CD137-mediated pathogenesis from chronic hepatitis to hepatocellular carcinoma in hepatitis B virus-transgenic mice.
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.
Key Laboratory of Infection and Immunity, Institute of Biophysics, Graduate University, Chinese Academy of Sciences, Beijing, China.
Jun
J
Wang
Wenxia
W
Zhao
Liang
L
Cheng
Mingzhou
M
Guo
Dongling
D
Li
Xiaozhu
X
Li
Yi
Y
Tan
Suping
S
Ma
Suyun
S
Li
Yunsheng
Y
Yang
Lieping
L
Chen
Shengdian
S
Wang
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9