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Key Event Title
Impaired IL-1 signaling
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|All life stages||High|
Key Event Description
The pleiotropic cytokine IL-1 mediates its biological functions via association with the signaling receptor IL-1R1. These may include initiation of innate immunity and assistance of host defense against infection, and sometimes, mediation of autoinflammatory, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. The trimeric complex consists of IL-1, IL-1R1 and IL-1R3 (a coreceptor, formerly IL-1R accessory protein) allows for the approximation of the Toll-IL-1-Receptor (TIR) domains of each receptor chain. MyD88 then binds to the TIR domains. The binding of MyD88 triggers a cascade of kinases that produce a strong pro-inflammatory signal leading to activation of NF-κB (Dinarello, 2018; Weber et al., 2018). Therefore, decreased IL-1 production by macrophages, dendritic cells, epithelial cells, and endothelial cells or inhibition of IL-1 binding to IL-1R1 by anti-IL-1bantibody, IL-1RA, or soluble IL-1Ra1 inhibits the formation of the trimeric complex which results in impaired IL-1 signaling.
How It Is Measured or Detected
It is not possible to directly measure the activation of IL-1 signaling. Instead, the activation of IL-1 signaling can be indirectly measured by the activation of NF-kB or mRNA or protein expression of IL-1 responsive cytokines, such as IL-6 or IL-8, or cyclooxygenase 2.
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.
Evidence for Perturbation by Stressor
Chaudhary, L.R., Avioli, L.V., 1994. Dexamethasone regulates IL-1 beta and TNF-alpha-induced interleukin-8 production in human bone marrow stromal and osteoblast-like cells. Calcif Tissue Int 55, 16-20.
Dinarello, C.A., 2018. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 281, 8-27.
Gabay, C., Lamacchia, C., Palmer, G., 2010. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol 6, 232-241.
Huang, H., Wang, Y., 2017. The protective effect of cinnamaldehyde on lipopolysaccharide induced acute lung injury in mice. Cell Mol Biol (Noisy-le-grand) 63, 58-63.
Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.
Monick, M.M., Aksamit, T.R., Geist, L.J., Hunninghake, G.W., 1994. Dexamethasone inhibits IL-1 and TNF activity in human lung fibroblasts without affecting IL-1 or TNF receptors. Am J Physiol 267, L33-38.
Newman, S.P., Flower, R.J., Croxtall, J.D., 1994. Dexamethasone suppression of IL-1 beta-induced cyclooxygenase 2 expression is not mediated by lipocortin-1 in A549 cells. Biochem Biophys Res Commun 202, 931-939.
Weber, A.N.R., Cardona Gloria, Y., Cinar, O., Reinhardt, H.C., Pezzutto, A., Wolz, O.O., 2018. Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities. Cancer Immunol Immunother 67, 1797-1807.
Xu, F., Wang, F., Wen, T., Sang, W., Wang, D., Zeng, N., 2017. Inhibition of NLRP3 inflammasome: a new protective mechanism of cinnamaldehyde in endotoxin poisoning of mice. Immunopharmacol Immunotoxicol 39, 296-304.