AOP ID and Title:

Short Title: IL-1 inhibition

Authors

Yutaka Kimura (1) Setsuya Aiba (1) 

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

Corresponding author: Setsuya Aiba

Status

Abstract

The pleiotropic cytokine IL-1 mediates its biological functions via association with the signaling receptor IL-1R1. These may include initiation of innate immunity as well as acquired immunity, which are essential for assistance of host defense against infection. The trimeric complex consists of IL-1, IL-1R1 and IL-1R3 (a coreceptor, formerly IL-1R accessory protein) allows for the approximation of the Toll-IL-1-Receptor (TIR) domains of each receptor chain. MyD88 then binds to the TIR domains. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB. The activation of NF-κB plays a principal role in the immunological function of IL-1. Namely, it stimulates innate immunity such as activation of dendritic cells and macrophages. It also stimulates T cells via activated dendritic function or directly. The activation of T cells is crucial for B cell proliferation and their antibody production. The cooperation by T cells and B cells constitutes a main part of host defense against infection. Therefore, the impaired IL-1R1 signaling either by the decreased IL-1 production or the inhibition of IL-1β binding to IL-1R1 by IL-1 receptor antagonist（IL-1Ra）or anti-IL-1β antibody) results in the blockade of the effects of the pleiotropic cytokine IL-1β leading to increased susceptibility to infection.

 

In this AOP, we selected the impaired IL-1R signaling as a molecular initiating event (MIE), and suppression of NF-κB, suppression of T cell activation, and increased susceptibility to infection as key events (KE).

Background

The pleiotropic cytokine IL-1 mediates its biological functions via association with the signaling receptor IL-1R1. These may include initiation of innate immunity and assistance of host defense against infection, and sometimes, mediation of autoinflammatory, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. The trimeric complex consists of IL-1, IL-1R1 and IL-1R3 (a coreceptor, formerly IL-1R accessory protein) allows for the approximation of the Toll-IL-1-Receptor (TIR) domains of each receptor chain. MyD88 then binds to the TIR domains. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB and fundamental inflammatory responses such as the induction of cyclooxygenase type 2, production of multiple cytokines and chemokines, increased expression of adhesion molecules, or synthesis of nitric oxide. (Dinarello, 2018; Weber et al., 2010a, b). 

 

Molecules like nuclear or mitochondrial DNA, adenosine triphosphate (ATP), uridine triphosphate (UTP), uric acid and high mobility group box 1 (HMGB1) are classified as damage associated molecular patterns (DAMPs). DAMPs are secreted or produced upon cellular injury or death and induce sterile inflammation. On the other hand, bacterial products like lipopolysaccharide (LPS), peptidoglycans, lipoprotein flagellins, bacterial RNA and DNA are some of the well-characterized pathogen associated molecular patterns (PAMPs). These DAMPs and PAMPs with a few exceptions bind to pattern recognition receptors (PRRs) such as toll-like receptor (TLRs) and nucleotide oligomerization domain (NOD) like receptors (NLRs). Proinflammatory mediators such as DAMPs, PAMPs, and various inflammatory cytokines or mediators including IL-1β itself activate innate immune mechanisms in the host leading to IL-1β production (Handa et al., 2016; Newton and Dixit, 2012; Yang et al., 2017). Besides transcriptional regulation and posttranscriptional level by RNA-binding proteins, pro-IL-1β protein requires proteolytic cleavage by active caspase-1 as the effector component of stimulation-induced multi-protein inflammasomes to acquire functional activity. Altogether, these different layers of regulation allow to fine tune IL-1β production under different pathophysiological conditions (Bent et al., 2018).

 

Therefore, the inhibition of various targets in different layers from the stimulation of PRRs or the receptors of proinflammatory cytokines, e.g., IL-1, IL-18, or TNFa, to the activation of NF-κB or the inhibition of posttranscriptional regulation of pro-IL-1β cause impaired IL-1R1 signaling. In addition, since IL-1 also mediates autoinflammatory syndromes, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever, several inhibitors against IL-1R1 have been developed. They are IL-1 receptor antagonist（IL-1Ra）, anakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R). Several reports described that the administration of these drugs led to increased susceptibility to infection(De Benedetti et al., 2018; Fleischmann et al., 2003; Genovese et al., 2004; Imagawa et al., 2013; Kullenberg et al., 2016; Lachmann et al., 2009; Lequerre et al., 2008; Migkos et al., 2015; Schlesinger et al., 2012; Yokota et al., 2017). In addition to these human data, the experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection(Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000).

