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Event: 1700
Key Event Title
Impaired IL-1R1 signaling
Short name
Biological Context
Level of Biological Organization |
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Molecular |
Cell term
Cell term |
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macrophage |
Organ term
Organ term |
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immune system |
Key Event Components
Process | Object | Action |
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Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
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IL-1 inhibition | MolecularInitiatingEvent | Yutaka Kimura (send email) | Open for citation & comment | EAGMST Under Review |
Stressors
Taxonomic Applicability
Life Stages
Life stage | Evidence |
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All life stages | High |
Sex Applicability
Term | Evidence |
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Unspecific | High |
Key Event Description
- 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 PRPs 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 PRPs, the signaling through TLR4 is best characterized. In addition, it is beyond the scope of this AOP to cover all signaling through each PRP. 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). 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 (Mucke, 2012). Epigalocathechin gallate (EGCG) has been reported to inhibit NF-κB activation through inhibition of p65 phosphorylation (Wheeler et al., 2004).
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-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 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).
- 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 (anti-IL-1β antibody) (Church and McDermott, 2009).
How It Is Measured or Detected
- Real time polymerase chain reaction to measure IL-1a or IL-1b mRNA
- Enzyme-linked immunosorbent assay (ELISA) to detect IL-1a or IL-1 b protein
- Competitive inhibition binding experiments using 125I-IL-1 a 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).
- Measure the ability of the reagent to neutralize the bioactivity of human IL-1β on primary human fibroblasts in vitro(Alten et al., 2008)
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. 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.
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 -7M) 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).
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-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).
Various IRAK4 inhibitors are currently under the investigation on the possibility of clinical use for autoimmune disorders (Chaudhary et al., 2015).
References
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