Signal Transducer and Activator of Transcription 5 in Enterocytes Promotes Intestinal Mucosal Wound Healing by Regulation of Epithelial Tight Junction Assembly

Abstract

MethodsWe generated intestinal epithelial‐specific STAT5 knock out mice (STAT5 IEC KO) using cre‐mediated recombination to delete stat5 locus in IEC. STAT5 IEC KO mice were then treated with 3 % dextran sodium sulfate (DSS) either for seven days or for five days followed by 5 days of water. STAT5 IEC KO mice also exposed to NSAIDs chow for two weeks. We significantly knocked down GM‐CSF signaling and STAT5 expression in Caco‐2 and HT‐29 monolayer.ResultsSTAT5 IEC KO mice revealed an increased para‐cellular permeability and bacterial translocation in mesenteric lymph nude. STAT5 IEC KO mice were more susceptible to NSAIDs‐induced ileitis and DSS‐induced colitis, precluding mucosal healing after stopping DSS administration compared to littermate control mice (STAT5 IEC WT). Intestinal epithelial cells (IEC) monolayer exhibited a hyperpermeability under either GM‐CSF signaling or STAT5 knocking down; phosphoserine‐MLC was elevated and tight junction (TJ) assembly was disrupted in either IEC monolayer with STAT5 knock down or STAT5‐depleted IEC.ConclusionSTAT5 signaling in enterocytes is required for maintaining intestinal mucosal barrier function and promotes intestinal mucosal wound healing. Targeting on the activity of STAT5 signaling in enterocytes may be a novel therapeutic approach for treating intestinal barrier dysfunction in the sepsis and inflammatory bowel disease. This work was supported by Crohns and Colitis Foundation of America (XH), CCHMC Trustee Award (XH) and NIH clinical and translational research award KL2 (RR026315, XH).