Background: 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.
Methods: Colitis was induced in IEC-specific STAT3-deficient mice (STAT3[INCREMENT]IEC) and littermate controls (STAT3Flx/Flx) with 4% DSS for 7 days, followed by water consumption for 21 days. Epithelial and immune mediators and severity of colitis were determined.
Results: 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 STAT3Flx/Flx controls. In STAT3[INCREMENT]IEC mice, colonic expression of STAT3 target genes Reg3β and Reg3γ, which mediate epithelial restitution, were significantly decreased, whereas expression of interleukin (IL)-17a, IFNγ, 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.
Conclusions: 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.
Article first published online 6 February 2013
*Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
†Cancer and Cell Biology Program, University of Cincinnati College of Medicine, Cincinnati, Ohio
‡Division of Pathology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.
Reprints: Lee A. Denson, MD, MLC 2010, 3333 Burnet Avenue, Cincinnati, OH 45229 (e-mail: firstname.lastname@example.org)
Supported by the Cincinnati Children’s Hospital Research Foundation Digestive Health Center (1P30DK078392-01) and grants from the National Institutes of Health (R01 DK078683 and DK068164) (L.A.D.).
The authors have no conflicts of interest to disclose.
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Received June 14, 2012
Accepted July 02, 2012