Biochemical modulation of interferon-αaction in viral hepatitis

乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）引起慢性肝病，并与肝细胞癌的发展密切相关。干扰素-α (IFN-α)已被用作抗HBV和HCV的抗病毒药物。然而，超过一半的慢性感染这些病毒的患者对IFN-α治疗仅表现出短暂或无反应。因此，几种有或没有IFN-α的替代治疗方式目前正在这些患者中进行试验。IFN-α诱导转录因子干扰素刺激基因因子3 （ISGF3）通过与启动子中的干扰素刺激调控元件（ISRE）结合，激活IFN诱导的抗病毒基因，如2'5'-OAS和PKR。我们在HBV增强子-1区发现了isre样序列，并阐明了该序列的作用。HBV增强子-1中的isre样序列与ISGF3相互作用，介导IFN-α-诱导的增强子活性抑制，这种抑制通过ISGF3成分p48的过表达或IL- 1β的共同处理而增强。此外，p48过表达或IL-1β联合IFN-α可有效刺激PKR在人肝癌细胞中的表达及其活性。香叶酮（GGA）是一种类异戊二烯化合物，在临床上被用作抗溃疡药物。由于一些类异戊二烯类包括类维生素a在多种细胞中具有抗肿瘤和抗病毒活性，我们研究了GGA是否可以在人肝癌细胞中诱导抗病毒蛋白。GGA通过诱导ISGF3的形成刺激2’5’-OAS和PKR基因的表达。此外，GGA刺激ISGF3组分1、2 （STAT1、STAT2）和p48的信号转导和转录激活因子的表达，并诱导STAT1的磷酸化。这些结果提示p48过表达、IL-1β或GGA可能是刺激IFN-α诱导的抗病毒基因表达的调节因子。

Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic liver disease, and are closely linked to development of hepatocellular carcinoma. Interferon-α (IFN-α) has been used as an antiviral agent against HBV and HCV.However, more than half of patients chronically infected by these viruses show only transient or no response to IFN-α treatment. Thus, several alternative treatment modalities with or without IFN-α are now on trial in these patients. IFN-α induces transcription factors, interferon stimulated gene factor 3 (ISGF3) which activates IFN-inducible antiviral genes such as 2'5'-OAS and PKR through binding to the interferon stimulated regulatory element (ISRE) in the promoters. We found the ISRE-like sequence in the HBV enhancer-1 region and elucidated the role of this sequence. The ISRE-like sequence in the HBV enhancer-1 interacted with ISGF3 and mediated the IFN-α-induced suppression of the enhancer activity, which was augmented by overexpression of p48, a component of ISGF3, or by IL- 1β co-treatment. Further more, p48 overexpression or IL-1β in combination with IFN-α effectively stimulated the expression of PKR and its activity in human hepatoma cells. Geranylgeranylacetone (GGA), an isoprenoid compound, is used clinically as an anti-ulcer drug. Since some isoprenoids including retinoids have anti-tumor and anti-viral activities in a variety of cells, we investigated whether GGA could induce anti-viral proteins in human hepatoma cells. GGA stimulated both 2'5'-OAS and PKR gene expression through inducing the formation of ISGF3. In addition, GGA stimulated expression of signal transducers and activators of transcription 1, 2 (STAT1, STAT2) and p48, components of ISGF3, and induced the phosphorylation of STAT1. These results suggest that p48 overexpression, IL-1β or GGA are possible modulators stimulating the IFN-α-induced antiviral gene expression.