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Amelioration of pancreatic fibrosis in mice with defective TGF-beta signaling.

Yoo, BM  | Yeo, M  | Oh, TY | Choi, JH  | Kim, WW  | Kim, JH  | Cho, SW  | Kim, SJ | Hahm, KB
Pancreas, 30(3). : e71-e79, 2005
Journal Title
OBJECTIVES: Pancreatic fibrosis is a characteristic feature of chronic pancreatic injury, which is a result of the imbalance between synthesis and degradation of extracellular matrix (ECM) proteins. Transforming growth factor-beta (TGF-beta) plays a central role in biosynthesis and turnover of the ECM. In this study, we evaluated the role of TGF-beta signaling in pancreatic fibrosis induced by repetitive acute pancreatic injuries with mice of dominant-negative mutant of TGF-beta receptor II selectively in pancreas.

METHODS: TGF-beta signaling was inactivated by overexpressing a dominant-negative mutant form of TGF-beta type II receptor (pS2-dnR II) only in the pancreas under control of pS2/TFF1 promoter. Pancreatic fibrosis was induced by repeated intraperitoneal injections of 40 microg/kg cerulein for 5 or 10 weeks.

RESULTS: Repeated administration of cerulein induced significant pancreatic fibrosis, but of which fibrosis was remarkably attenuated in pS2-dnR II mice compared with wild-type littermates (P < 0.01). The ameliorated fibrosis was due to the reduction of synthesis of ECM proteins such as collagen type I, fibronectin, and ICAM-1. DNA binding activity of transcriptional factors including nuclear factor (NF)-kappaB and AP-1, responsible for the induction of immediate early genes of inflammatory responses, were significantly decreased in pS2-dnR II mice. While TGF-beta1 treatment in isolated pancreatic stellate cells (PSCs) stimulated the expression of alpha-SMA and fibronectin, PSCs transfected with TGF-beta dnRII showed attenuation of the ECM components.

CONCLUSION: Conditional loss of TGF-beta signaling selectively in the pancreas led to a failure in fibrogenic responses of repeated injections of cerulein, signifying that the modulation of TGF-beta signaling could be the therapeutic target for the prevention of chronic fibrosing pancreatitis.

Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Gastroenterology
Journal Papers > Research Organization > Genomic Research Center for Gastroenterology
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
Ajou Authors
김, 욱환  |  김, 진홍  |  여, 말희  |  유, 병무  |  조, 성원  |  최, 준혁  |  함, 기백
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