Friedman Steven G, Czura Christopher J, Tracey Kevin J
Division of Vascular Surgery, North Shore University Hospital, North Shore-Long Island Jewish Research Institute, Manhasset, New York, USA.
Curr Opin Clin Nutr Metab Care. 2003 May;6(3):283-7. doi: 10.1097/01.mco.0000068966.34812.b9.
Products of infection, ischemia, and injury stimulate the innate immune system to release proinflammatory cytokines, which act locally to activate specific cellular immune responses and initiate recovery. In pathological cases, however, cytokines are released systemically, resulting in progressive tissue injury, hypotension, organ dysfunction, or death. Observations that animals frequently succumb to systemic inflammation long after the peak activity of tumor necrosis factor and interleukin-1beta suggest that later-acting, downstream inflammatory factors can mediate the pathological sequelae of lethal systemic inflammation. Here, the authors review evidence that the chromosomal protein high mobility group box 1 is a late-acting, downstream mediator of pathological inflammation.
High mobility group box 1 recently has been identified as a proinflammatory cytokine with significantly delayed release kinetics, as compared with tumor necrosis factor and interleukin-1beta, in animal models of lethal systemic inflammation induced by endotoxin or peritonitis. Administration of exogenous high mobility group box 1 induces acute lung injury, intestinal barrier dysfunction, and lethal systemic inflammatory responses. Its functional cytokine domain has been mapped to the DNA-binding B box, providing structural information that may be useful in the rational design of new therapeutics that target the protein's activity.
Several high mobility group box 1 antagonists have recently been identified. These inhibitors may prove effective in a significantly wider therapeutic window than has been available for previous anti-cytokine strategies, because high mobility group box 1 appears in serum with a significantly delayed kinetics as compared with other cytokines.
感染、缺血及损伤产物会刺激先天性免疫系统释放促炎细胞因子，这些因子在局部发挥作用以激活特定的细胞免疫反应并启动恢复过程。然而，在病理情况下，细胞因子会全身性释放，导致进行性组织损伤、低血压、器官功能障碍或死亡。有观察表明，在肿瘤坏死因子和白细胞介素-1β的活性达到峰值很久之后，动物仍常常死于全身性炎症，这表明后期起作用的下游炎症因子可介导致死性全身性炎症的病理后遗症。在此，作者综述了有关染色体蛋白高迁移率族蛋白B1是病理性炎症后期起作用的下游介质的证据。
与肿瘤坏死因子和白细胞介素-1β相比，高迁移率族蛋白B1最近在由内毒素或腹膜炎诱导的致死性全身性炎症动物模型中被确定为一种促炎细胞因子，其释放动力学明显延迟。给予外源性高迁移率族蛋白B1会诱发急性肺损伤、肠道屏障功能障碍及致死性全身性炎症反应。其功能性细胞因子结构域已被定位到DNA结合B盒，这提供了可能有助于合理设计针对该蛋白活性的新疗法的结构信息。
最近已鉴定出几种高迁移率族蛋白B1拮抗剂。这些抑制剂可能在比以往抗细胞因子策略更宽的治疗窗内证明有效，因为与其他细胞因子相比，高迁移率族蛋白B1在血清中出现的动力学明显延迟。
