Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury

Hepatology. 2002 Jan;35(1):49-61. doi: 10.1053/jhep.2002.30083.


During chronic liver injury, transforming growth factor beta (TGF-beta) plays a prominent role in stimulating liver fibrogenesis by myofibroblast-like cells derived from hepatic stellate cells (HSCs). On the other hand, Smad 7 was recently shown to antagonize the TGF-beta-induced activation of signal-transducing Smads (2 and 3). In this study, we investigated the regulatory mechanisms of the TGF-beta signals in rat HSCs during acute liver injury and myofibroblasts (MFBs) during chronic liver injury, focusing on the roles of Smad 2 and antagonistic Smad 7. In acute liver injury, HSC-derived TGF-beta increased plasminogen activator inhibitor type 1 (PAI-1) and alpha2(I) procollagen (COL1A2) transcripts. Smad 2 in HSCs during liver injury and primary cultured HSCs were activated by an autocrine mechanism, because high levels of Smad 2 phosphorylation and induction of PAI-1 transcript by TGF-beta were observed in HSCs. Thereafter, Smad 7 induced by TGF-beta negatively regulated the Smad 2 action. These results indicated that endogenous TGFbeta-mediated Smad 7 in HSCs terminated the fibrotic signals mediated by signal-transducing Smads, and might be involved in the transient response to autocrine TGF-beta signal after acute liver injury. By contrast, Smad 7 was not induced by the autocrine TGF-beta signal, and constitutive Smad 2 activation was observed in MFBs throughout chronic liver injury, although Smad 7 could inhibit the TGF-beta signal requiring Smad 2 phosphorylation by activated TGF-beta receptor in cultured MFBs. This constitutive phosphorylation of Smad 2 by endogenous TGF-beta under a low level of Smad 7 could be involved in the progression of liver fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Carbon Tetrachloride / administration & dosage
  • Cell Division
  • Cell Line
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury
  • Chronic Disease
  • Collagen / genetics
  • Collagen Type I
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Fibroblasts / metabolism
  • Gene Expression
  • Hepatocytes / metabolism
  • Liver / metabolism*
  • Liver Diseases / metabolism*
  • Male
  • Phosphorylation
  • Plasminogen Activator Inhibitor 1 / genetics
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Wistar
  • Signal Transduction*
  • Smad2 Protein
  • Smad7 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transfection
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology*


  • Collagen Type I
  • DNA-Binding Proteins
  • Plasminogen Activator Inhibitor 1
  • RNA, Messenger
  • Smad2 Protein
  • Smad2 protein, rat
  • Smad7 Protein
  • Smad7 protein, rat
  • Trans-Activators
  • Transforming Growth Factor beta
  • Collagen
  • Carbon Tetrachloride