Interferon-γ inhibits hepatitis B virus-induced NF-κB activation through nuclear localization of NF-κB-inducing kinase

Background & Aims: Nuclear factor-kappa B (NF-kappa B) signaling pathway is an important regulating pathway in liver diseases, including hepatocellular carcinoma. In our study, immunohistochemical analysis showed that NF-kappa B-inducing kinase (NIK), an upstream kinase of I kappa B 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-kappa B 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-kappa B-dependent luciferase reporter gene assay, electrophoretic mobility shift assay, immunoblot analysis, and fluorescent microscopy analysis. Results: HBV induced NIK-dependent NF-kappa B activation. However, interferon (IFN)-gamma induced NIK nuclear localization and inhibited NF-kappa B 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-kappa B activation. Conclusions: IFN-gamma selectively inhibits HBV-mediated NF-kappa B activation. This inhibition is accomplished by NIK nuclear localization, which is a novel mechanism of NF-kappa B inhibition.