Summary of the AOP

Events

Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)

Key Event Relationships

Stressors

Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability Taxonomic Applicability Sex 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)

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, 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; Migkos et al., 2015). As IL-1 signaling antagonists, two drugs went up to the market, canakinumab (anti-IL-1b antibody) and rilonacept (soluble IL-1R). Several reports described that the administration of these drugs led to increased susceptibility to infection (De Benedetti et al., 2018; Imagawa et al., 2013; Lachmann et al., 2009; Schlesinger et al., 2012).

In a similar way, defect of MyD88 signaling caused by knockout of mice gene or deficiency in human patient leads to the increased susceptibility to bacterial or tuberculosis infection (von Bernuth et al., 2012).

Mice lacking NF-kB p50 are unable effectively to clear L. monocytogenes and are more susceptible to infection with S. peumoniae (Sha et al., 1995).

Weight of Evidence Summary

The recent review of IL-1 pathway by Weber et al. 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 et al., 1990), IL-6 (Goh et al., 2014), and T cell proliferation (Seckinger et al., 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; 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, 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 et al., 2010a, b)

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

In T lineage cells, the temporal regulation of NF-κB controls the stepwise differentiation and antigen-dependent selection of conventional and specialized subsets of T cells in response to T cell receptor and costimulatory, cytokines and growth factor signals. Cytokines include cytokines produced from macrophage or monocyte such as IL-1β. (Gerondakis et al., 2014)

Suppression of T cell activation leads to Increase, Increased susceptibility to infection

First type immunity drives resistance to viruses and intracellular bacteria, such as Listeria monocytogenes, Salmonella spp. and Mycobacteria spp., as well as to intracellular protozoan parasites such as Leishmania spp. The T helper 1 signature cytokine interferon-γ has a central role in triggering cytotoxic mechanisms including macrophage polarization towards an antimicrobial response associated with the production of high levels of reactive oxygen species and reactive nitrogen species, activation of CD8 cytotoxic T lymphocytes and natural killer cells to kill infected cells via the perforin and/or granzyme B-dependent lytic pathway or via the ligation of surface death receptors; and B cell activation towards the production of cytolytic antibodies that target infected cells for complement and Fc receptor-mediated cellular cytotoxicity.

Resistance to extracellular metazoan parasites and other large parasites is mediated and/or involves second type immunity. Pathogen neutralization is achieved via different mechanisms controlled by T 2 signature cytokines, including interleukin-4, IL-5 and IL-13, and by additional type 2 cytokines such as thymic stromal lymphopoietin, IL-25 or IL-33, secreted by damaged cell. T 2 signature cytokines drive B cell activation towards the production of high-affinity pathogen-specific IgG1 and IgE antibodies that function via Fc-dependent mechanisms to trigger the activation of eosinophils, mast cells and basophils, expelling pathogens across epithelia.

T17 immunity confers resistance to extracellular bacteria such as Klebsiella pneumoniae, Escherichia coli, Citrobacter rodentium, Bordetella pertussis, Porphyromonas gingivalis and Streptococcus pneumoniae, and also to fungi such as Candida albicans, Coccidioides posadasii, Histoplasma capsulatum and Blastomyces dermatitidis. Activation of T 17 cells by cognate T cell receptor (TCR–MHC class II interactions and activation of group 3 innate lymphoid cells (ILC3s) via engagement of IL-1 receptor (IL-1R) by IL-1β secreted from damaged cells lead to the recruitment and activation of neutrophils. T 17 immunopathology is driven to a large extent by products of neutrophil activation, such as ROS and elastase (reviewed by Soares et al. (Soares et al., 2017).

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

Empirical support

1. Impaired IL-1R signaling.

Decreased production of IL-1 or inhibition of the binding of IL-1 to IL-1R impair IL-1R signaling.

1-1. 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). The list of representative chemicals and their mechanism to inhibit NF-κB is shown in Table 1. 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-1β (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-1β (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-1β (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-1β 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; Migkos et al., 2015; Schlesinger et al., 2012; Yokota et al., 2017).

1-3. IL-1 deficient mice

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, Jin and Dubin, 2017; Yamada et al., 2000). Moreover, polymorphism of IL-1β 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). RelB deficient mice had an impaired cellular immunity, as observed in contact sensitivity reaction (Weih et al., 1995).

