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|
|Homo sapiens||Homo sapiens||High||NCBI|
|All life stages||High|
Key Event Description
Decreased IL-1 production by macrophages can be induced by suppressed IL-1 b mRNA induction or suppressed maturation of pro-IL-1b which leads to decreased IL-1b secretion. Indeed, dexamethasone significantly suppresses IL-1β mRNA induction by monocytes after LPS stimulation (Finch-Arietta and Cochran 1991). In contrast, minocycline suppresses IL-1 signaling by the inhibition of caspase-1 activation, which is an essential enzyme for maturation of pro- IL-1β and the secretion of mature IL-1β (Vincent and Mohr 2007). Decreased IL-1 production by macrophages
How It Is Measured or Detected
The inhibition can be measured by quantitating phosphorylated NF-kB or the proteins or mRNA of IL-6 and IL-8 and 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 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
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).
Chemical:20384 Dexamethasone, minocycline, innamicaldehyde
Dexamethasone is one of the representatives that significantly suppress IL-1β production from monocytes (Finch-Arietta and Cochran 1991). Minocycline also suppress IL-1 signaling by the inhibition of caspase-1 activation, which is an essential enzyme for maturation of pro- IL-1β and the secretion of mature IL-1β(Vincent and Mohr 2007). Recently, it has been reported that cinnamicaldehyde suppresses serum IL-1β level in endotoxin poisoning mice (Xu, et al. 2016). These data suggest that chemicals as well as drugs can suppress IL-1 signaling through their inhibitory effects on IL-1β.