Tryptophan Metabolite Activation of the Aryl Hydrocarbon Receptor Regulates IL10 Receptor Expression on Intestinal Epithelia

IL10 is a potent anti-inflammatory cytokine that inhibits the production of pro-inflammatory mediators. Signaling by IL10 occurs through the IL10 receptor (IL10R), which is expressed in numerous cell types, including intestinal epithelial cells (IEC), where it is associated with development and maintenance of barrier function. Guided by an unbiased metabolomics screen, we identified tryptophan (Trp) metabolism as a major modifying pathway in IFN-γ-dominant murine colitis. In parallel, we demonstrated that IFN-γ induction of IDO1, an enzyme that catalyzes the conversion of Trp to kynurenine (Kyn), induces IL10R1 expression. Based on these findings, we hypothesized that IL10R1 expression on IEC is regulated by Trp metabolites. Analysis of the promoter region of IL10R1 revealed a functional aryl hydrocarbon response element (AHRE), which is induced by Kyn in luciferase-based IL10R1 promoter assays. Additionally, this analysis confirmed that IL10R1 protein levels were increased in response to Kyn in IEC in vitro. Studies utilizing in vitro wounding assays revealed that Kyn accelerates IL10-dependent wound closure. Finally, reduction of murine DSS colitis through Kyn administration correlates with colonic IL10R1 expression. Together, these results provide evidence on the importance of IL10 signaling in intestinal epithelia and implicate AHR in the regulation of IL10R1 expression in the colon.