Upstream eventInhibition of IL-1 binding to IL-1 receptor
Inhibition, Nuclear factor kappa B (NF-kB)
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of IL-1 binding to IL-1 receptor leading to increased susceptibility to infection||adjacent||High||Not Specified|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
The signaling cascade after IL-1R activation leads to NF-kB activation via the interaction with various signaling molecules.
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). 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)(Weber et al., 2010)
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).
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Adachi, O., Kawai, T., Takeda, K., et al., 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., et al., 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., et al., 2015. Efficacy and safety of biological agents in adult-onset Still's disease. Scand J Rheumatol 44, 309-314.
Li, W.D., Ran, G.X., Teng, H.L., et al., 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., et al., 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., et al., 2003. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299, 2076-2079.
Radons, J., Dove, S., Neumann, D., et al., 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., et al., 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.