Induction of tumor necrosis factor alpha production by human hepatocytes in chronic viral hepatitis.
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.
González-Amaro
R
R
Sección de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Spain.
García-Monzón
C
C
García-Buey
L
L
Moreno-Otero
R
R
Alonso
J L
JL
Yagüe
E
E
Pivel
J P
JP
López-Cabrera
M
M
Fernández-Ruiz
E
E
Sánchez-Madrid
F
F
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*
D000911:Antibodies, Monoclonal; D000939:Epitopes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha