Inflammatory Effects Of High Mobility Group Protein 1

高迁移率族蛋白(HMGB1)是一种促进转录的非组蛋白DNA结合蛋白。最近，研究人员表明，HMGB1在脓毒症和感染性休克的发展过程中还发挥着其他关键作用。在肿瘤坏死因子、白介素1或内毒素的刺激下，HMGB1作为败血症的晚期介质(即8至15小时后)从单个核细胞释放出来。它在败血症小鼠和败血症患者的血液中检测到，当给败血症小鼠服用时，它会恶化结果。它在发育中的大脑中扮演着迁移神经元轴突的角色，并激活纤溶酶原。其中一些作用是通过RAGE受体(高级糖基化产物的受体)实现的，RAGE受体在糖尿病的慢性炎症中发挥作用。这一新的炎症轴在人类脓毒症中的特征仍有待研究。为了研究HMGB1的靶细胞及其在急性炎症中的作用，我们在细菌和酵母表达系统中制备了重组人HMGB1，并诱导了人原代细胞释放HMGB1。这使我们有机会研究天然和重组蛋白在靶细胞中的作用，包括内皮细胞(血液2003；101：2652)、呼吸道上皮细胞和单个核细胞。 此外，我们正在开发完整分子的生物活性多肽片段，以研究结构和功能之间的关系。我们将研究人类细胞系和移行的人类细胞在内毒素作用下RAGE的表达及其对HMGB1的反应。HMGB1还将在从内毒素攻击的志愿者身上获得的血液和炎症灌洗液中进行研究(方案92-CC-0141)。寡核苷酸基因阵列将用于研究HMGB1在靶细胞上启动的炎症轴。这些数据将为HMGB1在人类对细菌产物的急性炎症中的作用提供重要的新信息。

High mobility group protein (HMGB1) is a non-histone DNA binding protein that facilitates transcription. Recently, investigators have shown that HMGB1 has other roles that may be critical in the development of sepsis and septic shock. HMGB1 is released as a late mediator of sepsis (i.e., after 8 to 15 hours) from mononuclear cells stimulated with TNF, IL-1, or endotoxin. It is detected in the blood of septic mice and in septic patients and it worsens outcome when given to septic mice. It plays a role in migrating axons of neurons in the developing brain and it activates plasminogen. Some of the actions are through the RAGE receptor (receptor for advanced glycation products) which plays a role in chronic inflammation in diabetes. This novel axis of inflammation remains to be characterized in human sepsis. In order to study the target cells and contribution of HMGB1 to acute human inflammation, we have produced recombinant human HMGB1 in bacterial and yeast expression systems and have induced the release of HMGB1 from primary human cell lines. This has afforded us the opportunity to study native and recombinant protein effects in target cells including endothelium (Blood 2003;101:2652), respiratory epithelium, and mononuclear cells. In addition, we are developing biologically active peptide fragments of the intact molecule in order to study structure function relationships. Cell lines and migrating human cells from humans challenged with endotoxin will be studied for the expression of RAGE and their responses to HMGB1. HMGB1 will also be studied in blood and inflammatory lavage obtained from volunteers challenged with endotoxin (protocol 92-CC-0141). Oligonucleotide gene arrays will be used to study the inflammatory axis initiated by HMGB1 on target cells. These data should provide important new information regarding the role of HMGB1 in acute human inflammation to bacterial products.