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|
|Dexamethosone, IL-1 receptor antagonist（IL-1Ra）(Anakinra), anti-IL-1b antibod (Canakinumab), soluble IL-1R (Rilonacept).|
|Homo sapiens||Homo sapiens||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 and fundamental inflammatory responses such as the induction of cyclooxygenase type 2, production of multiple cytokines and chemokines, increased expression of adhesion molecules, or synthesis of nitric oxide. (Dinarello 2018)(Weber, et al. 2010). 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-1b antibody, 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
The inhibition can be measured by quantitating phosphorylated NF-kB or the proteins or mRNA of IL-6 , IL-8 or other IL-1–responsive cytokines or COX-2 produced by IL-1 stimulated macrophages or macrophage cell lines in the presence of inhibitors (Ref).
Domain of Applicability
Although there were several reports regarding sex deference of IL-1 immune function (Musabak et al. 2003, Klein et al. 2016) or MyD88 immune function (Hannah et al. 2008, Klein et al. 2010, Klein et al. 2016), there was no report which cleary indicated sex deference in IL-1 signaling.
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 (Ref).
Dexamethasone can suppress phosphorelation of NF-kB or the induction of the proteins or mRNA of IL-1–responsive cytokines or COX-2 by IL-1 stimulated macrophages or macrophage cell lines (Ref).