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-β (TGF-β) plays a central role in biosynthesis and turnover of the ECM. In this study, we evaluated the role of TGF-β signaling in pancreatic fibrosis induced by repetitive acute pancreatic injuries with mice of dominant-negative mutant of TGF-β receptor II selectively in pancreas.

Methods:

TGF-β signaling was inactivated by overexpressing a dominant-negative mutant form of TGF-β type II receptor (pS 2-dnR II) only in the pancreas under control of pS2/TFF1 promoter. Pancreatic fibrosis was induced by repeated intraperitoneal injections of 40 μg/kg cerulein for 5 or 10 weeks.

Results:

Repeated administration of cerulein induced significant pancreatic fibrosis, but of which fibrosis was remarkably attenuated in pS 2-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)-κB and AP-1, responsible for the induction of immediate early genes of inflammatory responses, were significantly decreased in pS 2-dnR II mice. While TGF-β1 treatment in isolated pancreatic stellate cells (PSCs) stimulated the expression of α-SMA and fibronectin, PSCs transfected with TGF-β dnRII showed attenuation of the ECM components.

Conclusion:

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