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 biolo gical activities, including some aspects of the immune reaction and in flammatory 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 fac tor involved in the immunoregulatory perturbations in patients with ch ronic 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 s erum IL-6 in patients with CLD with HBV infection, IL-6 productions ob served in HBV-X-transfected cells, and transcriptional transactivation s of the IL-6 gene by HBV-X, We determined serum levels of IL-6 in pat ients with chronic hepatitis B (CH-B), chronic hepatitis C (CH-C), liv er cirrhosis (LC) caused by hepatitis B, and LC with hepatocellular ca rcinoma (HCC) caused by hepatitis B (LC + HCC), Mean serum levels of I L-6 in all CLD patients were higher than those in normal controls, and the difference was statistically significant (P < 0.05), Mean IL-6 le vels of LC and LC + HCC patients were significantly higher than those of CH-B patients (P < 0,05), Because the etiological factor in all cas es except CH-C (CH-B, LC, and LC + HCC) was HBV, we checked the possib ility of HBV-transactivator-X activation of IL-6 promoter. Using delet ion constructs of 5'-flanking regulatory regions of the IL-6 gene link ed to the chloramphenicol acetyltransferase gene as a reporter, we fou nd that the binding of nuclear factor-KB to a cis element is essential and sufficient for the induction of the IL-6 gene by HBV-X, We also f ound that HBV-X enhances the binding of two subunits of nuclear factor -kappa B (p65 and p52) to their target DNA binding sequences. These ob servations are relevant, in that HBV-X might play an important role in hepatic inflammation and diseases by up-regulating IL-6 production, w hich can eventually lead to LC and HCC.