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Human interleukin 6 gene is activated by hepatitis B virus-X protein in human hepatoma cells.
Clin Cancer Res. 1998 Jul; 4(7):1711-7.CC

Abstract

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.

Authors+Show Affiliations

Molecular Cell Biology Research Division, Korea Research Institute of Bioscience and Biotechnology, KIST, Taejon.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9676846

Citation

Lee, Y, et al. "Human Interleukin 6 Gene Is Activated By Hepatitis B virus-X Protein in Human Hepatoma Cells." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 4, no. 7, 1998, pp. 1711-7.
Lee Y, Park US, Choi I, et al. Human interleukin 6 gene is activated by hepatitis B virus-X protein in human hepatoma cells. Clin Cancer Res. 1998;4(7):1711-7.
Lee, Y., Park, U. S., Choi, I., Yoon, S. K., Park, Y. M., & Lee, Y. I. (1998). Human interleukin 6 gene is activated by hepatitis B virus-X protein in human hepatoma cells. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 4(7), 1711-7.
Lee Y, et al. Human Interleukin 6 Gene Is Activated By Hepatitis B virus-X Protein in Human Hepatoma Cells. Clin Cancer Res. 1998;4(7):1711-7. PubMed PMID: 9676846.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human interleukin 6 gene is activated by hepatitis B virus-X protein in human hepatoma cells. AU - Lee,Y, AU - Park,U S, AU - Choi,I, AU - Yoon,S K, AU - Park,Y M, AU - Lee,Y I, PY - 1998/7/24/pubmed PY - 1998/7/24/medline PY - 1998/7/24/entrez SP - 1711 EP - 7 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 4 IS - 7 N2 - 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. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/9676846/Human_interleukin_6_gene_is_activated_by_hepatitis_B_virus_X_protein_in_human_hepatoma_cells_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=9676846 DB - PRIME DP - Unbound Medicine ER -