Molecular Mechanism For Resistance To Interferon Therapy

干扰素- α (ifn - α)目前是治疗慢性病毒性肝炎的主要选择，然而，超过60%的患者反应不佳，重度饮酒者无反应。我们的实验室专注于参与IFN信号抑制和治疗抵抗的宿主因子。我们之前已经证明肝脏中的ifn - α信号被多种宿主因子抑制，包括IL-1、IL-10、tnf - α和饮酒。今年，我们已经确定了另一个宿主因子，IFN- γ，也参与了对IFN治疗的耐药性。我们证明了ifn - γ抑制ifn - α信号传导并诱导肝脏中STAT1的表达。STAT1的过表达会减弱肝细胞中的ifn - α信号。此外，慢性酒精性肝病患者肝脏中ifn - α信号成分和抗病毒蛋白的表达减少。综上所述，我们的研究结果表明，包括酒精在内的多种宿主因素有助于慢性丙型肝炎患者对ifn - α治疗的抵抗。

Interferon-alpha (IFN-alpha) is currently the primary choice of treatment for chronic viral hepatitis, however, more than 60% of patients respond poorly and heavy drinkers do not respond. Our laboratory is focusing on the host factors that are involved in suppression of IFN signaling and resistance to therapy. We have previously demonstrated that IFN-alpha signaling in the liver is suppressed by multiple host factors, including IL-1, IL-10, TNF-alpha and alcohol drinking. In this year, we have identified that another host factor, IFN-gamma, is also involved in resistance to IFN therapy. We demonstrate that IFN-gamma suppresses IFN-alpha signaling and induces expression of STAT1 in the liver. Overexpression of STAT1 attenuates IFN-alpha signaling in hepatocytes. Furthermore, expression of IFN-alpha signaling components and antiviral proteins in the liver are decreased in chronic alcoholic liver disease. Taken together, our findings suggest that multiple host factors including alcohol contribute to the resistance to IFN-alpha therapy in chronic hepatitis C patients.