Effect of interferon-alpha, ribavirin, pentoxifylline, and interleukin-18 antibody on hepatitis C sera-stimulated hepatic stellate cell proliferation.
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.
Departments of Medicine and Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Fareeha
F
Khan
Kevork M
KM
Peltekian
Theresa C
TC
Peterson
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016174:Hepacivirus; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000473:pathology*; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology; D020382:Interleukin-18 / Q000276:immunology; D010431:Pentoxifylline / Q000276:immunology / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012254:Ribavirin / Q000276:immunology / Q000494:pharmacology; D044967:Serum; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D016898:Interferon-alpha; D020382:Interleukin-18; D016755:Proto-Oncogene Proteins c-jun; D012254:Ribavirin; D010431:Pentoxifylline