 

Quantitative Consideration

IL-1Ra blocks IL-1 signaling:

IL-lra alone at concentrations as high as 1 mg/mL did not induce IL-la, IL-lβ, TNFa, or IL-6 synthesis. Suppression of IL-1-induced IL-1, TNFa, or IL-6 synthesis was dose-dependent (P ≦ .0001). At a twofold molar excess, IL-lra inhibited IL-1-induced IL-1 or TNFa synthesis by 50% (P < .01); an equimolar concentration of IL-lra inhibited synthesis of these two cytokines by over 20% (P < .05). A 10-fold molar excess of IL-lra over IL-lβ reduced IL-lβ-induced IL-la by 95% (P = .01) and IL-la-induced IL-1β by 73% (P < .01). In elutriated monocytes, a 10-fold molar excess of IL-lra reduced IL-lβ-induced IL-la by 82% (P < .05), TNFa by 64% (P = .05), and IL-6 by 47% (P < .05). (Granowitz et al., 1992)

Canakinumab (ACZ885, Ilaris):

The antibody binds to human IL-1β with high affinity (about 40 pmol/l). The antibody was found to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro 44.6 pmol/l (7.1 ± 0.56 ng/ml; n = 6) of ED50. Application of Canakinumab intraperitoneally 2 hours before injecting the IL-1β producing cells completely suppressed joint swelling (0.06 mg/kg of EC50) (Alten et al., 2008).

Primary human fibroblasts are stimulated with recombinant IL-1b or conditioned medium obtained from LPS-stimulated human PBMCs in the presence of various concentrations of Cankinumab or IL-1RA ranging from 6 to 18,000 pM. Supernatant is taken after 16 h stimulation and assayed for IL-6 by ELISA. Canakinumab typically have 1 nM or less of EC50 for inhibition of IL-6 production (Canakinumab Patent Application WO02/16436.)

Rilonacept (IL-1 Trap, Arcalyst):

Incubation of the human MRC5 fibroblastic cell line with IL-1β induces secretion of IL-6. At a constant amount of IL-1β (4 pM), the IC50 of the IL-1 trap is ∼2 pM. Another unique property of the IL-1 trap is that it not only blocks IL-1β, but also blocks IL-1α with high affinity (KD = ∼3 pM; data not shown). The titration curve of IL-1 trap in the presence of 10 pM IL-1β shows an IC50 of 6.5 pM, which corresponds to a calculated KD of 1.5 pM (This affinity is 100 times higher than that of the soluble single component receptor IL-1RI (Economides et al., 2003).

Considerations for Potential Applications of the AOP (optional)

The impaired IL-1 signaling can lead to decreased host resistance to various infections. Therefore, the test guideline to detect chemicals that decrease IL-1 signaling is required to support regulatory decision-making. This AOP can promote the understanding of the usefulness of the test guideline.

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Appendix 1

List of MIEs in this AOP

Event: 1700: Impaired IL-1R1 signaling

Short Name: Impaired IL-1R1 signaling

AOPs Including This Key Event

Stressors

Biological Context

Cell term

Organ term

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-κB/Rel and AP-1 activation (Jeon et al., 2000).

Dex suppresses LPS-induced gene expression of IL-1β in rat lung. (in vivo) (Qiu et al., 1997)

Dex inhibits the release of IL-1β by human leukocyte stimulated with Streptococcus pneumoniae stimulation (van Furth et al., 1995).

Treatment of peripheral blood monocytes with 2 mg/ml LPS potently increased IL-1β release (p= 0.001) and Dex (10 ^-7 M) significantly reduced both resting and stimulated IL-1β release (p 0.009).) (Morand et al., 1993)

Dex effectively blocks the glutamine antagonist acivicin-induced expression of IL-1β mRNA by HL-60 leukemia cells (Weinberg et al., 1992)

Various inhibitors for NF‐κB, such as dimethyl fumarate, curcumin, iguratimod, epigalocathechin gallate (EGCG), DHMEQ inhibits lLPS-induced NF-κB activation and LPS-induced secretion of IL-1β (McGuire et al., 2016; Peng et al., 2012) (Wang et al., 2018) (Mucke, 2012)(Wheeler et al., 2004)(Wang et al., 2020) (Suzuki and Umezawa, 2006) (Suzuki and Umezawa, 2006).

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.

