Hepatitis C virus-replicating hepatocytes induce fibrogenic activation of hepatic stellate cells.
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.
Schulze-Krebs
Anja
A
Department of Medicine I, University of Erlangen-Nuremberg, Germany.
Preimel
Dorothee
D
Popov
Yury
Y
Bartenschlager
Ralf
R
Lohmann
Volker
V
Pinzani
Massimo
M
Schuppan
Detlef
D
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
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