Abstract
IL‐10 is a potent anti‐inflammatory cytokine that inhibits the production of numerous pro‐inflammatory mediators in a number of cell types. Studies in animal models and in humans have demonstrated a critical role of IL‐10 signaling in a broad range of chronic inflammatory conditions, including inflammatory bowel disease. Our recent studies identified a prominent role for intestinal epithelial cell (IEC) IL‐10 signaling in inflammatory resolution during colitis. At present, little is known about how IL‐10 signaling interfaces with epithelial function in health and during inflammation. Based on our previous studies implicating enhanced restitution of epithelial monolayers in response to IL‐10, we hypothesized that IL‐10 signaling in IECs influences epithelial barrier maintenance and healing. Initial studies in IEC cell lines revealed that lentiviral‐mediated knockdown of IL‐10R1 resulted in significant defects in the formation of epithelial barrier function, measured by transepithelial resistance and paracellular flux assays (p<0.01). Studies in vivo using conditional IEC IL‐10R1 knockout mice identified a baseline defect in barrier function as evidenced by increased FITC‐dextran permeability with concomitant increases associated with ongoing inflammation (e.g. DSS colitis). Ongoing studies to identify regulatory mechanisms of IEC IL‐10R1 revealed a prominent role of the aryl hydrocarbon receptor (AHR) in induction of IL‐10R1 during inflammation. Parallel studies in AHR knockdown cell lines revealed barrier defects similar to the loss of IL‐10R1. We next utilized a scratch wound assay to define epithelial restitution and the role of this AHR‐IL‐10R1 axis. Induction of IL‐10R1 via the AHR ligand FICZ significantly increased IL‐10‐dependent wound healing. This response was abolished in cells lacking either IL‐10R1 or AHR. Together, these results provide compelling evidence on the importance of IL‐10 signaling in intestinal epithelial barrier function and restitution following injury.Support or Funding InformationThis work was supported by NIH grants DK099452, DK095491, DK50189, and by the Crohn's and Colitis Foundation of America.
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