Molecular Mechanism For Resistance To Interferon Therapy

干扰素治疗耐药的分子机制

• 批准号: 6675119
• 负责人: bin gao
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6675119
• 关键词: JAK kinase; alcoholic liver cirrhosis; cytokine receptors; drug interactions; drug resistance; enzyme activity; enzyme induction /repression; genetically modified animals; human tissue; immunotherapy; infectious hepatitis; interferon alpha; laboratory mouse; liver pharmacology; nonhuman therapy evaluation; pharmacogenetics; protein tyrosine phosphatase; tissue /cell culture; tumor necrosis factor alpha

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.

干扰素-alpha（IFN-Alpha）目前是慢性病毒肝炎治疗的主要选择，但是，超过60％的患者反应良好，饮酒者不反应。我们的实验室专注于抑制IFN信号传导和对治疗抗性的宿主因素。我们以前已经证明，肝脏中的IFN-Alpha信号被多种宿主因素抑制，包括IL-1，IL-10，TNF-Alpha和饮酒。在今年，我们确定另一个宿主因素IFN-Gamma也参与了对IFN疗法的抗性。我们证明，IFN-GAMMA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-Alpha信号传导。此外，在慢性酒精性肝病中，肝脏中IFN-α信号传导成分和抗病毒蛋白的表达降低。综上所述，我们的发现表明，包括酒精在内的多个宿主因素有助于慢性丙型肝炎患者对IFN-Alpha疗法的抗性。

项目成果

Expression of interferon alfa signaling components in human alcoholic liver disease.

干扰素α信号成分在人类酒精性肝病中的表达。

• DOI: 10.1053/jhep.2002.31169
• 发表时间: 2002
• 期刊: Hepatology (Baltimore, Md.)
• 作者: Nguyen,Van-Anh;Gao,Bin
• 通讯作者: Gao,Bin