Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription.
The majority of persons with chronic hepatitis C virus (HCV) infection develop liver fibrosis. Transforming growth factor (TGF)-beta 1 plays a pivotal role in the pathogenesis of post-inflammatory liver scarring. To clarify the influence of HCV infection on liver fibrosis, a reporter assay was used to investigate the effect of viral proteins on TGF-beta 1 expression in human hepatoma cells. Of all HCV proteins investigated (core, E1/E2/p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), only the core protein activated the TGF-beta 1 promoter and upregulated TGF-beta 1 expression measured by an RNase protection assay. Bases -376 to -331 bp in the promoter region of TGF-beta 1 are responsible for upregulation by HCV core protein, and the nuclear protein that binds to this region increased with the stimulation of HCV core protein. Blocking the mitogen-activated protein kinase pathway prevented upregulation of TGF-beta 1 by HCV core protein. The immunological response is supposed to be a major factor to cause the secretion of TGF-beta 1 from non-parenchymal cells, but the results suggest that the HCV core protein expression may upregulate directly TGF-beta 1 transcription in parenchymal cells and suggest a new paradigm for exacerbation of liver fibrosis by HCV infection.
Taniguchi
Hiroyoshi
H
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Kato
Naoya
N
Otsuka
Motoyuki
M
Goto
Tadashi
T
Yoshida
Hideo
H
Shiratori
Yasushi
Y
Omata
Masao
M
D016174:Hepacivirus / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000503:physiopathology* / Q000821:virology; D006801:Humans; D008103:Liver Cirrhosis / Q000503:physiopathology / Q000821:virology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014758:Viral Core Proteins / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism
C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014758:Viral Core Proteins; D014764:Viral Proteins; D020928:Mitogen-Activated Protein Kinases