Upstream eventDecreased IL-1 production
Impaired IL-1 signaling
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of IL-1 signaling||adjacent||High||High|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
The initial step of IL-1 signaling is the bidning of IL-1 to IL-1 receptor. So, the decreased IL-1 production leads to decreased IL-1 signaling.
Evidence Supporting this KER
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 after binding of IL-1 to IL-1 receptor. Therefore, lack of IL-1 molecule cannot trigger IL-1 signaling.
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
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.
Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.