Human interleukin 6 gene is activated by hepatitis B virus-X protein in human hepatoma cells.
Interleukin 6 (IL-6) is a pleiotropic cytokine that induces many biological activities, including some aspects of the immune reaction and inflammatory responses. In the liver, IL-6 regulates the synthesis of a broad spectrum of acute-phase proteins. IL-6 is also known to be a factor involved in the immunoregulatory perturbations in patients with chronic liver diseases (CLDs). Here, we report that IL-6 can be induced by hepatitis B virus (HBV)-X protein, as evidenced by high levels of serum IL-6 in patients with CLD with HBV infection, IL-6 productions observed in HBV-X-transfected cells, and transcriptional transactivations of the IL-6 gene by HBV-X. We determined serum levels of IL-6 in patients with chronic hepatitis B (CH-B), chronic hepatitis C (CH-C), liver cirrhosis (LC) caused by hepatitis B, and LC with hepatocellular carcinoma (HCC) caused by hepatitis B (LC+HCC). Mean serum levels of IL-6 in all CLD patients were higher than those in normal controls, and the difference was statistically significant (P < 0.05). Mean IL-6 levels of LC and LC+HCC patients were significantly higher than those of CH-B patients (P < 0.05). Because the etiological factor in all cases except CH-C (CH-B, LC, and LC+HCC) was HBV, we checked the possibility of HBV-transactivator-X activation of IL-6 promoter. Using deletion constructs of 5'-flanking regulatory regions of the IL-6 gene linked to the chloramphenicol acetyltransferase gene as a reporter, we found that the binding of nuclear factor-kappaB to a cis element is essential and sufficient for the induction of the IL-6 gene by HBV-X. We also found that HBV-X enhances the binding of two subunits of nuclear factor-kappaB (p65 and p52) to their target DNA binding sequences. These observations are relevant, in that HBV-X might play an important role in hepatic inflammation and diseases by up-regulating IL-6 production, which can eventually lead to LC and HCC.
Molecular Cell Biology Research Division, Korea Research Institute of Bioscience and Biotechnology, KIST, Taejon.
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Lee
U S
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Park
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Choi
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SK
Yoon
Y M
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Park
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YI
Lee
D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000097:blood*; D005822:Genetic Vectors; D006521:Hepatitis, Chronic / Q000097:blood*; D006525:Hepatitis, Viral, Human / Q000097:blood*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D008103:Liver Cirrhosis / Q000097:blood*; D008113:Liver Neoplasms / Q000097:blood*; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; D016328:NF-kappa B; D015534:Trans-Activators