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.
Lara-Pezzi
E
E
Unidades de Biología Molecular y, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
Majano
P L
PL
Gómez-Gonzalo
M
M
García-Monzón
C
C
Moreno-Otero
R
R
Levrero
M
M
López-Cabrera
M
M
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