Journal
JOURNAL OF HEPATOLOGY
Volume 54, Issue 1, Pages 26-33Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2010.08.006
Keywords
Hepatitis B virus X protein; Interleukin-6; Myeloid differentiation factor 88; IL-1 receptor-associated kinase; Mitogen-activated protein kinase; Nuclear factor-kappa B
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Funding
- National Natural Science Foundation of China [30771090]
- National Basic Research Program of China [2007CB51905]
- State S&T Projects of China [2008ZX10002-007]
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Background & Aims: 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. Methods: 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-kappa B 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. Results: 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-kappa B. Inactivation of these signaling molecules blocked IL-6 synthesis as well. HBx-stimulated the expression of MyD88. Conclusions: 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. (C) 2010 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.
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