Inflammatory Effects of High Mobility Group Protein 1

高迁移率族蛋白(HMG-1)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，HMG-1在脓毒症和感染性休克的发展过程中还有其他可能至关重要的作用。在肿瘤坏死因子、白介素1或内毒素的刺激下，HMG-1可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。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HMG-1的靶细胞及其在急性炎症中的作用，我们在细菌表达系统中生产了重组人HMG-1，并将其用于研究内皮细胞和包括肺泡巨噬细胞在内的单个核细胞的炎症反应。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HMG-1的反应。HMG-1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HMG-1在靶细胞上启动的炎症轴。这些数据应该提供关于HMG-1在人类对细菌产物的急性炎症中的作用的重要新信息。

High mobility group protein (HMG-1) is a non-histone DNA binding protein that facilitates transcription. Recently, investigators have shown that HMG-1 has other roles that may be critical in the development of sepsis and septic shock. HMG-1 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 HMG-1 to acute human inflammation, we are producing recombinant human HMG-1 in a bacterial expression system and are using the protein to study inflammatory responses in endothelium and mononuclear cells including alveolar macrophages. 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 HMG-1. HMG-1 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 HMG-1 on target cells. These data should provide important new information regarding the role of HMG-1 in acute human inflammation to bacterial products.