LPS treatment induced a significant upregulation of the mRNA and release of IL-1β from retinal microglia. Minocycline inhibited its releases. Thus, minocycline might exert its antiinflammatory effect on microglia by inhibiting the expression and release of IL-1β (Wang et al., 2005).

Caspase-1 inhibition reduced the release of IL-1β in organotypic slices exposed to LPS+ATP. Administration of pralnacasan (intracerebroventricular, 50 μg) or belnacasan (intraperitoneal, 25–200 mg/kg) to rats blocked seizure-induced production of IL-1β in the hippocampus, and resulted in a twofold delay in seizure onset and 50% reduction in seizure duration (Ravizza et al., 2006).

Belnacasan, an orally active IL-1β converting enzyme/caspase-1 inhibitor, blocked IL-1β secretion with equal potency in LPS-stimulated cells from familial cold urticarial associated symdrome and control subjects (Stack et al., 2005).

In LPS-induced acute lung injury (ALI) mice model, LPS induced inflammatory cytokines such as TNF-α, IL-6, IL-13 and IL-1β were significantly decreased by cinnamaldehyde (CA) (Huang and Wang, 2017).

The suppressing capacities of six cinnamaldehyde-related compounds were evaluated and compared by using the LPS-primed and ATP-activated macrophages. At concentrations of 25~100 mM, cinnamaldehyde and 2-methoxy cinnamaldehyde dose-dependently inhibited IL-1β secretion (Ho et al., 2018).

In vitro, CA decreased the levels of pro-IL-1β and IL-1β in cell culture supernatants, as well as the expression of NLRP3 and IL-1β mRNA in cells. In vivo, CA decreased IL-1β production in serum. Furthermore, CA suppressed LPS-induced NLRP3, p20, Pro-IL-1β, P2X7 receptor (P2X7R) and cathepsin B protein expression in lung, as well as the expression of NLRP3 and IL-1β mRNA (Xu et al., 2017).

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).

IL-1 is known to mediates autoinflammatory syndrome, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. Blocking of binding of IL-1 to IL-1R1 by anakinra, canakinumab, and rilonacept have been already used to treat these autoinflammatory syndrome associated with overactivation of IL-1 signaling (Quartier, 2011).

Domain of Applicability

Taxonomic Applicability Life Stage Applicability Sex 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. 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).

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

Key Event Description

1. 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 lto the activation of NF-κB or the inhibition of posttranscriptional regulation of pro-IL-1β cause impaired IL-1R1 signaling. Among various PRRs, the signaling through TLR4 is best characterized. In addition, it is beyond the scope of this AOP to cover all signaling through each PRR. So, this AOP focuses on TLR4 signaling.

 

Binding of LPS to TLR4 and the coreceptor MD2 triggers interactions between the cytoplasmic TIR domain of TLR4 and TIR-containing adaptor proteins (Mal, MyD88, and TRAM). MyD88 binds IRAK4, which requires its kinase activity to bind the kinases IRAK1 and IRAK2 sequentially. The MyD88–IRAK complex also engages the ubiquitin ligase TRAF6 to make polyubiquitin chains that activate the IKK complex for NF-kB- and ERK-dependent gene transcription. Ubiquitin ligases cIAP1 and cIAP2 recruited to the TLR4 signaling complex regulate translocation of a subset of signaling components to the cytoplasm, where TAK1 activation initiates a MAPK cascade, p38a and JNK, which stimulates gene expression. TLR4 activated at the plasma membrane is endocytosed but can signal within the endosomal compartment via the adaptors TRAM and TRIF. The kinase and ubiquitin ligase combination of RIP1 and Peli1 interacts with TRIF to signal NF-kB activation, whereas TBK1 and TRAF3 stimulate IRF3-dependent transcription. Through these signaling cascades, NF‑κB, activator protein-1 (AP-1), cAMP responsive element binding protein (CREB)/ activating transcription factor (ATF), CCAAT-enhancer-binding protein b (c/EBP b), and interferon regulatory factor 3 (IRF3) are activated. These transcription factors induce the expression of various inflammatory cytokines e.g., IL-1β, TNFα, IL-6 and several chemokines (reviewed by Newton and Dixit (Newton and Dixit, 2012)).

