Loss of TGF-β signaling contributes to autoimmune pancreatitis
Ki-Baik Hahm, … , Jeffrey E. Green, Seong-Jin Kim
Ki-Baik Hahm, … , Jeffrey E. Green, Seong-Jin Kim
Published April 15, 2000
Citation Information: J Clin Invest. 2000;105(8):1057-1065. https://doi.org/10.1172/JCI8337.
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Article

Loss of TGF-β signaling contributes to autoimmune pancreatitis

Abstract

Recent observations suggest that immune response is involved in the development of pancreatitis. However, the exact pathogenesis underlying this immune-mediated response is still under debate. TGF-β has been known to be an important regulating factor in maintaining immune homeostasis. To determine the role of TGF-β in the initiation or progression of pancreatitis, TGF-β signaling was inactivated in mouse pancreata by overexpressing a dominant-negative mutant form of TGF-β type II receptor in the pancreas, under control of the pS2 mouse trefoil peptide promoter. Transgenic mice showed marked increases in MHC class II molecules and matrix metalloproteinase expression 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, TGF-β signaling seems to be essential either in maintaining the normal immune homeostasis and suppressing autoimmunity or in preserving the integrity of pancreatic acinar cells.

Authors

Ki-Baik Hahm, Young-Hyuck Im, Cecile Lee, W. Tony Parks, Yung-Jue Bang, Jeffrey E. Green, Seong-Jin Kim

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Figure 1

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Generation of pS2 dominant-negative mutant TGF-β RII mice. (a) A schemat...
Generation of pS2 dominant-negative mutant TGF-β RII mice. (a) A schematic representation of the transgene. The mpS2 fragment spans bp –2400 to bp +5. The 0.6-kb human TGF-β RII fragment spans +322 to + 911 and contains a HA tag sequence and a segment of the mP1 that provides an intron and a polyadenylation site. Transgenic mice were generated using inbred FVB/N zygotes. Of the 10 mice born, 4 were positive for pS2-dnRII (which was bred into lines) and designated pS2-1 though pS2-4. Pups from pS2-1 and pS2-2 were used for the current experiments. (b–e) Tissue distribution of pS2 and dnRII expression. (b) Using total RNAs isolated from the intestines of wild-type mice and pS2-dnRII transgenic mice, RT-PCR was performed using the specific primer sets for human TGF-β RII, mouse ITF, and mouse GAPDH. (c) Western blotting analysis of dnRII protein. (d) Immunohistochemical staining was performed for the presence of human dnRII using human anti–TGF-β RII (residues 1–28) antibody. (e) A HA tag was used for identifying the pS2-dnRII with immunohistochemical staining, which showed presence of the HA tag in the pancreata of transgenic mice alone. (d and e) × 200.