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-α是目前治疗慢性病毒性肝炎的主要选择，然而，超过60%的患者反应较差，酗酒者没有反应。我们的实验室正在专注于参与抑制干扰素信号和抵抗治疗的宿主因素。我们先前已经证明，肝脏中的干扰素-α信号被多种宿主因素抑制，包括IL-1、IL-10、肿瘤坏死因子-α和饮酒。今年，我们发现了另一种宿主因子，干扰素-γ，也参与了对干扰素治疗的抵抗。我们证明，干扰素-γ抑制干扰素-α信号转导，并诱导肝脏中STAT1的表达。STAT1的过表达减弱了肝细胞中的干扰素-α信号。此外，在慢性酒精性肝病中，肝脏中干扰素-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导致了慢性丙型肝炎患者对干扰素-α治疗的抵抗。

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