Biochemical modulation of interferon-αaction in viral hepatitis

干扰素-α 在病毒性肝炎中作用的生化调节

• 批准号: 11670515
• 负责人: NAKAO Kazuhiko
• 金额: $ 2.24万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670515/
• 关键词: Viral hepatitis; Interferon-α; IL-β; p48; ISGF3; Geranylgeranylacetone; B型肝炎ウイルス

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.

B型肝炎病毒（HBV）和C型肝炎病毒（HCV）引起慢性肝病，并且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，但半数以上的慢性HBV和HCV感染患者对IFN-α治疗仅表现为一过性或无应答。因此，目前正在这些患者中试验几种使用或不使用IFN-α的替代治疗方式。IFN-α诱导转录因子，干扰素刺激基因因子3（ISGF 3），其通过与启动子中的干扰素刺激调节元件（ISRE）结合来激活IFN诱导的抗病毒基因，例如2 '5'-OAS和PKR。我们在HBV增强子-1区域发现了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ISGF 3相互作用并介导IFN-α诱导的增强子活性抑制，该抑制可通过过表达p48（ISGF 3的一种组分）或IL- 1β共同处理而增强。p48过表达或IL-1β与IFN-α联合应用均能有效刺激PKR的表达和活性。香叶基香叶基丙酮（GGA）是一种类异戊二烯化合物，临床上用作抗溃疡药物。由于包括类维生素A在内的一些类异戊二烯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ISGF 3的形成刺激2 '5'-OAS和PKR基因的表达。此外，GGA刺激信号转导和转录激活因子1，2（STAT 1，STAT 2）和p48，ISGF 3的组件的表达，并诱导STAT 1的磷酸化。这些结果表明，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剂。

项目成果

Kazuhiko Nakao et al.: "p48(ISGF-3γ) is involved in interferon-α-induced suppression of hepatitis B virus enhancer-1 activity"The Journal of Biological Chemistry. 274・40. 28075-28078 (1999)

Kazuhiko Nakao等人：“p48(ISGF-3γ)参与干扰素α诱导的乙型肝炎病毒增强子1活性的抑制”《生物化学杂志》274·40(1999)。

Kazuhiko Nakao, Keisuke Nakata, Mayumi Yamashita, Youko Tamada, Keisuke Hamasaki, Hiroki Ishikawa, Yuji Kato, Katsumi Eguchi, Nobuko Ishii.: "p48 (ISGF-3γ) is involved in interferon-α-induced suppression of hepatitis B virus enhancer-1 activity."The Journ

Kazuhiko Nakao、Keisuke Nakata、Mayumi Yamashita、Youko Tamada、Keisuke Hamasaki、Hiroki Ishikawa、Yuji Kato、Katsumi Eguchi、Nobuko Ishii.：“p48 (ISGF-3γ) 参与干扰素 α 诱导的乙型肝炎病毒增强子抑制- 1 项活动。《杂志》

Kazuhiko Nakao et al.: "p48 (ISGF-3γ) is involved in interferon-α-induced suppression of hepatitis B virus enhancer-1 activity"The Journal of Biological Chemistry. 274. 28075-28078 (1999)

Kazuhiko Nakao 等人：“p48 (ISGF-3γ) 参与干扰素 α 诱导的乙型肝炎病毒增强子 1 活性抑制”《生物化学杂志》274. 28075-28078 (1999)。

Tatsuki Ichikawa et al.: "Geranylgeranylaceton induces antiviral gene expression in human hepatoma cells"Biochemical Biophysical Research Communications. 280・3. 933-939 (2001)

Tatsuki Ichikawa 等人：“香叶基香叶基丙酮诱导人肝癌细胞中的抗病毒基因表达”生物化学生物物理研究通讯280·3（2001）。

Tatsuki Ichikawa et al.: "Geranylgeranylaceton induces antiviral gene expression in human hepatoma cells"Biochemical Biophysical Research Communications. 280. 933-939 (2001)

Tatsuki Ichikawa 等人：“香叶基香叶基丙酮诱导人肝癌细胞中的抗病毒基因表达”《生物化学生物物理研究通讯》。