API

Relationship: 1920

Title

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Impaired IL-1 signaling leads to Inhibition, Nuclear factor kappa B (NF-kB)

Upstream event

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Impaired IL-1 signaling

Downstream event

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Inhibition, Nuclear factor kappa B (NF-kB)

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI
Rattus norvegicus Rattus norvegicus High NCBI

Sex Applicability

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Sex Evidence
Mixed High

Life Stage Applicability

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Term Evidence
Not Otherwise Specified High

Key Event Relationship Description

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Impaired IL-1 signaling leads to suppression of NF-kB activation

Evidence Supporting this KER

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Biological Plausibility

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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-1RacP(Cavalli et al., 2015). Through conserved cytosolic regions called Toll- and IL-1R–like (TIR) domains (Radons et al., 2003), 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 (Brikos et al., 2007; Li et al., 2002). Mice lacking MYD88 or IRAK4 show severe defects in IL-1 signaling (Adachi et al., 1998; Medzhitov et al., 1998; Suzuki et al., 2002). Similarly, humans with mutations in the IRAK4 gene have defects in IL-1RI and Toll-like receptor (TLR) signaling (Picard et al., 2003). IL-1, IL-1RI, IL-RAcP, MYD88, and IRAK4 form a stable IL-1–induced first signaling module. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB.(Brikos et al., 2007), reviewed by (Weber et al., 2010).

Empirical Evidence

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Uncertainties and Inconsistencies

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Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent.  Again, age-dependent difference in IL-1 signaling is not known. 

The IL1B gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849).

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

References

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Adachi, O., Kawai, T., Takeda, K., Matsumoto, M., Tsutsui, H., Sakagami, M., Nakanishi, K., Akira, S., 1998. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143-150.

Brikos, C., Wait, R., Begum, S., O'Neill, L.A., Saklatvala, J., 2007. Mass spectrometric analysis of the endogenous type I interleukin-1 (IL-1) receptor signaling complex formed after IL-1 binding identifies IL-1RAcP, MyD88, and IRAK-4 as the stable components. Mol Cell Proteomics 6, 1551-1559.

Cavalli, G., Franchini, S., Aiello, P., Guglielmi, B., Berti, A., Campochiaro, C., Sabbadini, M.G., Baldissera, E., Dagna, L., 2015. Efficacy and safety of biological agents in adult-onset Still's disease. Scand J Rheumatol 44, 309-314.

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

Li, W.D., Ran, G.X., Teng, H.L., Lin, Z.B., 2002. Dynamic effects of leflunomide on IL-1, IL-6, and TNF-alpha activity produced from peritoneal macrophages in adjuvant arthritis rats. Acta Pharmacol Sin 23, 752-756.

Medzhitov, R., Preston-Hurlburt, P., Kopp, E., Stadlen, A., Chen, C., Ghosh, S., Janeway, C.A., Jr., 1998. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 2, 253-258.

Picard, C., Puel, A., Bonnet, M., Ku, C.L., Bustamante, J., Yang, K., Soudais, C., Dupuis, S., Feinberg, J., Fieschi, C., Elbim, C., Hitchcock, R., Lammas, D., Davies, G., Al-Ghonaium, A., Al-Rayes, H., Al-Jumaah, S., Al-Hajjar, S., Al-Mohsen, I.Z., Frayha, H.H., Rucker, R., Hawn, T.R., Aderem, A., Tufenkeji, H., Haraguchi, S., Day, N.K., Good, R.A., Gougerot-Pocidalo, M.A., Ozinsky, A., Casanova, J.L., 2003. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299, 2076-2079.

Radons, J., Dove, S., Neumann, D., Altmann, R., Botzki, A., Martin, M.U., Falk, W., 2003. The interleukin 1 (IL-1) receptor accessory protein Toll/IL-1 receptor domain: analysis of putative interaction sites in vitro mutagenesis and molecular modeling. J Biol Chem 278, 49145-49153.

Suzuki, N., Suzuki, S., Duncan, G.S., Millar, D.G., Wada, T., Mirtsos, C., Takada, H., Wakeham, A., Itie, A., Li, S., Penninger, J.M., Wesche, H., Ohashi, P.S., Mak, T.W., Yeh, W.C., 2002. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416, 750-756.

Weber, A., Wasiliew, P., Kracht, M., 2010. Interleukin-1 (IL-1) pathway. Sci Signal 3, cm1