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From the Gastrointestinal Research Group,* University of Calgary, Calgary, Canada; and the Gastrointestinal Unit,* Center for Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts
In vitro studies suggest that transforming growth factor (TGF)-ß has potent effects on gastrointestinal mucosal integrity, wound repair, and neoplasia. However, the multiplicity of actions of this peptide on many different cell types confounds efforts to define the role of TGF-ß within the intestinal epithelium in vivo. To delineate these effects selective blockade of intestinal epithelial TGF-ß activity was undertaken through targeted expression of a dominant-negative (DN) TGF-ß RII to intestinal epithelial cells in vitro and in vivo. Stable intestinal epithelial cell (IEC)-6 lines overexpressing TGF-ß RII-DN (nucleotides -7 to 573) were established. Transgenic mice overexpressing TGF-ß RII-DN under the regulation of a modified liver fatty acid-binding promoter (LFABP-PTS4) were constructed. In vitro healing was assessed by wounding of confluent monolayers. Colitis was induced by the addition of dextran sodium sulfate (2.5 to 7.5% w/v) to their drinking water. Overexpression of TGF-ß RII-DN in intestinal epithelial cell-6 cells resulted in a marked reduction in cell migration and TGF-ß-stimulated wound healing in vitro. TGF-ß RII-DN transgenic mice did not exhibit baseline intestinal inflammation or changes in survival, body weight, epithelial cell proliferation, aberrant crypt foci, or tumor formation. TGF-ß RII-DN mice were markedly more susceptible to dextran sodium sulfate-induced colitis and exhibited impaired recovery after colonic injury. TGF-ß is required for intestinal mucosal healing and TGF-ß modulation of the intestinal epithelium plays a central role in determining susceptibility to injury.
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