Interferon-gamma inhibits hepatitis B virus-induced NF-kappaB activation through nuclear localization of NF-kappaB-inducing kinase.
OBJECTIVE
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.
Park
Sung Gyoo
SG
School of Biological Sciences, Seoul National University, Korea.
Ryu
Hyun Mi
HM
Lim
Seong-Oe
SO
Kim
Yong-Il
YI
Hwang
Soon B
SB
Jung
Guhung
G
D000998:Antiviral Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000201:enzymology / Q000821:virology; D004790:Enzyme Induction; D017930:Genes, Reporter; D006515:Hepatitis B virus / Q000472:pathogenicity*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000096:biosynthesis; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010957:Plasmids; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D000097782:NF-kappaB-Inducing Kinase
D000998:Antiviral Agents; D007371:Interferon-gamma; D008156:Luciferases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase