title: Induction of tumor necrosis factor alpha production by human hepatocytes in chronic viral hepatitis.
abstract: Tumor necrosis factor alpha (TNF-alpha) is a multifunctional cytokine that has an important role in the pathogenesis of inflammation, cachexia, and septic shock. Although TNF-alpha is mainly produced by macrophages, there is evidence regarding TNF-alpha production by cells that are not derived from bone marrow. TNF-alpha production by normal and inflamed human liver was assessed at both mRNA and protein levels. Using a wide panel of novel anti-TNF-alpha monoclonal antibodies and a specific polyclonal antiserum, TNF-alpha immunoreactivity was found in hepatocytes from patients chronically infected with either hepatitis B virus (HBV) or hepatitis C virus. Minimal TNF-alpha immunoreactivity was detected in the mononuclear cell infiltrate and Kupffer cells. In situ hybridization experiments using a TNF-alpha RNA probe showed a significant expression of TNF-alpha mRNA in hepatocytes, Kupffer cells, and some infiltrating mononuclear cells. By contrast, TNF-alpha was detected at low levels in liver biopsies from normal individuals or patients with alcoholic liver disease and low expression of TNF-alpha mRNA was observed in these specimens. Transfection of HepG2 hepatoblastoma cells with either HBV genome or HBV X gene resulted in induction of TNF-alpha expression. Our results demonstrate that viral infection induces, both in vivo and in vitro, TNF-alpha production in hepatocytes, and indicate that the HBV X protein may regulate the expression of this cytokine. These findings suggest that TNF-alpha may have an important role in human liver diseases induced by viruses.
authors.affiliation: Sección de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: González-Amaro
authors.forename: C
authors.initials: C
authors.lastname: García-Monzón
authors.forename: L
authors.initials: L
authors.lastname: García-Buey
authors.forename: R
authors.initials: R
authors.lastname: Moreno-Otero
authors.forename: J L
authors.initials: JL
authors.lastname: Alonso
authors.forename: E
authors.initials: E
authors.lastname: Yagüe
authors.forename: J P
authors.initials: JP
authors.lastname: Pivel
authors.forename: M
authors.initials: M
authors.lastname: López-Cabrera
authors.forename: E
authors.initials: E
authors.lastname: Fernández-Ruiz
authors.forename: F
authors.initials: F
authors.lastname: Sánchez-Madrid
mesh_terms: D000911:Antibodies, Monoclonal; D002460:Cell Line; D000939:Epitopes / Q000032:analysis; D006509:Hepatitis B / Q000378:metabolism* / Q000473:pathology; D006526:Hepatitis C / Q000378:metabolism* / Q000473:pathology; D018197:Hepatoblastoma / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha