Hepatitis B virus X protein stimulates IL-6 expression in hepatocytes via a MyD88-dependent pathway

Hepatitis B virus (HBV) X protein (HBx) has been implicated in HBV-associated carcinogenesis by activating signal transduction pathways and influencing gene transcription in liver cells. We aimed 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.

HBx was overexpressed in hepatic and hepatoma cell lines and IL-6 expression levels were measured by quantitative RT-PCR and ELISA. The activation of IRAK-1, ERKs/p38, and NF-κB was determined by Western blotting using specific anti-phosphoprotein antibodies. The role of MyD88 in these processes was analyzed by MyD88 RNAi and expression of an inactive MyD88 mutant.

Expression of HBx in hepatic and hepatoma cells led to a dramatic enhancement of IL-6 synthesis and secretion. Dysfunction of MyD88 in these cells prevented the HBx-triggered IL-6 production. HBx expression also activated downstream signaling proteins of MyD88 including IRAK-1, ERKs/p38, and NF-κB. Inactivation of these signaling molecules blocked IL-6 synthesis as well. HBx-stimulated the expression of MyD88.

In hepatocytes and hepatoma cells, HBx stimulates the production of IL-6 in a MyD88-dependent manner, indicating that parenchymal liver cells are an additional source of high levels of IL-6 in the HBV-infected liver microenvironment. HBx could be involved in HBV-mediated liver carcinogenesis, through this mechanism of action.