.vaccine.2010.10.045
Handa, P., Vemulakonda, A., Kowdley, K.V., et al. (2016), Mitochondrial DNA from hepatocytes as a ligand for TLR9: Drivers of nonalcoholic steatohepatitis? World J Gastroenterol 22: 6965-6971, 10.3748/wjg.v22.i31.6965
Hannum, C.H., Wilcox, C.J., Arend, W.P., et al. (1990), Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343: 336-340, 10.1038/343336a0
Horino, T., Matsumoto, T., Ishikawa, H., et al. (2009), Interleukin-1 deficiency in combination with macrophage depletion increases susceptibility to Pseudomonas aeruginosa bacteremia. Microbiol Immunol 53: 502-511, 10.1111/j.1348-0421.2009.00143.x
Imagawa, T., Nishikomori, R., Takada, H., et al. (2013), Safety and efficacy of canakinumab in Japanese patients with phenotypes of cryopyrin-associated periodic syndrome as established in the first open-label, phase-3 pivotal study (24-week results). Clin Exp Rheumatol 31: 302-309,
Jain, A., Kaczanowska, S., Davila, E. (2014), IL-1 receptor-associated kinase signaling and its role in inflammation, cancer, progression, and therapy resistance. Frontiers in Immunology 5:553.
Juffermans, N.P., Florquin, S., Camoglio, L., et al. (2000), Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis 182: 902-908, 10.1086/315771
Kapur, S., Bonk, M.E. (2009), Rilonacept (arcalyst), an interleukin-1 trap for the treatment of cryopyrin-associated periodic syndromes. P t 34: 138-141
Kircher, B., Latze, K., Gastl, G., Nachbaur, D. (2003), Comparative in vitro study of the immunomodulatory activity of humanized and chimeric anti-CD25 monoclonal antibodies. Clinical and Experimental Immunology, 134 (3), 426–430, 10.1111/j.1365-2249.2003.02324.x
Klein, S.L., Flanagan, K.L. (2016), Sex differences in immune responses. Nat Rev Immunol 16: 626-638, 10.1038/nri.2016.90
Kuipers, K., Lokken, K.L., Zangari, T., et al. (2018), Age-related differences in IL-1 signaling and capsule serotype affect persistence of Streptococcus pneumoniae colonization. PLoS Pathog 14: e1007396, 10.1371/journal.ppat.1007396
Kullenberg, T., Lofqvist, M., Leinonen, M., et al. (2016), Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford) 55: 1499-1506, 10.1093/rheumatology/kew208
Labow, M., Shuster, D., Zetterstrom, M., et al. (1997), Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice. J Immunol 159: 2452-2461,
Lachmann, H.J., Kone-Paut, I., Kuemmerle-Deschner, J.B., et al. (2009), Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360: 2416-2425, 10.1056/NEJMoa0810787
Lee, K.L., Ambler, C.M., Anderson, D.R., et al. (2017), Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoli ne-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. J Med Chem 60: 5521-5542, 10.1021/acs.jmedchem.7b00231
Lequerre, T., Quartier, P., Rosellini, D., et al. (2008), Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 67: 302-308, 10.1136/ard.2007.076034
Matsunaga, N., Tsuchimori, N., Matsumoto, T., et al. (2011), TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol 79: 34-41, 10.1124/mol.110.068064
McGuire, V.A., Ruiz-Zorrilla Diez, T., Emmerich, C.H., et al. (2016), Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. Sci Rep 6: 31159, 10.1038/srep31159
Motsinger-Reif, A.A., Antas, P.R., Oki, N.O., et al. (2010), Polymorphisms in IL-1beta, vitamin D receptor Fok1, and Toll-like receptor 2 are associated with extrapulmonary tuberculosis. BMC Med Genet 11: 37, 10.1186/1471-2350-11-37
Mucke, H.A. (2012), Iguratimod: a new disease-modifying antirheumatic drug. Drugs Today (Barc) 48: 577-586, 10.1358/dot.2012.48.9.1855758
Newton, K., Dixit, V.M. (2012), Signaling in innate immunity and inflammation. Cold Spring Harb Perspect Biol 4, 10.1101/cshperspect.a006049
Peng, H., Guerau-de-Arellano, M., Mehta, V.B., et al. (2012), Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor kappaB (NF-kappaB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. J Biol Chem 287: 28017-28026, 10.1074/jbc.M112.383380
