Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|IL-1 receptor antagonist（IL-1Ra）(Anakinra)|
|anti-IL-1b antibody (Canakinumab)|
|soluble IL-1R (Rilonacept)|
|Pralnacasan (VX-740) and Belnacasan (VX-765)|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
|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
Overview for Molecular Initiating Event
IL-1 is known to mediates autoinflammatory syndrome, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. The stressors of this MIE, such as anakinra, canakinumab, and rilonacept have been already used to treat these autoinflammatory syndrome associated with overactivation of IL-1 signaling reviewed by Gabay et al (Gabay et al., 2010).
Dex suppression of IL-1 b-induced cyclooxygenase 2 expression is not mediated by lipocortin-1 in A549 cells (Newman et al., 1994).
Dex (10-7M) regulates IL-1b and TNF-a-induced interleukin-8 production in human bone marrow stromal and osteoblast-like cells(Chaudhary and Avioli, 1994).
Dex blocks the induction of IL-6 and IL-8 by IL-1-stimualted human lung fibroblasts(Monick et al., 1994).
The study was intended to examine the protective effect of cinnamaldehyde (CM) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice model. The results of the investigation confirmed that, LPS induced inflammatory cytokines such as TNF-α, IL-6, IL-13 and IL-1β were significantly decreased by CM (Huang and Wang, 2017).
In vitro, CA decreased the levels of pro-IL-1β and IL-1β in cell culture supernatants, as well as the expression of NLRP3 and IL-1β mRNA in cells. In vivo, CA decreased IL-1β production in serum. Furthermore, CA suppressed LPS-induced NLRP3, p20, Pro-IL-1β, P2X7 receptor (P2X7R) and cathepsin B protein expression in lung, as well as the expression of NLRP3 and IL-1β mRNA (Xu et al., 2017).
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.