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Gastroenterology. 2010 Jun;138(7):2509-18, 2518.e1. doi: 10.1053/j.gastro.2010.03.008. Epub 2010 Mar 12.

Hepatitis C virus regulates transforming growth factor beta1 production through the generation of reactive oxygen species in a nuclear factor kappaB-dependent manner.

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  • 1Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.



The generation of oxidative stress and transforming growth factor beta1 (TGF-beta1) production play important roles in liver fibrogenesis. We have previously shown that hepatitis C virus (HCV) increases hepatocyte TGF-beta1 expression. However, the mechanisms by which this induction occurs have not been well studied. We explored the possibility that HCV infection regulates TGF-beta1 expression through the generation of reactive oxygen species (ROS), which act through > or =1 of the p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor kappaB (NFkappaB) signaling pathways to induce TGF-beta1 expression.


We used small molecule inhibitors and short interfering RNAs to knock down these pathways to study the mechanism by which HCV regulates TGF-beta1 production in the infectious JFH1 model.


We demonstrated that HCV induces ROS and TGF-beta1 expression. We further found that JFH1 induces the phosphorylation of p38MAPK, JNK, ERK, and NFkappaB. We also found that HCV-mediated TGF-beta1 enhancement occurs through a ROS-induced and p38 MAPK, JNK, ERK1/2, NFkappaB-dependent pathway.


These findings provide further evidence to support the hypothesis that HCV enhances hepatic fibrosis progression through the generation of ROS and induction of TGF-beta1. Strategies to limit the viral induction of oxidative stress appear to be warranted to inhibit fibrogenesis.

Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

[PubMed - indexed for MEDLINE]
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