TY - JOUR
T1 - CD137-mediated pathogenesis from chronic hepatitis to hepatocellular carcinoma in hepatitis B virus-transgenic mice
AU - Wang, Jun
AU - Zhao, Wenxia
AU - Cheng, Liang
AU - Guo, Mingzhou
AU - Li, Dongling
AU - Li, Xiaozhu
AU - Tan, Yi
AU - Ma, Suping
AU - Li, Suyun
AU - Yang, Yunsheng
AU - Chen, Lieping
AU - Wang, Shengdian
PY - 2010/12/15
Y1 - 2010/12/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78650635187&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78650635187&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1000927
DO - 10.4049/jimmunol.1000927
M3 - Article
C2 - 21059892
AN - SCOPUS:78650635187
SN - 0022-1767
VL - 185
SP - 7654
EP - 7662
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -