title: Hepatitis C virus-replicating hepatocytes induce fibrogenic activation of hepatic stellate cells.
abstract: OBJECTIVE
  The mechanism by which hepatitis C virus induces liver fibrosis remains largely obscure. To characterize the profibrogenic potential of hepatitis C virus, we used the hepatitis C virus replicon cell line Huh-7 5-15, which stably expresses the nonstructural hepatitis C virus genes NS3 through NS5B, and hepatic stellate cells as fibrogenic effector cells.
  
  
  METHODS
  Rat and human hepatic stellate cells were incubated with conditioned media from replicon cells, and expression of fibrosis-related genes was quantified by using real-time polymerase chain reaction, protein, and functional assays. Transforming growth factor beta1 activity was determined by bioassay.
  
  
  RESULTS
  Hepatitis C virus replicon cells release factors that differentially modulate hepatic stellate cell expression of key genes involved in liver fibrosis in a clearly profibrogenic way, up-regulating procollagen alpha1(I) and procollagen alpha1(III) and down-regulating fibrolytic matrix metalloproteinases. Transforming growth factor beta1 expression and bioactivity were increased severalfold in hepatitis C virus-replicating vs mock-transfected hepatoma cells. However, transforming growth factor beta1 activity was responsible for only 50% of the profibrogenic activity.
  
  
  CONCLUSIONS
  Hepatitis C virus nonstructural genes induce an increased expression of transforming growth factor beta1 and other profibrogenic factors in infected hepatocytes. The direct induction of profibrogenic mediators by hepatitis C virus in infected hepatocytes explains the frequent observation of progressive liver fibrosis despite a low level of inflammation and suggests novel targets for antifibrotic therapies in chronic hepatitis C.
authors: Department of Medicine I, University of Erlangen-Nuremberg, Germany.
authors: Anja
authors: A
authors: Schulze-Krebs
authors: Dorothee
authors: D
authors: Preimel
authors: Yury
authors: Y
authors: Popov
authors: Ralf
authors: R
authors: Bartenschlager
authors: Volker
authors: V
authors: Lohmann
authors: Massimo
authors: M
authors: Pinzani
authors: Detlef
authors: D
authors: Schuppan
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000235:genetics / Q000254:growth & development*; D006526:Hepatitis C / Q000473:pathology* / Q000821:virology; D022781:Hepatocytes / Q000473:pathology* / Q000821:virology*; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
chemical_list: D017077:Culture Media, Conditioned; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1