CD137-mediated pathogenesis from chronic hepatitis to hepatocellular carcinoma in hepatitis B virus-transgenic mice

Jun Wang, Wenxia Zhao, Liang Cheng, Mingzhou Guo, Dongling Li, Xiaozhu Li, Yi Tan, Suping Ma, Suyun Li, Yunsheng Yang, Lieping Chen, Shengdian Wang

Research output: Contribution to journalArticle

Abstract

Chronic hepatitis B virus (HBV) infection is characterized by sustained liver inflammation with an influx of lymphocytes, which contributes to the development of cirrhosis and hepatocellular carcinoma. The mechanisms underlying this immune-mediated hepatic pathogenesis remain ill defined. We report in this article that repetitive infusion of anti-CD137 agonist mAb in HBV-transgenic mice closely mimics this process by sequentially inducing hepatitis, fibrosis, cirrhosis, and, ultimately, liver cancer. CD137 mAb initially triggers hepatic inflammatory infiltration due to activation of nonspecific CD8+ T cells with memory phenotype. CD8+ T cell-derived IFN-γ plays a central role in the progression of chronic liver diseases by actively recruiting hepatic macrophages to produce fibrosis-promoting cytokines and chemokines, including TNF-α, IL-6, and MCP-1. Importantly, the natural ligand of CD137 was upregulated significantly in circulating CD14+ monocytes in patients with chronic hepatitis B infection and closely correlated with development of liver cirrhosis. Thus, sustained CD137 stimulation may be a contributing factor for liver immunopathology in chronic HBV infection. Our studies reveal a common molecular pathway that is used to defend against viral infection but also causes chronic hepatic diseases.

Original languageEnglish (US)
Pages (from-to)7654-7662
Number of pages9
JournalJournal of Immunology
Volume185
Issue number12
DOIs
StatePublished - Dec 15 2010

ASJC Scopus subject areas

  • Immunology

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    Wang, J., Zhao, W., Cheng, L., Guo, M., Li, D., Li, X., Tan, Y., Ma, S., Li, S., Yang, Y., Chen, L., & Wang, S. (2010). CD137-mediated pathogenesis from chronic hepatitis to hepatocellular carcinoma in hepatitis B virus-transgenic mice. Journal of Immunology, 185(12), 7654-7662. https://doi.org/10.4049/jimmunol.1000927