Enterocyte STAT5 promotes mucosal wound healing via suppression of myosin light chain kinase-mediated loss of barrier function and inflammation.
Bottom Line: Consistently, knockdown of stat5 in IEC monolayers led to increased NF-κB DNA binding to MLCK promoter, myosin light chain phosphorylation and tight junction (TJ) permeability, which were potentiated by administration of tumour necrosis factor-α (TNF-α), and prevented by concurrent NF-κB knockdown.Collectively, enterocyte STAT5 signalling protects against TJ barrier dysfunction and promotes intestinal mucosal wound healing via an interaction with NF-κB to suppress MLCK.Targeting IEC STAT5 signalling may be a novel therapeutic approach for treating intestinal barrier dysfunction in IBD.
Affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.Show MeSH
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Mentions: NF-κB activation promotes chronic intestinal inflammation in both CD and UC (Han et al, 2006; Schreiber et al, 1998). Our data exhibited that nuclear levels of RelA/p65 remained at significantly higher levels in the colonic mucosa of STAT5IEC KO mice than in littermate controls either under basal conditions or during water recovery after the cessation of DSS (Fig 4A). In addition, colonic IκBα expression, an endogenous suppressor of NF-κB activity, was consistently and remarkably reduced under basal conditions or in the water recovery group in STAT5IEC KO mice compared to STAT5IEC WT mice (Fig 4B). Most importantly, our data exhibited that depletion of IEC STAT5 in mice increased basal NF-κB activity in IECs, as determined by the nuclear abundance and phosphorylation of RelA/p65 (Fig 4C and D). Together, these data suggest that there is an interaction between IEC STAT5 and NF-κB in the regulation of the intestinal immune response to injury. IEC STAT5 could suppress NF-κB nuclear activation by stabilizing IκBα to ameliorate mucosal inflammation (STAT5 → IκBα⊣ NF-κB).
Affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.