Hepatitis C Virus Regulates Transforming Growth Factor β1 Production Through the Generation of Reactive Oxygen Species in a Nuclear Factor κB-Dependent Manner

BACKGROUND & AIMS: The generation of oxidative stress and transforming growth factor beta 1 (TGF-beta 1) production play important roles in liver fibrogenesis. We have previously shown that hepatitis C virus (HCV) increases hepatocyte TGF-beta 1 expression. However, the mechanisms by which this induction occurs have not been well studied. We explored the possibility that HCV infection regulates TGF-beta 1 expression through the generation of reactive oxygen species (ROS), which act through >= 1 of the p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor kappa B (NF kappa B) signaling pathways to induce TGF-beta 1 expression. METHODS: We used small molecule inhibitors and short interfering RNAs to knock down these pathways to study the mechanism by which HCV regulates TGF-beta 1 production in the infectious JFH1 model. RESULTS: We demonstrated that HCV induces ROS and TGF-beta 1 expression. We further found that JFH1 induces the phosphorylation of p38MAPK, JNK, ERK, and NF kappa B. We also found that HCV-mediated TGF-beta 1 enhancement occurs through a ROS-induced and p38 MAPK, JNK, ERK1/2, NF kappa B-dependent pathway. CONCLUSIONS: These findings provide further evidence to support the hypothesis that HCV enhances hepatic fibrosis progression through the generation of ROS and induction of TGF-beta 1. Strategies to limit the viral induction of oxidative stress appear to be warranted to inhibit fibrogenesis.