Pilkington, S.M., Ogden, S., Eaton, L.H., et al. (2018), Lower levels of interleukin-1beta gene expression are associated with impaired Langerhans' cell migration in aged human skin. Immunology 153: 60-70, 10.1111/imm.12810
Roell, M.K., Issafras, H., Bauer, R.J., et al. (2010), Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity. J Biol Chem 285: 20607-20614, 10.1074/jbc.M110.115790
Schlesinger, N., Alten, R.E., Bardin, T., et al. (2012), Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis 71: 1839-1848, 10.1136/annrheumdis-2011-200908
Seckinger, P., Kaufmann, M.T., Dayer, J.M. (1990), An interleukin 1 inhibitor affects both cell-associated interleukin 1-induced T cell proliferation and PGE2/collagenase production by human dermal fibroblasts and synovial cells. Immunobiology 180: 316-327, 10.1016/s0171-2985(11)80295-0
Sha, W.C., Liou, H.C., Tuomanen, E.I., et al. (1995), Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 80: 321-330,
Soares, M.P., Teixeira, L., Moita, L.F. (2017), Disease tolerance and immunity in host protection against infection. Nat Rev Immunol 17: 83-96, 10.1038/nri.2016.136
Suzuki, E., Umezawa, K. (2006), Inhibition of macrophage activation and phagocytosis by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin. Biomed Pharmacother 60: 578-586, 10.1016/j.biopha.2006.07.089
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, 10.4049/jimmunol.1500106
Vallabhapurapu, S., Karin, M. (2009), Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27: 693-733, 10.1146/annurev.immunol.021908.132641
Vincent, J.A., Mohr, S. (2007), Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes 56: 224-230, 10.2337/db06-0427
von Bernuth, H., Picard, C., Puel, A., et al. (2012), Experimental and natural infections in MyD88- and IRAK-4-deficient mice and humans. Eur J Immunol 42: 3126-3135, 10.1002/eji.201242683
Wang, F., Han, Y., Xi, S., et al. (2020), Catechins reduce inflammation in lipopolysaccharide-stimulated dental pulp cells by inhibiting activation of the NF-kappaB pathway. Oral Dis 26: 815-821, 10.1111/odi.13290
Wang, Y., Tang, Q., Duan, P., et al. (2018), Curcumin as a therapeutic agent for blocking NF-kappaB activation in ulcerative colitis. Immunopharmacol Immunotoxicol 40: 476-482, 10.1080/08923973.2018.1469145
Weber, A., Wasiliew, P., Kracht, M. (2010a), Interleukin-1 (IL-1) pathway. Sci Signal 3: cm1, 10.1126/scisignal.3105cm1
Weber, A., Wasiliew, P., Kracht, M. (2010b), Interleukin-1beta (IL-1beta) processing pathway. Sci Signal 3: cm2, 10.1126/scisignal.3105cm2
Wheeler, D.S., Catravas, J.D., Odoms, K., et al. (2004), Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1 beta-dependent proinflammatory signal transduction in cultured respiratory epithelial cells. J Nutr 134: 1039-1044, 10.1093/jn/134.5.1039
Wojtowicz, A., Gresnigt, M.S., Lecompte, T., et al. (2015), IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation. J Infect Dis 211: 1646-1657, 10.1093/infdis/jiu636
Xu, F., Wang, F., Wen, T., et al. (2017), Inhibition of NLRP3 inflammasome: a new protective mechanism of cinnamaldehyde in endotoxin poisoning of mice. Immunopharmacol Immunotoxicol 39: 296-304, 10.1080/08923973.2017.1355377
Yamada, H., Mizumo, S., Horai, R., et al. (2000), Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice. Lab Invest 80: 759-767
Yanagihara, Y., Kiniwa, M., Ikizawa K., Yamaya H., Shida, T., Matsuura, N., Koda A. (2013), Suppression of IgE Production by IPD-1151 T (Suplatast Tosilate), a New Dimethylsulfonium Agent: (1)Regulation of Murine IgE Response. The Japanese Journal of Pharmacology 61 (1): 23-30, 10.1254/jjp.61.23
Yang, Han, Z., Oppenheim, J.J. (2017), Alarmins and immunity. Immunol Rev 280: 41-56, 10.1111/imr.12577
Yokota, S., Imagawa, T., Nishikomori, R., et al. (2017), Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndrome: results from an open-label, phase III pivotal study in Japanese patients. Clin Exp Rheumatol 35 Suppl 108: 19-26,