Relationship: 2002
Title
Upstream event
Inhibition of IL-1 binding to IL-1 receptorDownstream event
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 |
Taxonomic Applicability
| 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
| Sex | Evidence |
|---|---|
| Unspecific | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| 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
Biological Plausibility
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)
Empirical Evidence
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).
Quantitative Understanding of the Linkage
Domain of Applicability
References
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.