Recent findings demonstrate that the TGF-beta receptor (TGF-beta RII) complex is a new addition to the family of human tumor suppressor genes and that inactivation of this tumor suppressor is important in the genesis of multiple human malignancies. Results suggest that the stomach and colon may be uniquely vulnerable to the development of malignancy in response to defects in the TGF-beta signaling pathway. To study the role of the TGF-beta signaling pathway during gastric or colorectal carcinogenesis in vivo, transgenic mice expressing a dominant negative mutant form of the TGF-beta RII (dnRII) targeted to the colon using the intestinal trefoil peptide (ITF) promoter and to the stomach using the pS2 promoter have been generated. pS2-dnRII mice appeared to develop normally and were indistinguishable from their wild-type littermates. Transgenic mice, ITF-dnRII, showed increased expression of major histocompatibility complex (MHC) class II expression and matrix metalloproteinase (MMP) in intestinal epithelial cells. In a model of colitis induced by oral administration of dextran sodium sulfate (DSS), the transgenic mice showed increased susceptibility to DSS-induced IBD. The disease in these mice was characterized by extensive mucosal ulceration, marked inflammatory cell infiltrations, T and B cell hyperactivation, and the generation of autoantibodies against intestinal goblet cells. pS2-dnRII transgenic mice showed marked increases in MHC class II molecules and MMP expressions in pancreatic acinar cells. These mice also showed increased susceptibility to cerulein-induced pancreatitis. This pancreatitis was characterized by severe pancreatic edema, inflammatory cell infiltration, T and B cell hyperactivation, IgG-type autoantibodies against pancreatic acinar cells, and IgM-type autoantibodies against pancreatic ductal epithelial cells. Therefore, the combination of immune dysregulation with autoimmunity and an increased capacity for extracellular matrix degradation seen in these transgenic mice suggests that a deficiency of TGF-beta signaling may underlie the development of inflammatory bowel disease and pancreatitis. - Carcinogenesis, Inflammation, receptor, TGF beta, Transgenic Mice, - Human Tissues, Fluids, Cells, etc. & Neither Human Subjects nor Human Tissues
