Cytokine signaling in the intestinal epithelium
Cytokine signaling pathways have been demonstrated to be critical in onset, progression, and restitution of inflammation. Indeed, IL-10 signaling pathways have been shown to play a critical protective role in inflammatory disease. Importantly, mutations in the IL-10 receptor have been associated with a severe early onset form of colitis. However, the role of IL-10 signaling in the intestinal epithelium remains largely unknown.
We have investigated potential anti-inflammatory mechanisms of IL-10 signaling in the epithelium using models of IBD. In vitro studies revealed that inflammatory mediators induce the expression of the IL-10 receptor ( IL-10R1) on intestinal epithelia. Receptor activation functionally induces canonical IL-10 target gene expression in epithelia, concomitant with enhanced barrier restitution. Importantly, knockdown of IL-10R1 in intestinal epithelial cells in vitro as well as in vivo utilizing a conditional IL-10R1 mouse knockout model results in impaired barrier function.
Based upon these results we hypothesize a crucial and underappreciated role of epithelial IL-10 signaling in the maintenance and restitution of epithelial barrier and of the temporal regulation of these pathways during inflammation. Current work in the lab focuses on elucidating the role of epithelial IL-10 signaling in the maintenance and reformation of mucosal barrier.