IFN-gamma abrogates profibrogenic TGF-beta signaling in liver by targeting expression of inhibitory and receptor Smads.
OBJECTIVE
In a randomized open-labeled multicenter trial with patients suffering from chronic HBV infection, we recently identified a benefit of 9-month IFN-gamma treatment resulting in decreased fibrosis scores and a reduced number of alpha-smooth muscle actin-positive hepatic stellate cells (HSCs). Approaches opposing profibrogenic activities of TGF-beta may be amenable in chronic liver disease. According to experimental models, IFN-gamma counteracts several TGF-beta effects.


METHODS
The crosstalk of IFN-gamma and TGF-beta signaling relevant for fibrogenesis was investigated in primary cultured rat HSCs and a cell line representing activated HSCs.


RESULTS
In vitro studies with HSCs demonstrate that TGF-beta-dependent activation of (CAGA)9-MLP-Luc, a Smad3/4 responsive reporter construct, was significantly decreased by IFN-gamma, indicating a TGF-beta antagonizing function. IFN-gamma induced the activity of the Smad7 promoter and Smad7 protein expression via STAT-1 signaling. In contrast to TGF-beta, IFN-gamma was able to induce Smad7 expression in activated HSCs providing increased protein levels for at least 12h. In addition, expression of Smad2/3 was reduced by IFN-gamma and activation of Smads2/3 was abrogated.


CONCLUSIONS
IFN-gamma displays antifibrotic effects in liver cells via STAT-1 phosphorylation, upregulation of Smad7 expression and impaired TGF-beta signaling.
Weng
Honglei
H
Institute of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, People's Republic of China.
Mertens
Peter R
PR
Gressner
Axel M
AM
Dooley
Steven
S
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000517:prevention & control*; D010766:Phosphorylation; D051381:Rats; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051897:Smad Proteins, Inhibitory / Q000235:genetics / Q000378:metabolism; D051896:Smad Proteins, Receptor-Regulated / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D000199:Actins; D003094:Collagen; D007371:Interferon-gamma; D050794:STAT1 Transcription Factor; D051897:Smad Proteins, Inhibitory; D051896:Smad Proteins, Receptor-Regulated; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; C498862:Acta2 protein, rat