Molecular mechanism of the TGF-β/Smad7 signaling pathway in ulcerative colitis

Aberrant TGF-beta/Smad7 signaling has been reported to be an important mechanism underlying the pathogenesis of ulcerative colitis. Therefore, the present study aimed to investigate the effects of a number of potential anti-colitis agents on intestinal epithelial permeability and the TGF-beta/Smad7 signaling pathway in an experimental model of colitis. A mouse model of colitis was first established before anti-TNF-alpha and 5-aminosalicyclic acid (5-ASA) were administered intraperitoneally and orally, respectively. Myeloperoxidase (MPO) activity, histological index (HI) of the colon and the disease activity index (DAI) scores were then detected in each mouse. Transmission electron microscopy (TEM), immunohistochemical and functional tests, including Evans blue (EB) and FITC-dextran (FD-4) staining, were used to evaluate intestinal mucosal permeability. The expression of epithelial phenotype markers E-cadherin, occludin, zona occludens (ZO-1), TGF-beta and Smad7 were measured. In addition, epithelial myosin light chain kinase (MLCK) expression and activity were measured. Anti-TNF-alpha and 5-ASA treatments was both found to effectively reduce the DAI score and HI, whilst decreasing colonic MPO activity, plasma levels of FD-4 and EB permeation of the intestine. Furthermore, anti-TNF-alpha and 5-ASA treatments decreased MLCK expression and activity, reduced the expression of Smad7 in the small intestine epithelium, but increased the expression of TGF-beta. In mice with colitis, TEM revealed partial epithelial injury in the ileum, where the number of intercellular tight junctions and the expression levels of E-cadherin, ZO-1 and occludin were decreased, all of which were alleviated by anti-TNF-alpha and 5-ASA treatment. In conclusion, anti-TNF-alpha and 5-ASA both exerted protective effects on intestinal epithelial permeability in an experimental mouse model of colitis. The underlying mechanism may be mediated at least in part by the increase in TGF-beta expression and/or the reduction in Smad7 expression, which can inhibit epithelial MLCK activity and in turn reduce mucosal permeability during the pathogenesis of ulcerative colitis.