Molecular Mechanisms of Transforming Growth Factor-β/Smad7 Signaling Pathway in Ulcerative Colitis

Abstract Background and AimsAbnormal transforming growth factor-β (TGF-β)/Smad7 signaling pathway may be an important mechanism of IBD.Therefore, this study was to investigate whether anti-colitis drugs modulate intestinal epithelial permeability in experimental colitis and to determine its TGF-β/Smad7 signaling pathway. MethodsA murine colitis model was induced, and then anti-TNF-α and 5-ASA were administered intraperitoneally and orally respectively. Myeloperoxidase(MPO) activity, histological index(HI) of colon and the disease activity index(DAI) scores of mice were detected. Transmission electron microscopy (TEM), immunohistochemical and functional tests which included two methods: one was Evans blue(EB) and the other was FITC-dextran(FD-4), were used to evaluate intestinal mucosal permeability. The expression of epithelial E-cad, Occludin, ZO-1, TGF –β and Smad7 were analyzed. Epithelial MLCK expression and activity were determined.ResultsAnti-TNF-α and 5-ASA both effectively reduced the DAI score and HI, and decreased colonic MPO activity, plasma levels of FD-4 and EB permeation of the intestine. Moreover, anti-TNF-α and 5-ASA downregulated the MLCK expression and activity and the expression of Smad7 in the small intestinal epithelium, and increased the expression of TGF-β(P < 0.050). In colitis mice, TEM revealed partial ileal epithelial injury, intercellular TJs and the expression of E-cadherin, ZO-1 and occludin were decreased, which were alleviated by anti-TNF-α and 5-ASA.ConclusionsAnti-TNF-α and 5-ASA both showed a significant effect on intestinal epithelial permeability in experimental colitis. The mechanism can be clarified as the increase of TGF-β expression or the decrease of Smad7 expression which could inhibit epithelial MLCK and then reduce the mucosal permeability of ulcerative colitis.