Hepatitis C Virus E1 Protein Enhances Macrophage iNOS Expression In Vitro

Abstract

ObjectiveHepatitis C virus (HCV) is a single-stranded RNA virus that causes chronic hepatitis, cirrhosis, and liver cancer. Approximately 170 million individuals are infected with HCV worldwide. The pathogenesis of HCV-associated liver injury is thought to be due to the host antiviral immune response, including the T cell response, and excessive production of proinflammatory cytokines, reactive oxygen species, and nitric oxide (NO). Interferon-{gamma} (IFN-{gamma}) is a key cytokine in the adaptive immune response that is primarily secreted from CD4+ T helper cells to induce cytotoxic T lymphocyte (CTL) cell response against HCV infection. Another important role of IFN-{gamma} is the activation of macrophages in the liver resulting in inhibition of viral replication and increased NO production. Enhanced inducible nitric oxide synthase (iNOS) expression and NO production observed in the liver of HCV-infected patients is positively correlated with viral load and hepatic inflammation. HCV-infected macrophages are major producers of NO in the liver. It is not completely understood how HCV proteins affect iNOS expression and what the role of IFN-{gamma} is in HCV protein expression in HCV-infected macrophages. In this study, we examined the effect of INF-{gamma} and HCV proteins on iNOS expression in the Raw264.7 cell line. ResultsConsistent with other studies, HCV core and NS5A proteins induced iNOS expression in macrophages. Moreover, HCV E1 protein-enhanced iNOS expression is highest in the presence and absence of IFN-{gamma} activation. ConclusionThese results indicate that hepatitis C virus core, NS5A, E1 protein regulates iNOS protein expression in IFN-{gamma}-activated and resting macrophage cell lines. These findings points to a future research direction for understanding the pathogenesis of HCV-related liver inflammation.