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

• Published in: The Journal of immunology (1950) 2010-12, Vol.185 (12), p.7654-7662
• Main Authors: Wang, Jun, Zhao, Wenxia, Cheng, Liang, Guo, Mingzhou, Li, Dongling, Li, Xiaozhu, Tan, Yi, Ma, Suping, Li, Suyun, Yang, Yunsheng, Chen, Lieping, Wang, Shengdian
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - virology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Hepatitis B virus; Hepatitis B virus - genetics; Hepatitis B virus - immunology; Hepatitis B, Chronic - genetics; Hepatitis B, Chronic - immunology; Hepatitis B, Chronic - metabolism; Humans; Immunologic Memory - drug effects; Immunologic Memory - genetics; Immunologic Memory - immunology; Lipopolysaccharide Receptors - genetics; Lipopolysaccharide Receptors - immunology; Lipopolysaccharide Receptors - metabolism; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - immunology; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Liver Neoplasms, Experimental - virology; Mice; Mice, Transgenic; Monocytes - immunology; Monocytes - metabolism; Monocytes - pathology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - agonists; Tumor Necrosis Factor Receptor Superfamily, Member 9 - biosynthesis; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism; Up-Regulation - drug effects; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1000927

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.