title: Amelioration of pancreatic fibrosis in mice with defective TGF-beta signaling.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Genome Research Center for Gastroenterology, Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Byung Moo
authors.initials: BM
authors.lastname: Yoo
authors.forename: Marie
authors.initials: M
authors.lastname: Yeo
authors.forename: Tae Young
authors.initials: TY
authors.lastname: Oh
authors.forename: Joon Hyuck
authors.initials: JH
authors.lastname: Choi
authors.forename: Wook Whan
authors.initials: WW
authors.lastname: Kim
authors.forename: Jin Hong
authors.initials: JH
authors.lastname: Kim
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Cho
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Ki-Baik
authors.initials: KB
authors.lastname: Hahm
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002108:Ceruletide / Q000633:toxicity; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000473:pathology / Q000502:physiology; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D016326:Extracellular Matrix Proteins; D016328:NF-kappa B; D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002108:Ceruletide; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II