A56 EVALUATING THE DYNAMICS OF CYP3A11 AND REG3G MODULATION BY IL-22

Abstract

Abstract Background IL-22 is a cytokine produced by a number of immune cell populations, including type 3 innate lymphoid cells. We have shown previously that IL-22 suppresses the expression Cyp3a11 in the mouse intestine, a gene that encodes a drug metabolizing enzyme that accounts for roughly 70% of total drug metabolism. In addition, IL-22 induces the expression of Reg3g, the gene that encodes an antimicrobial C-type lectin that has bactericidal activity against Gram+ bacteria in the small intestine. Modulation of these proteins can influence both the oral bioavailability of drugs and microbial composition. Aims The aim of this study was to define the existence of reversible modulation of IL-22 on Cyp3a11 and Reg3g expression in the intestinal epithelium. Methods In vitro enteroids from each part of the mouse small intestine were cultured in 3D in the presence or absence of IL-22 for 5 days. Cyp3a11 and Reg3g transcript expression was evaluated by qPCR followed by protein analysis to define their modulation at varying timepoints after IL-22 treatment cessation. Results IL-22 reduced Cyp3a11 expression, an effect that normalized the day after treatment cessation. However, 4 days after treatment cessation there was rebound hyperexpression of Cyp3a11 in duodenal enteroids, which normalized the following day. IL-22 reduced the expression and activity of Cyp3a11 which normalized soon after stopping IL-22 treatment. In contrast, IL-22 induced the expression of Reg3g, an effect that lasted up to 5 days after treatment cessation. The effect of IL-22 on Cyp3a11 expression and activity was rapidly reversed in contrast to the effect on Reg3g which was more prolonged. Conclusions IL-22 suppresses the expression of Cyp3a11 and induces the expression of Reg3g. The reversible nature of these effects is different between both, with the increased expression of Reg3g 5 days after IL-22 treatment cessation. These data suggest that the regulation of gene expression, protein or enzyme activity by IL-22 may exhibit varying temporal effects and should be considered when assessing its role in intestinal mucosal biology. Funding Agencies This work was funded by the Dr. Lloyd Sutherland Chair in IBD/GI Research and the Weston Foundation.