The hepatitis B virus X protein up-regulates tumor necrosis factor alpha gene expression in hepatocytes.
Human hepatocytes infected by hepatitis B virus (HBV) produce the proinflammatory cytokine, tumor necrosis factor (TNF-). In this study, we explored the mechanism of induction of TNF- synthesis by HBV. We found that the stable HBV-transfected hepatoma cell line, 2. 2.15, expressed high-molecular-weight (HMW) TNF- mRNAs, which were absent in the parent HepG2 cells. Treatment of 2.2.15 cells with interferon alfa (IFN-) and/or interleukin-1beta (IL-1beta) reduced both viral gene transcription and TNF- mRNA expression. Transient or stable transfection of hepatocyte-derived cell lines with HBV X protein (HBx) expression vectors induced the production of biologically active TNF-. In these cells, the HBx-induced TNF- was detected both as cell-associated and soluble forms. Luciferase gene-expression assays showed that the TNF- gene promoter contained target sequences for HBx trans-activation within the proximal region of the promoter. These results indicate that the hepatocyte TNF- synthesis induced by HBV is transcriptionally up-regulated by HBx. Thus, HBx may have a role in the induction of the intrahepatic inflammatory processes that take place during acute and chronic hepatitis B.
Unidades de Biología Molecular y, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
E
E
Lara-Pezzi
P L
PL
Majano
M
M
Gómez-Gonzalo
C
C
García-Monzón
R
R
Moreno-Otero
M
M
Levrero
M
M
López-Cabrera
D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006511:Hepatitis B Antigens / Q000502:physiology; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology; D007739:L Cells; D008113:Liver Neoplasms; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
D006511:Hepatitis B Antigens; D016898:Interferon-alpha; D007375:Interleukin-1; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D008156:Luciferases