Therefore, chemicals that affect the signaling pathway leading to the activation of these transcription factors are supposed to suppress IL-1β production. Among them, the chemical substances that affect NF-κB signaling have been investigated most thoroughly. 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-1β (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-1β (Wang et al., 2020). DHMEQ inhibits lLPS-induced NF-κB activation by inhibiting its nuclear translocation from the cytoplasm. It also inhibits LPS-induced secretion of IL-1β (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.

Beside transcriptional regulation of IL-1β 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 et al., 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 cinnamicaldehyde suppresses serum IL-1β level in endotoxin poisoning mice (Xu et al., 2017).

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).

How it is Measured or Detected

1. Real time polymerase chain reaction to measure IL-1α or IL-1β mRNA
2. Enzyme-linked immunosorbent assay (ELISA) to detect IL-1α or IL-1 b protein
3. Competitive inhibition binding experiments using ¹²⁵I-IL-1α to type I IL-1R present on EL4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R (McIntyre et al., 1991; Shuck et al., 1991).
4. Measure the ability of the reagent to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro(Alten et al., 2008)

References

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Huang, H., Wang, Y., 2017. The protective effect of cinnamaldehyde on lipopolysaccharide induced acute lung injury in mice. Cell Mol Biol (Noisy-le-grand) 63, 58-63.

Jeon, Y.J., Han, S.H., Lee, Y.W., et al., 2000. Dexamethasone inhibits IL-1 beta gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-kappa B/Rel and AP-1 activation. Immunopharmacology 48, 173-183.

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.

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

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.

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.

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.

McIntyre, K.W., Stepan, G.J., Kolinsky, K.D., et al., 1991. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med 173, 931-939.

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Mucke, H.A., 2012. Iguratimod: a new disease-modifying antirheumatic drug. Drugs Today (Barc) 48, 577-586.

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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.

Qiu, H.B., Pan, J.Q., Zhao, Y.Q., et al., 1997. Effects of dexamethasone and ibuprofen on LPS-induced gene expression of TNF alpha, IL-1 beta, and MIP-1 alpha in rat lung. Zhongguo Yao Li Xue Bao 18, 165-168.

Quartier, P., 2011. Interleukin-1 antagonists in the treatment of autoinflammatory syndromes, including cryopyrin-associated periodic syndrome. Open Access Rheumatol 3, 9-18.

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Stack, J.H., Beaumont, K., Larsen, P.D., et al., 2005. IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol 175, 2630-2634.

Suzuki, E., Umezawa, K., 2006. Inhibition of macrophage activation and phagocytosis by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin. Biomed Pharmacother 60, 578-586.

Vallabhapurapu, S., Karin, M., 2009. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27, 693-733.

van Furth, A.M., Seijmonsbergen, E.M., Langermans, J.A., et al., 1995. Effect of xanthine derivates and dexamethasone on Streptococcus pneumoniae-stimulated production of tumor necrosis factor alpha, interleukin-1 beta (IL-1 beta), and IL-10 by human leukocytes. Clin Diagn Lab Immunol 2, 689-692.

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.

Wang, A.L., Yu, A.C., Lau, L.T., et al., 2005. Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47, 152-158.

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.

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.

Weinberg, J.B., Mason, S.N., Wortham, T.S., 1992. Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by pentoxifylline and dexamethasone: dissociation of acivicin-induced TNF-alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid differentiation. Blood 79, 3337-3343.

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.

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.

 

List of Key Events in the AOP

Event: 202: Inhibition, Nuclear factor kappa B (NF-kB)

Short Name: Inhibition, Nuclear factor kappa B (NF-kB)

Key Event Component

AOPs Including This Key Event

Stressors

Biological Context

Cell term

Organ term

Domain of Applicability

Taxonomic Applicability Life Stage Applicability Sex Applicability

The binding of sex steroids to their respective steroid receptors directly influences NF-κB signaling, resulting in differential production of cytokines and chemokines (McKay and Cidlowski, 1999; Pernis, 2007). 17b-estradiol regulates pro-inflammatory responses that are transcriptionally mediated by NF‑κB through a negative feedback and/or transrepressive interaction with NF-κB (Straub, 2007). Progesterone suppresses innate immune responses and NF-κB signal transduction reviewed by Klein et al. (Klein and Flanagan, 2016). Androgen-receptor signaling antagonises transcriptional factors NF-κB(McKay and Cidlowski, 1999).

Evidence for perturbation of this molecular initiating event by stressor

Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-κB/Rel and AP-1 activation (Jeon et al., 2000).

