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Impaired IL-1 signaling leads to Inhibition, Nuclear factor kappa B (NF-kB)
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|Not Otherwise Specified||High|
Key Event Relationship Description
Impaired IL-1 signaling leads to suppression of NF-kB activation
Evidence Supporting this KER
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).
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent. Again, age-dependent difference in IL-1 signaling is not known.
The IL1B gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849).
These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.
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