Biochemical modulation of interferon-αaction in viral hepatitis

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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.