Clinical Cancer Research, Vol 4, Issue 7 1711-1717, Copyright © 1998 by American Association for Cancer Research

ARTICLES

Human interleukin 6 gene is activated by hepatitis B virus-X protein in human hepatoma cells

Y Lee, US Park, I Choi, SK Yoon, YM Park and YI Lee
Molecular Cell Biology Research Division, Korea Research Institute of Bioscience and Biotechnology, KIST, Taejon.

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.

This article has been cited by other articles:

				C. Porta, M. De Amici, S. Quaglini, C. Paglino, F. Tagliani, A. Boncimino, R. Moratti, and G. R. Corazza Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma Ann. Onc., February 1, 2008; 19(2): 353 - 358. [Abstract] [Full Text] [PDF]

				A. Budhu and X. W. Wang The role of cytokines in hepatocellular carcinoma J. Leukoc. Biol., December 1, 2006; 80(6): 1197 - 1213. [Abstract] [Full Text] [PDF]

				S. R. Paludan Requirements for the Induction of Interleukin-6 by Herpes Simplex Virus-Infected Leukocytes J. Virol., September 1, 2001; 75(17): 8008 - 8015. [Abstract] [Full Text] [PDF]

				T. H. Mogensen and S. R. Paludan Molecular Pathways in Virus-Induced Cytokine Production Microbiol. Mol. Biol. Rev., March 1, 2001; 65(1): 131 - 150. [Abstract] [Full Text] [PDF]

				S.-F. Chang, H. J. Netter, E. Hildt, R. Schuster, S. Schaefer, Y.-C. Hsu, A. Rang, and H. Will Duck Hepatitis B Virus Expresses a Regulatory HBx-Like Protein from a Hidden Open Reading Frame J. Virol., January 1, 2001; 75(1): 161 - 170. [Abstract] [Full Text]

				W.-L. Shih, M.-L. Kuo, S.-E. Chuang, A.-L. Cheng, and S.-L. Doong Hepatitis B Virus X Protein Inhibits Transforming Growth Factor-beta -induced Apoptosis through the Activation of Phosphatidylinositol 3-Kinase Pathway J. Biol. Chem., August 11, 2000; 275(33): 25858 - 25864. [Abstract] [Full Text] [PDF]