Deletion of intestinal epithelial cell STAT3 promotes T-lymphocyte STAT3 activation and chronic colitis following acute dextran sodium sulfate injury in mice.

ABSTRACT: Intestinal epithelial cell (IEC) STAT3 is required for wound healing following acute dextran sodium sulfate (DSS) injury. We hypothesized that loss of IEC STAT3 would promote the development of chronic colitis following acute DSS injury.Colitis was induced in IEC-specific STAT3-deficient mice (STAT3)[INCREMENT]IEC and littermate controls (STAT3 Flx/Flx) with 4% DSS for 7 days, followed by water consumption for 21 days. Epithelial and immune mediators and severity of colitis were determined.Survival, colon length, and histologic injury were significantly worse at day 28 in STAT3[INCREMENT]IEC mice. IEC proliferation and apoptosis did not vary by genotype at day 14 or day 28. The colonic lamina propria frequency of pSTAT3* cells was increased at day 28 and correlated with histologic injury in STAT3 [INCREMENT]IEC mice. The frequency of colonic F480* pSTAT3* macrophages and CD3* pSTAT3* T lymphocytes were increased in STAT3[INCREMENT]IEC mice as compared with STAT3 Flx/Flx controls. In STAT3[INCREMENT]IEC mice, colonic expression of STAT3 target genes Reg3? and Reg3?, which mediate epithelial restitution, were significantly decreased, whereas expression of interleukin (IL)-17a, IFN?, CXCL2, CXCL10, and CCL2 were significantly increased and correlated with the increase in histologic severity at day 28(P < 0.05). IL-17a expression also correlated with the increased lamina propria frequency of CD3* pSTAT3* T lymphocytes.Loss of intestinal epithelial STAT3 leads to more severe chronic inflammation following acute injury, which is not accounted for by a sustained defect in epithelial proliferation or apoptosis 7 or 21 days after 1 cycle of DSS but rather defective REG3 expression and expansion of pSTAT3* lymphocytes and IL-17A expression.

SUBMITTER: Willson TA 

PROVIDER: S-EPMC4330009 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature