Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
J Mol Med (Berl). 2010 Dec;88(12):1289-98. doi: 10.1007/s00109-010-0681-7. Epub 2010 Sep 17.
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.
高迁移率族蛋白 B1（HMGB1）是一种核因子，在损伤后作为炎症的早期内源性警报素释放到细胞外，并作为脓毒症中致死性的晚期介质。尽管 HMGB1 已被牵涉到急性肺损伤、类风湿关节炎和同种异体移植物排斥反应中，但它在 T 细胞介导的肝炎中的作用仍不清楚。在这里，我们研究了 HMGB1 在伴刀豆球蛋白 A（Con A）诱导的肝损伤中的作用和潜在机制。我们发现在 Con A 处理后，坏死区域和肝细胞的细胞质中检测到高水平的 HMGB1。外源性重组 HMGB1 的给药增强了 Con A 诱导的肝炎，而 HMGB1 的阻断则通过降低血清转氨酶、相关的肝坏死和死亡率，保护动物免受 T 细胞介导的肝炎。通过中和抗体阻断 HMGB1 抑制了促炎细胞因子的产生、NFκB 活性和 T/NKT 细胞的晚期激活。这些发现因此表明 HMGB1 在 Con A 诱导的肝炎中是一个关键因素。阻断细胞外 HMGB1 可能代表预防 T 细胞介导的肝炎中肝损伤的一种新的治疗策略。
