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Amelioration of pancreatic fibrosis in mice with defective TGF-beta signaling.
Pancreas. 2005 Apr; 30(3):e71-9.P

Abstract

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.

Authors+Show Affiliations

Genome Research Center for Gastroenterology, Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15782092

Citation

Yoo, Byung Moo, et al. "Amelioration of Pancreatic Fibrosis in Mice With Defective TGF-beta Signaling." Pancreas, vol. 30, no. 3, 2005, pp. e71-9.
Yoo BM, Yeo M, Oh TY, et al. Amelioration of pancreatic fibrosis in mice with defective TGF-beta signaling. Pancreas. 2005;30(3):e71-9.
Yoo, B. M., Yeo, M., Oh, T. Y., Choi, J. H., Kim, W. W., Kim, J. H., Cho, S. W., Kim, S. J., & Hahm, K. B. (2005). Amelioration of pancreatic fibrosis in mice with defective TGF-beta signaling. Pancreas, 30(3), e71-9.
Yoo BM, et al. Amelioration of Pancreatic Fibrosis in Mice With Defective TGF-beta Signaling. Pancreas. 2005;30(3):e71-9. PubMed PMID: 15782092.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amelioration of pancreatic fibrosis in mice with defective TGF-beta signaling. AU - Yoo,Byung Moo, AU - Yeo,Marie, AU - Oh,Tae Young, AU - Choi,Joon Hyuck, AU - Kim,Wook Whan, AU - Kim,Jin Hong, AU - Cho,Sung Won, AU - Kim,Seong Jin, AU - Hahm,Ki-Baik, PY - 2005/3/23/pubmed PY - 2006/2/24/medline PY - 2005/3/23/entrez SP - e71 EP - 9 JF - Pancreas JO - Pancreas VL - 30 IS - 3 N2 - 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. SN - 1536-4828 UR - https://www.unboundmedicine.com/medline/citation/15782092/Amelioration_of_pancreatic_fibrosis_in_mice_with_defective_TGF_beta_signaling_ L2 - https://doi.org/10.1097/01.mpa.0000157388.54016.0a DB - PRIME DP - Unbound Medicine ER -