Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|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
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.
Evidence for Perturbation by Stressor
Fenini, G., Contassot, E., French, L.E., 2017. Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases. Front Pharmacol 8, 278.
Finch-Arietta, M.B., Cochran, F.R., 1991. Cytokine production in whole blood ex vivo. Agents Actions 34, 49-52.
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.
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.
Jeon, Y.J., Han, S.H., Lee, Y.W., Lee, M., Yang, K.H., Kim, H.M., 2000. Dexamethasone inhibits IL-1 beta gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-kappa B/Rel and AP-1 activation. Immunopharmacology 48, 173-183.
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.
Qiu, H.B., Pan, J.Q., Zhao, Y.Q., Chen, D.C., 1997. Effects of dexamethasone and ibuprofen on LPS-induced gene expression of TNF alpha, IL-1 beta, and MIP-1 alpha in rat lung. Zhongguo Yao Li Xue Bao 18, 165-168.
Ravizza, T., Lucas, S.M., Balosso, S., Bernardino, L., Ku, G., Noe, F., Malva, J., Randle, J.C., Allan, S., Vezzani, A., 2006. Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47, 1160-1168.
Stack, J.H., Beaumont, K., Larsen, P.D., Straley, K.S., Henkel, G.W., Randle, J.C., Hoffman, H.M., 2005. IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol 175, 2630-2634.
van Furth, A.M., Seijmonsbergen, E.M., Langermans, J.A., van der Meide, P.H., van Furth, R., 1995. Effect of xanthine derivates and dexamethasone on Streptococcus pneumoniae-stimulated production of tumor necrosis factor alpha, interleukin-1 beta (IL-1 beta), and IL-10 by human leukocytes. Clin Diagn Lab Immunol 2, 689-692.
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.