Interferon-gamma inhibits hepatitis B virus-induced NF-kappaB activation through nuclear localization of NF-kappaB-inducing kinase

Gastroenterology. 2005 Jun;128(7):2042-53. doi: 10.1053/j.gastro.2005.03.002.

Abstract

Background & aims: Nuclear factor-kappaB (NF-kappaB) signaling pathway is an important regulating pathway in liver diseases, including hepatocellular carcinoma. In our study, immunohistochemical analysis showed that NF-kappaB-inducing kinase (NIK), an upstream kinase of IkappaB kinases, nuclear localization occurs only in liver tissues obtained from hepatitis B surface antigen (HBsAg)(+) patients but not in tissues from HBsAg(-) patients. The aim of the present study was to identify the inducer of NIK nuclear localization and determine whether the NIK nuclear localization affects the hepatitis B virus (HBV)-mediated NF-kappaB activation.

Methods: The experiments were performed on HepG2.2.15 cells and on HepG2 cells transfected with pHBV1.2x, a plasmid encoding all HBV messages, using NF-kappaB-dependent luciferase reporter gene assay, electrophoretic mobility shift assay, immunoblot analysis, and fluorescent microscopy analysis.

Results: HBV induced NIK-dependent NF-kappaB activation. However, interferon (IFN)-gamma induced NIK nuclear localization and inhibited NF-kappaB activation in HepG2.2.15 cells and in HepG2 cells transfected with pHBV1.2x. When NIK nuclear localization was inhibited by deletion of nuclear localization signal on NIK, IFN-gamma did not induce the NIK nuclear localization and did not inhibit NF-kappaB activation.

Conclusions: IFN-gamma selectively inhibits HBV-mediated NF-kappaB activation. This inhibition is accomplished by NIK nuclear localization, which is a novel mechanism of NF-kappaB inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Nucleus / enzymology
  • Cell Nucleus / virology
  • Enzyme Induction
  • Genes, Reporter
  • Hepatitis B virus / pathogenicity*
  • Humans
  • Interferon-gamma / pharmacology*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Luciferases / biosynthesis
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Plasmids
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Antiviral Agents
  • NF-kappa B
  • Interferon-gamma
  • Luciferases
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase