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

Background & AimsThe generation of oxidative stress and transforming growth factor β1 (TGF-β1) production play important roles in liver fibrogenesis. We have previously shown that hepatitis C virus (HCV) increases hepatocyte TGF-β1 expression. However, the mechanisms by which this induction occurs have not been well studied. We explored the possibility that HCV infection regulates TGF-β1 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 κB (NFκB) signaling pathways to induce TGF-β1 expression.MethodsWe used small molecule inhibitors and short interfering RNAs to knock down these pathways to study the mechanism by which HCV regulates TGF-β1 production in the infectious JFH1 model.ResultsWe demonstrated that HCV induces ROS and TGF-β1 expression. We further found that JFH1 induces the phosphorylation of p38MAPK, JNK, ERK, and NFκB. We also found that HCV-mediated TGF-β1 enhancement occurs through a ROS-induced and p38 MAPK, JNK, ERK1/2, NFκB-dependent pathway.ConclusionsThese findings provide further evidence to support the hypothesis that HCV enhances hepatic fibrosis progression through the generation of ROS and induction of TGF-β1. Strategies to limit the viral induction of oxidative stress appear to be warranted to inhibit fibrogenesis. The generation of oxidative stress and transforming growth factor β1 (TGF-β1) production play important roles in liver fibrogenesis. We have previously shown that hepatitis C virus (HCV) increases hepatocyte TGF-β1 expression. However, the mechanisms by which this induction occurs have not been well studied. We explored the possibility that HCV infection regulates TGF-β1 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 κB (NFκB) signaling pathways to induce TGF-β1 expression. We used small molecule inhibitors and short interfering RNAs to knock down these pathways to study the mechanism by which HCV regulates TGF-β1 production in the infectious JFH1 model. We demonstrated that HCV induces ROS and TGF-β1 expression. We further found that JFH1 induces the phosphorylation of p38MAPK, JNK, ERK, and NFκB. We also found that HCV-mediated TGF-β1 enhancement occurs through a ROS-induced and p38 MAPK, JNK, ERK1/2, NFκB-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-β1. Strategies to limit the viral induction of oxidative stress appear to be warranted to inhibit fibrogenesis.