Murao K, Imachi H, Yu X, Cao W M, Nishiuchi T, Chen K, Li J, Ahmed R A M, Wong N C W, Ishida T
Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan.
Gut. 2008 May;57(5):664-71. doi: 10.1136/gut.2006.111443. Epub 2007 Nov 12.
Infection with the hepatitis C virus (HCV) causes acute hepatitis. This disease has a high probability of becoming chronic and leading to cirrhosis, but a more deadly consequence is hepatocellular carcinoma. Interferon alpha (IFN alpha)-based treatment combined with ribavirin is the major therapeutic choice available for the treatment of chronic HCV infection.
The scavenger receptor class B type I (SR-BI) or its human homologue CD36 and LIMPII Analogous-1 (hSR-BI/CLA-1) has recently been shown to interact with HCV envelope glycoprotein E2, thus suggesting that it might participate in entry of the virus into host cells. This rationale underlies current interest in the potential role of IFN alpha in hSR-BI/CLA-1 expression in HepG2 cells.
It was shown that endogenous hepatocyte expression of hSR-BI/CLA-1 was suppressed by exposure to IFN alpha. Decreased hSR-BI/CLA-1 expression in IFN alpha-treated cells was due to lower transcriptional activity of the promoter. A potential pathway for the effect of IFN alpha on hSR-BI/CLA-1 promoter activity was identified when the inhibitory action of IFN was abrogated in signal transducer and activator of transcription 1 (STAT1)/STAT2 knocked-down cells. Exposure of HepG2 cells to IFN alpha elicited a rapid phosphorylation of STAT1/STAT2, a known target of IFN alpha signalling. In addition, the mutagenesis of a STAT1/STAT2 response element in the hSR-BI/CLA-1 promoter abolished the ability of IFN alpha to suppress promoter activity.
Together, these results indicate that the STAT1/STAT2 pathway participates in IFN alpha inhibition of hSR-BI/CLA-1 expression, and raise the possibility that lowering the expression of this gene may be of therapeutic value for treating HCV infections.
丙型肝炎病毒（HCV）感染会引发急性肝炎。这种疾病很有可能发展为慢性肝炎并导致肝硬化，但更致命的后果是肝细胞癌。基于干扰素α（IFNα）联合利巴韦林的治疗是目前治疗慢性HCV感染的主要选择。
清道夫受体B1型（SR-BI）或其人类同源物CD36和LIMPII类似物-1（hSR-BI/CLA-1）最近被证明可与HCV包膜糖蛋白E2相互作用，因此表明它可能参与病毒进入宿主细胞的过程。这一理论依据引发了当前对IFNα在HepG2细胞中hSR-BI/CLA-1表达潜在作用的关注。
研究表明，暴露于IFNα会抑制hSR-BI/CLA-1的内源性肝细胞表达。IFNα处理的细胞中hSR-BI/CLA-1表达降低是由于启动子的转录活性较低。当在信号转导和转录激活因子1（STAT1）/STAT2敲低的细胞中消除IFN的抑制作用时，确定了IFNα对hSR-BI/CLA-1启动子活性影响的潜在途径。将HepG2细胞暴露于IFNα会引发STAT1/STAT2的快速磷酸化，STAT1/STAT2是IFNα信号传导的已知靶点。此外，hSR-BI/CLA-1启动子中STAT1/STAT2反应元件的诱变消除了IFNα抑制启动子活性的能力。
这些结果共同表明，STAT1/STAT2途径参与了IFNα对hSR-BI/CLA-1表达的抑制，并增加了降低该基因表达可能对治疗HCV感染具有治疗价值的可能性。