Various inhibitors for NF‐κB, such as dimethyl fumarate, curcumin, iguratimod, epigalocathechin gallate (EGCG), and DHMEQ inhibits lLPS-induced NF-κB activation and LPS-induced secretion of IL-1β (McGuire et al., 2016; Mucke, 2012; Peng et al., 2012; Suzuki and Umezawa, 2006; Wang et al., 2020; Wang et al., 2018; Wheeler et al., 2004).

TAK-242 (Matsunaga et al., 2011) inhibit TLR4 itself. There are several IRAK4 inhibitors (Lee et al., 2017). These molecules block the upstream signal to NF‐κB activation. IRAK4 has recently attracted attention as a therapeutic target for inflammation and tumor diseases (Chaudhary et al., 2015).

LPS treatment induced a significant upregulation of the mRNA and release of IL-1β from retinal microglia. Minocycline inhibited its releases. Thus, minocycline might exert its antiinflammatory effect on microglia by inhibiting the expression and release of IL-1β (Wang et al., 2005).

Caspase-1 inhibition reduced the release of IL-1β in organotypic slices exposed to LPS+ATP. Administration of pralnacasan (intracerebroventricular, 50 μg) or belnacasan (intraperitoneal, 25–200 mg/kg) to rats blocked seizure-induced production of IL-1β in the hippocampus, and resulted in a twofold delay in seizure onset and 50% reduction in seizure duration (Ravizza et al., 2006).

Belnacasan, an orally active IL-1β converting enzyme/caspase-1 inhibitor, blocked IL-1β secretion with equal potency in LPS-stimulated cells from familial cold urticarial associated symdrome and control subjects (Stack et al., 2005).

In LPS-induced acute lung injury (ALI) mice model, LPS induced inflammatory cytokines such as TNF-α, IL-6, IL-13 and IL-1β were significantly decreased by cinnamaldehyde (CA) (Huang and Wang, 2017).

The suppressing capacities of six cinnamaldehyde-related compounds were evaluated and compared by using the LPS-primed and ATP-activated macrophages. At concentrations of 25~100 mM, cinnamaldehyde and 2-methoxy cinnamaldehyde dose-dependently inhibited IL-1β secretion (Ho et al., 2018).

In vitro, CA decreased the levels of pro-IL-1β and IL-1β in cell culture supernatants, as well as the expression of NLRP3 and IL-1β mRNA in cells. In vivo, CA decreased IL-1β production in serum. Furthermore, CA suppressed LPS-induced NLRP3, p20, Pro-IL-1β, P2X7 receptor (P2X7R) and cathepsin B protein expression in lung, as well as the expression of NLRP3 and IL-1β mRNA (Xu et al., 2017).

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).

IL-1 is known to mediates autoinflammatory syndrome, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. Blocking of binding of IL-1 to IL-1R1 by anakinra, canakinumab, and rilonacept have been already used to treat these autoinflammatory syndrome associated with overactivation of IL-1 signaling (Quartier, 2011).

Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF‐κB/Rel and AP-1 activation (Jeon et al., 2000).

Inhibition of IL-1 binding to IL-1R or the decreased production of IL-1b leads to the suppression of IL-1R signaling leading to NF‐κB activation.

Key Event Description

The NF-κB pathway consists of a series of events where the transcription factors of the NF-κB family play the key role. The canonical NF-κB pathway can be activated by a range of stimuli, including TNF receptor activation by TNF-a. Upon pathway activation, the IKK complex will be phosphorylated, which in turn phosphorylates IkBa. This NF-κB inhibitor will be K48-linked ubiquitinated and degradated, allowing NF-κB to translocate to the nucleus. There, this transcription factor can express pro-inflammatory and anti-apoptotic genes. Furthermore, negative feedback genes are also transcribed and include IkBa and A20. When the NF-κB pathway is inhibited, its translocation will be delayed (or absent), resulting in less or no regulation of NF-κB target genes. This can be achieved by IKK inhibitors, proteasome inhibitors, nuclear translocation inhibitors or DNA-binding inhibitors (Gupta et al., 2010; Liu et al., 2017). Therefore, inhibition of IL-1R activation suppresses NF-κB.

