High-mobility group box 1 exacerbates concanavalin A-induced hepatic injury in mice
High-mobility group box 1 exacerbates concanavalin A-induced hepatic injury in mice
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DOI：
10.1007/s00109-010-0681-7
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发表时间：
2010-12-01
影响因子：
4.7
通讯作者：
Gong, Fei-li
中科院分区：
文献类型：
--
作者：
Gong, Quan;Zhang, Hui;Gong, Fei-li
高迁移率族蛋白1（HMGB 1）是一种细胞外释放的核因子，作为损伤后炎症的早期内源性警报素和脓毒症的晚期致死性介质。尽管HMGB 1与急性肺损伤、类风湿性关节炎和同种异体移植排斥有关，但其在T细胞介导的肝炎中的作用仍不清楚。本研究旨在探讨HMGB 1在刀豆球蛋白A（ConA）诱导的肝损伤中的作用及其机制。我们证明，高水平的HMGB 1被检测到的坏死区域和细胞质中的肝细胞Con A治疗后。外源性重组HMGB 1的管理增强刀豆蛋白A诱导的肝炎，而HMGB 1的封锁保护动物从T细胞介导的肝炎证明血清转氨酶降低，与肝坏死和死亡率降低。通过中和抗体阻断HMGB 1可抑制促炎细胞因子的产生、NF κ B活性和晚期T/NKT细胞活化。因此，这些发现表明HMGB 1在Con A诱导的肝炎中是一个关键因素。细胞外HMGB 1的阻断可能代表了一种新的治疗策略，以防止T细胞介导的肝炎肝损伤。
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, NF kappa B 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.