13 372

Cited 0 times in

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.
MeSH terms
AnimalsCaerulein/toxicityCells, CulturedExtracellular Matrix Proteins/metabolismFibrosisMaleMiceMice, Inbred StrainsMice, TransgenicNF-kappa B/metabolismPancreas/pathologyPancreas/physiologyPancreatitis, Chronic/chemically inducedPancreatitis, Chronic/metabolism*Pancreatitis, Chronic/pathology*Protein-Serine-Threonine KinasesReceptors, Transforming Growth Factor beta/genetics*Receptors, Transforming Growth Factor beta/metabolismSignal Transduction/physiology*Transcription Factor AP-1/metabolismTranscription, Genetic/drug effectsTranscription, Genetic/physiologyTransfectionTransforming Growth Factor beta/metabolism*Transforming Growth Factor beta1
Appears in Collections:
Journal Papers > Research Organization > Genomic Research Center for Gastroenterology
Journal Papers > School of Medicine / Graduate School of Medicine > Gastroenterology
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
AJOU Authors
유, 병무여, 말희최, 준혁김, 욱환김, 진홍조, 성원함, 기백
Full Text Link
RIS (EndNote)
XLS (Excel)


해당 아이템을 이메일로 공유하기 원하시면 인증을 거치시기 바랍니다.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.