Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
IL-17A is a cytokine produced by immune cells and acts on non-immune cells such as epithelial cells to stimulate the production of chemokines and antimicrobial peptides. This IL-17A-initiated activation of cells is important for amplifying inflammation and eliminating fungi and bacteria, while an uncontrolled increase in IL-17A action leads to disease, as shown in psoriasis, multiple sclerosis, rheumatoid arthritis patients, and their mouse models. In this study, we report that the IL-17A-induced response is affected by environmental chemicals. We have found IκB-ζ as an IL-17A-induced protein by gene expression analysis using epidermal keratinocytes, and that IκB-ζ plays a role in the expression of other IL-17A-induced genes. The mechanism of IκB-ζ induction by IL-17A was the mRNA stabilization, which is caused by the inactivation of Regnase-1, an mRNA degrading enzyme. The signaling leading to the inactivation of Regnase-1 was inhibited by dimethyl fumarate, a drug used for multiple sclerosis treatment. On the other hand, benzo[a]pyrene, a ligand for aryl hydrocarbon receptor, suppressed the function of Regnase-1 and increased the amount of IκB-ζ mRNA and IL-6 mRNA, which are degradation targets by Regnase-1. In summary, the IL-17A signaling pathway and mRNA stability control mechanisms are positively or negatively affected by various environmental chemicals. These mechanisms may be targets for chemical-induced changes in inflammatory and immune responses.
