Inflammatory Effects Of High Mobility Group Protein 1

高迁移率基团蛋白（HMGB1）是一种促进转录的非组蛋白DNA结合蛋白。最近，研究人员发现HMGB1在脓毒症和感染性休克的发展中具有其他重要作用。HMGB1作为脓毒症的晚期介质（即在8至15小时后）从受TNF、IL-1或内毒素刺激的单核细胞中释放出来。它在脓毒症小鼠和脓毒症患者的血液中检测到，当给予脓毒症小鼠时，它会恶化结果。它在发育中的大脑神经元轴突的迁移中起作用，并激活纤溶酶原。一些作用是通过RAGE受体（晚期糖基化产物受体）进行的，它在糖尿病的慢性炎症中起作用。这种新的炎症轴在人类败血症中仍有待研究。为了研究HMGB1的靶细胞及其在人类急性炎症中的作用，我们在细菌和酵母表达系统中制备了重组人HMGB1，并诱导人原代细胞系释放HMGB1。这使我们有机会研究天然蛋白和重组蛋白在靶细胞中的作用，包括内皮细胞（Blood 2003;101:2652）、呼吸上皮细胞和单核细胞。

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.