Interferon α decreases expression of human scavenger receptor class BI, a possible HCV receptor in hepatocytes
Interferon α decreases expression of human scavenger receptor class BI, a possible HCV receptor in hepatocytes
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DOI：
10.1136/gut.2006.111443
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发表时间：
2008-05-01
期刊：
影响因子：
24.5
通讯作者：
Ishida, T.
中科院分区：
文献类型：
--
作者：
Murao, K.;Imachi, H.;Ishida, T.
背景：丙型肝炎病毒（HCV）感染可引起急性肝炎。这种疾病有很高的可能性成为慢性并导致肝硬化，但更致命的后果是肝细胞癌。基于干扰素α（IFN α）的治疗结合利巴韦林是可用于治疗慢性HCVinfection.Aims的主要治疗选择：清道夫受体B类I型（SR-BI）或其人类同源物CD 36和LIMPII类似物-1（hSR-BI/CLA-1）最近已被证明与HCV包膜糖蛋白E2相互作用，从而表明它可能参与病毒进入宿主细胞。结果：IFN α能抑制HepG 2细胞内源性hSR-BI/CLA-1的表达，IFN α对hSR-BI/CLA-1表达的抑制作用明显。IFN α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降低。在信号转导和转录激活因子1（STAT 1）/STAT 2敲低的细胞中，当IFN的抑制作用被废除时，鉴定了IFN α对hSR-BI/CLA-1启动子活性的影响的潜在途径。HepG 2细胞暴露于IFNa引起STAT 1/STAT 2的快速磷酸化，STAT 1/STAT 2是IFNa信号传导的已知靶点。此外，在hSR-BI/CLA-1启动子中的STAT 1/STAT 2应答元件的突变废除了IFNa抑制启动子activity.Conclusions的能力：总之，这些结果表明，STAT 1/STAT 2通路参与IFNa抑制hSR-BI/CLA-1的表达，并提高了降低该基因的表达可能具有治疗HCV感染的治疗价值的可能性。
Background: 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 a (IFN alpha)-based treatment combined with ribavirin is the major therapeutic choice available for the treatment of chronic HCV infection.Aims: 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 IFNa in hSR-BI/CLA-1 expression in HepG2 cells.Results: It was shown that endogenous hepatocyte expression of hSR-BI/CLA-1 was suppressed by exposure to IFNa. 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 IFNa 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 IFNa elicited a rapid phosphorylation of STAT1/STAT2,a known target of IFNa signalling. In addition, the mutagenesis of a STAT1/STAT2 response element in the hSR-BI/CLA-1 promoter abolished the ability of IFNa to suppress promoter activity.Conclusions: Together, these results indicate that the STAT1/STAT2 pathway participates in IFNa inhibtion 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.