High-mobility group box 1 exacerbates concanavalin A-induced hepatic injury in mice.
High-mobility group box 1 (HMGB1) is a nuclear factor released extracellularly as an early endogenous alarmin of inflammation following injury and as a late mediator of lethality in sepsis. Although HMGB1 has been implicated in acute lung injury, rheumatoid arthritis, and allograft rejection, its role in T-cell mediated hepatitis remains obscure. Here, we investigated the role and the underlying mechanisms of HMGB1 in concanavalin A (Con A) induced hepatic injury. We demonstrate that high levels of HMGB1 were detected in the necrotic area and in the cytoplasm of hepatocytes after Con A treatment. Administration of exogenous recombinant HMGB1 enhanced Con A-induced hepatitis, while blockade of HMGB1 protected animals from T cell-mediated hepatitis as evidenced by decreased serum transaminase, associated with reduced hepatic necrosis and mortality. Blockade of HMGB1 by a neutralizing antibody inhibited proinflammatory cytokine production, NFκB activity, and the late stage of T/NKT cell activation. These finding thus suggest a pivotal factor of HMGB1 in Con A-induced hepatitis. Blockage of extracellular HMGB1 may represent a novel therapeutic strategy to prevent hepatic injury in T cell-mediated hepatitis.
Gong
Quan
Q
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Zhang
Hui
H
Li
Jun-hua
JH
Duan
Li-hua
LH
Zhong
Shan
S
Kong
Xiao-ling
XL
Zheng
Fang
F
Tan
Zheng
Z
Xiong
Ping
P
Chen
Gang
G
Fang
Min
M
Gong
Fei-li
FL
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology*; D003208:Concanavalin A / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008954:Models, Biological; D055611:Natural Killer T-Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D019138:Antibodies, Blocking; D024243:HMGB1 Protein; D011994:Recombinant Proteins; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007371:Interferon-gamma