How it is Measured or Detected

NF-κB transcriptional activity: Beta lactamase reporter gene assay (Miller et al. 2010)

NF-κB transcription: Lentiviral NF-κBGFP reporter with flow cytometry (Moujalled et al. 2012)

IκBα phosphorylation: Western blotting (Miller et al. 2010)

NF-κB p65 (Total/Phospho) ELISA：

ELISA for IL-6, IL-8, and Cox

References

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,

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,

Gupta, S.C., Sundaram, C., Reuter, S., et al. (2010), Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta 1799: 775-787, 10.1016/j.bbagrm.2010.05.004

Ho, S.C., Chang, Y.H., Chang, K.S. (2018), Structural Moieties Required for Cinnamaldehyde-Related Compounds to Inhibit Canonical IL-1beta Secretion. Molecules 23, 10.3390/molecules23123241

Huang, H., Wang, Y. (2017), The protective effect of cinnamaldehyde on lipopolysaccharide induced acute lung injury in mice. Cell Mol Biol (Noisy-le-grand) 63: 58-63, 10.14715/cmb/2017.63.8.13

Jeon, Y.J., Han, S.H., Lee, Y.W., et al. (2000), Dexamethasone inhibits IL-1 beta gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-kappa B/Rel and AP-1 activation. Immunopharmacology 48: 173-183,

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,

Klein, S.L., Flanagan, K.L. (2016), Sex differences in immune responses. Nat Rev Immunol 16: 626-638, 10.1038/nri.2016.90

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

Liu, T., Zhang, L., Joo, D., et al. (2017), NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2, 10.1038/sigtrans.2017.23

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

McKay, L.I., Cidlowski, J.A. (1999), Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev 20: 435-459, 10.1210/edrv.20.4.0375

Mucke, H.A. (2012), Iguratimod: a new disease-modifying antirheumatic drug. Drugs Today (Barc) 48: 577-586, 10.1358/dot.2012.48.9.1855758

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

Pernis, A.B. (2007), Estrogen and CD4+ T cells. Curr Opin Rheumatol 19: 414-420, 10.1097/BOR.0b013e328277ef2a

Quartier, P. (2011), Interleukin-1 antagonists in the treatment of autoinflammatory syndromes, including cryopyrin-associated periodic syndrome. Open Access Rheumatol 3: 9-18, 10.2147/oarrr.S6696

Ravizza, T., Lucas, S.M., Balosso, S., et al. (2006), Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47: 1160-1168, 10.1111/j.1528-1167.2006.00590.x

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

Stack, J.H., Beaumont, K., Larsen, P.D., et al. (2005), IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol 175: 2630-2634,

Straub, R.H. (2007), The complex role of estrogens in inflammation. Endocr Rev 28: 521-574, 10.1210/er.2007-0001

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

Wang, A.L., Yu, A.C., Lau, L.T., et al. (2005), Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47: 152-158, 10.1016/j.neuint.2005.04.018

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

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

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

 

Event: 1702: Suppression of T cell activation

Short Name: Suppression of T cell activation

AOPs Including This Key Event

Biological Context

Cell term

Organ term

Domain of Applicability

Taxonomic Applicability Life Stage Applicability Sex Applicability

Key Event Description

T cells are key orchestrators of the response against pathogens and are also fundamental in maintaining self-tolerance. A number of clinically important conditions have been described in which T-cell functions are altered, as in AIDS or upon immunosuppression after application of various immunosuppressive drugs to treat autoimmune disorders or allogeneic graft rejection. T-cell progenitors differentiate in the thymus into immature T cells that acquire the expression of the T-cell receptor (TCR), which recognizes antigen peptides from pathogens presented along with major histocompatibility complex (MHC). In addition to the TCR, T cells are characterized by expression of the co-receptor molecules CD4 and CD8 on their cell surface. CD4+ T cells, also called T helper (Th) cells, recognize antigen/MHC-II complexes on antigen presenting cells (APCs) and coordinate the activation of other immune cells including B cells, macrophages, etc.

Therefore, CD4+ T cells are crucial for coordination of the immune response and for the elimination of invading pathogens. On the other hand, CD8+ T cells, referred to as T cytotoxic cells, recognize antigen/MHC-I complexes and are responsible for the killing of pathogen-infected cells.

