Effect of Interferon-Alpha, Ribavirin, Pentoxifylline, and Interleukin-18 Antibody on Hepatitis C Sera-Stimulated Hepatic Stellate Cell Proliferation

Abstract

Chronic hepatitis C virus (HCV) infection is a major cause of liver fibrosis ultimately leading to cirrhosis. Hepatic stellate cell (HSC) proliferation is crucial in fibrosis development. Current antiviral treatment for HCV involves interferon-alpha (IFN-alpha) and Ribavirin combination therapy. IL-18, a novel cytokine of the IL-1 family of cytokines, is involved in inflammation and may be important in HCV-related inflammation. We hypothesize that block of one of the crucial events will block fibrosis due to HCV. The effect of HCV patient sera with and without IFN-alpha, ribavirin, and IL-18 antibody on HSC proliferation was assessed by [(3)H]-thymidine incorporation assays. Western analysis was used to assess the effect of pentoxifylline (PTX) on c-Jun immediate early gene phosphorylation (p-c-Jun formation). We demonstrate that HCV patient sera-stimulated HSC proliferation. Ribavirin with or without IFN-alpha significantly decreased HCV sera-stimulated HSC proliferation by 50%. Western analysis revealed that HCV serum increased p-c-Jun levels, which were decreased with Ribavirin and PTX. ELISA results showed an elevation of IL-18 levels in HCV sera when compared to normal sera. IL-18 did not stimulate HSC proliferation. However, IL-18 antibody significantly decreased patient sera-stimulated HSC proliferation. In conclusion, Ribavirin decreased HSC proliferation and may act by decreasing p-c-Jun levels in HSCs. IL-18 alone did not stimulate HSC proliferation but IL-18 antibody decreased stimulation, suggesting that IL-18 may work in conjunction with some other factor to increase HSC proliferation.