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

Abstract

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. 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. 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. 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.