T-cell activation and differentiation depends on antigen presenting cells (APCs) such as dendritic cells (DCs), macrophages and B cells. depending on the insult affecting a given tissue. Different subsets of DCs can be generated that in turn are able to coordinate the differentiation of a particular Th subset. To date, the following Th subsets have been described: Th1, Th2, Th9, Th17, Th22, Tfh (follicular helper T cells), Tr1 (type 1regulatory T cells) and Treg (regulatory T cells), each possessing a specific function in the elimination of pathogens. (reviewed by Simeoni et al. (Simeoni et al., 2016))

Although CD4 T cells are able to commit to Th1, Th2 and Th17 lineages in the absence of IL-1R signaling at steady state, these committed CD4 T cells are unable to effectively secrete their cytokines upon TCR ligation. Namely, IL-1 is indispensable for CD4 T cell effector function. (Lin et al, 2015)

Moreover, since full activation of B cells and antibody production and class switch depends on T cell help. The impaired activation of T cells leads to impaired B cell activation and antibody production (reviewed by Mok (Mok, 2010)).

How it is Measured or Detected

T cell activation can be evaluated by measuring IL-2 production by ELISA or T cell proliferation by incorporation of the analysis of CFSE labeled T cells or [³H]thymidine incorporation.

References

Lin, D., Lei, L., Zhang, Y., et al. (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, 10.1002/eji.201445195

Mok, M.Y. (2010), The immunological basis of B-cell therapy in systemic lupus erythematosus. Int J Rheum Dis 13: 3-11, 10.1111/j.1756-185X.2009.01458.x

Simeoni, L., Thurm, C., Kritikos, A., et al. (2016), Redox homeostasis, T cells and kidney diseases: three faces in the dark. Clin Kidney J 9: 1-10, 10.1093/ckj/sfv135

Weih, F., Carrasco, D., Durham, S.K., et al. (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,

List of Adverse Outcomes in this AOP

Event: 986: Increase, Increased susceptibility to infection

Short Name: Increase, Increased susceptibility to infection

AOPs Including This Key Event

Stressors

Biological Context

Domain of Applicability

Taxonomic Applicability Life Stage Applicability Sex Applicability

The increased susceptibility to infection caused by IL-1RA or anti-IL-1 antibody has been reported in both humans and mice(De Benedetti et al., 2018; Fleischmann et al., 2003).

Key Event Description

 Severe combined immunodeficiencies (SCIDs) comprise a group of rare, monogenic diseases that are characterized by an early onset and a profound block in the development of T lymphocytes. Given that adaptive immunity is abrogated, patients with SCID are prone to recurrent infections caused by both non-opportunistic and opportunistic pathogens, leading to early death unless immunity can be restored　（reviewed by Fischer et al. (Fischer et al., 2015)）. Human immunodeficiency virus (HIV) is a retrovirus known to attack the CD4+ T lymphocytes. In individuals with chronic HIV infection not on treatment with antiretroviral agents, as the CD4+ count drops they are vulnerable to a multitude of infections which rarely occur in an immunocompetent host, hence the term opportunistic infections (Justiz Vaillant and Naik, 2021). Various immunosuppressive agents such as corticosteroids, antimetabolites, calcineurin inhibitors, glucocorticoids, antithymocyte globulin, antibodies against IL-2RA or CD28, which all suppress T cell function, increase the incidence of opportunistic infection (reviewed by Tasdogan et al. (Tasdogan et al., 2019).

How it is Measured or Detected

By comparison of the incidence of infection between individuals exposed to stressors and non-exposed individuals.

Regulatory Significance of the AO

Increased susceptibility to infection is the significant adverse outcome of drugs and chemicals present in the environment. Therefore, drugs or chemicals that have an effect that can cause immunosuppression must be under regulatory scrutiny.

References

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

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

Fischer, A., Notarangelo, L.D., Neven, B., et al. (2015), Severe combined immunodeficiencies and related disorders. Nat Rev Dis Primers 1: 15061, 10.1038/nrdp.2015.61

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

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

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

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,

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

Justiz Vaillant, A.A., Naik, R. 2021. HIV-1 Associated Opportunistic Infections, StatPearls. StatPearls Publishing

Copyright © 2021, StatPearls Publishing LLC., Treasure Island (FL).

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

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

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

Migkos, M.P., Somarakis, G.A., Markatseli, T.E., et al. (2015), Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra. Clin Exp Rheumatol 33: 734-736,

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

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

Tasdogan, B.E., Ma, M., Simsek, C., et al. (2019), Update on Immunosuppression in Liver Transplantation. Euroasian J Hepatogastroenterol 9: 96-101, 10.5005/jp-journals-10018-1301

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

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

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,

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,

Appendix 2

List of Key Event Relationships in the AOP