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Key Event Title
Decreased IL-1 production
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|All life stages||High|
Key Event Description
Decreased IL-1 production by macrophages can be induced by suppressed IL-1β mRNA induction or suppressed maturation of pro-IL-1β which leads to decreased IL-1b secretion. Dexamethasone is one of the representative drugs that significantly suppress IL-1β production from monocytes (Finch-Arietta and Cochran, 1991). Minocycline, and two prodrugs, pralnacasan (VX-740) and belnacasan(VX-765) that are orally absorbed and converted into the active principle, VRT-018858 and VRT-043198, respectively (Fenini et al., 2017) suppress IL-1 signaling by the inhibition of caspase-1 activation. Caspase-1 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., 2017). These data suggest that chemicals as well as drugs can suppress IL-1 signaling through their inhibitory effects on IL-1β production.
How It Is Measured or Detected
Inhibition of IL-1 mRNA expression is measured by quantitative real-time polymerase chain reaction. The production of IL-1β is measured by ELISA (Karpenko et al., 2018).
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.
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Ho, S.C., Chang, Y.H., Chang, K.S., 2018. Structural Moieties Required for Cinnamaldehyde-Related Compounds to Inhibit Canonical IL-1beta Secretion. Molecules 23.
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Karpenko, M.N., Vasilishina, A.A., Gromova, E.A., Muruzheva, Z.M., Bernadotte, A., 2018. Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-6, interleukin-10, and tumor necrosis factor-alpha levels in CSF and serum in relation to the clinical diversity of Parkinson's disease. Cell Immunol 327, 77-82.
Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.
Morand, E.F., Rickard, D., Goulding, N.J., 1993. Lack of involvement of lipocortin 1 in dexamethasone suppression of IL-1 release. Mediators Inflamm 2, 49-52.
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Vincent, J.A., Mohr, S., 2007. Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes 56, 224-230.
Wang, A.L., Yu, A.C., Lau, L.T., Lee, C., Wu le, M., Zhu, X., Tso, M.O., 2005. Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47, 152-158.
Weinberg, J.B., Mason, S.N., Wortham, T.S., 1992. Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by pentoxifylline and dexamethasone: dissociation of acivicin-induced TNF-alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid differentiation. Blood 79, 3337-3343.
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.