Loss of TGF-beta signaling contributes to autoimmune pancreatitis

Recent observations suggest that immune response is involved in the develop ment of pancreatitis. However, the exact pathogenesis underlying this immun e-mediated response is still under debate. TGF-beta has been known to be an important regulating factor in maintaining immune homeostasis. To determin e the role of TGF-beta in the initiation or progression of pancreatitis, TG F-beta signaling was inactivated in mouse pancreata by overexpressing a dom inant-negative mutant form of TGF-beta type II receptor in the pancreas, un der control of the pS2 mouse trefoil peptide promoter. Transgenic mice show ed marked increases in MHC class II molecules and matrix metalloproteinase expression in pancreatic acinar cells. These mice also showed increased sus ceptibility to cerulein-induced pancreatitis. This pancreatitis was charact erized by severe pancreatic edema, inflammatory cell infiltration, T- and B -cell hyperactivation, IgG-type autoantibodies against pancreatic acinar ce lls, and IgM-type autoantibodies against pancreatic ductal epithelial cells . Therefore, TGF-beta signaling seems to be essential either in maintaining the normal immune homeostasis and suppressing autoimmunity or in preservin g the integrity of pancreatic acinar cells.