Hepatitis B Virus X Protein Induces IL-6 Synthesis In Hepatocytes Via A MyD88-dependent Pathway

Background/Aims:Hepatitis B virus(HBV) X protein(HBx) mediates HBV-associated tumorigenesis by activating signal transduction pathways and influencing gene transcriptions in liver cells.We aim to investigate the underlying mechanisms for HBx-induced production of interleukin-6(IL-6),one of the major inflammatory mediators that stimulate hepatocellular carcinoma development.Methods:HBx was overexpressed in two lines of hepatocytes and the IL-6 expression level was measured by quantitative RT-PCR and ELISA respectively.The phosphorylation and activation of the IRAK-1,p38 and ERKs were determined by western blotting using specific phospho-protein antibodies.The role of MyD88 in the processes was identified by the use of MyD88 RNAi and expression of an inactive MyD88 mutant.Results:Expression of HBx in hepatocytes led a dramatic enhancement of IL-6 synthesis and secretion.Disfunction of MyD88 in these cells clearly prevented HBx-triggered IL-6 production.HBx expression also activated the kinases downstream of MyD88 including IRAK1,ERK and p38,and inactivation of these kinases blocked the synthesis of IL-6 as well.HBx stimulated the expression of MyD88.Conclusions:HBx enhances in hepatocytes in a MyD88-dependent manner the production of IL-6,indicating that hepatocyte could also be an origin of the high level IL-6 in HBV-infected liver microenvironment.This role of HBx could be involved in the mechanism of HBV-mediated liver carcinogenesis.