主编  王辉 
 副主编   林晨，杜忆华，曹孟德
出版日期 2008年05月30日 总第108期 半月刊 2001年12月24日创刊
免疫学论坛 留言簿 编辑（投稿）信箱

编委（按姓氏笔划）石瑛 孙书明 李万里 宋向凤 杜丽蕊 张国俊 张勇朝 郭继强 郝文慧 袁治国 徐春阳 高志涛

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本期目录

1.HMGB1从免疫系统内部介导免疫应答

2.肝脏缺血所致TLR4依赖的活性氧分子产生和钙粒子介导的信号诱导HMGB1释放

3.细胞对危险信号HMGB1的反应迁移到组织损伤部位需要NFkB的活化

4.在凋亡介导的致死性败血症中HMGB1的作用

5.TLR和RAGE受体信号途径通过HMGB1而整合和放大

6.严重败血症患者中HMGB1作为器官功能障碍和愈后的一个指标

7.HMGB1内源性危险信号

8.在自身免疫病发病机制中细胞死亡的作用：HMGB1和微粒作为细胞间炎症的介导者

9.RAG1/2裂解活性 的HMG盒区刺激是金属粒子依赖性的

10.HMGB1信号途径

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美国NIH免疫学讲座录像Mechanisms of Leukocyte Recruitment in Inflammation
Paul Kubes, Ph.D.

欢迎各位免疫学专业教师和研究生加入到翻译志愿者的行列！

HMGB1从免疫系统内部介导免疫应答

王亚荣 译

新乡医学院医学检验系 河南新乡453003


摘要
真核多细胞有机体在进化的过程面临两个主要挑战（途径）。一是为了消除和替代濒死的细胞，二是为了防御微生物的入侵。固有免疫系统基本功能也是清除细胞碎片，形成防御病原微生物入侵的第一防线。本文重点是高迁移率组蛋白盒1 （HMGB1），HMGB1作为固有免疫系统对细胞死亡和细菌入侵的一个共同信号，HMGB1作为一种核内蛋白，从另一个侧面也表明它作为核外表达时是作为一种介质被释放。作为内源性分子的HMGB1的作用促使免疫应答，在组织调节平衡和疾病发生中也起到很大的作用。


引言
多年研究表明，即使在没有细菌感染的情况濒死细胞也能触发炎症反应。近来研究表明，坏死细胞释放核蛋白HMGB1，作为内源性分子它具有炎性特征。HMGB1的释放导致了单核细胞向组织损伤部位募集，在创伤位，HMGB1清除了细胞碎片，防御了感染发生。此外，HMGB1也给损伤组织周围细胞以警报，启动固有免疫应答，促进损伤组织修复。与死亡细胞相比，凋亡细胞几乎不会诱发周围组织发生炎症，因为HMGB1保留在凋亡细胞中而没有被释放出来。并且表明固有免疫系统对细菌和炎性刺激应答时，固有免疫细胞主动分泌出HMGB1。HMGB1的主动分泌类似死亡细胞内HMGB1的释放。当固有免疫细胞遭受病原体刺激后HMGB1的细胞外释放或者受损细胞HMGB1的细胞外释放都代表一个保护应答。


HMGB1的结构特征
HMGB1早在30年前被发现，HMGB1是根据在聚丙烯酰胺凝胶电泳中具有很高的迁移率而得名。HMGB1分子量30KD，是一种含量丰富的非组盒内蛋白，在各种真核生物进化过程中高度保守（哺乳动物中同源性99%）。HMGB1存在于各类细胞中，但在不同种细胞生长的不同阶段HMGB1在核内的表达不同。HMGB1含有215个氨基酸残基形成，含有两个DNA接合域和一个负电荷的羧基末端，每个DNA接合域代表一个"HMG box"，即A box和B box。这两个结构域尽管只有20%氨基酸一致，但其在构象是相似。结构功能分析表明，HMGB1细胞因子活性存在于重组体B box上， A box是一种特殊的拮抗剂，通过减弱HMGB1诱导巨噬细胞分致致炎性细胞因子对B box起到拮抗作用。目前还不明确的是，否是HMGB1截头存在体内生成具有抑制性的碎片起到一个负反馈机制。
HMGB1在核内功能非常重要，几乎大多数的细胞中都含有丰富的HMGB1这种蛋白，每个细胞中大约含有100万个HMGB1分子。核分子HMGB1与DNA小沟可进行非特异性结合，这种结合诱导DNA双螺旋结构极度的弯曲变形，以便DNA与各种因子之间相互作用，包括P53，NF-KB，重组活化基因，糖基化受体蛋白和类固醇激素受体。HMGB1的核内功能对生命是非常重要的，HMGB1敲除后的小鼠出生后不久就死去。表型特征表现为形体较小，毛皮有折皱和裂纹，后爪较长，缺少脂肪。
HMGB1是一种高迁移率蛋白，通过荧光标记HMGB1和光漂白作用技术（光漂白后的荧光的丧失和光漂白后荧光的回收）揭示了HMGB1在细胞中的动力学研究。在这些研究中，表明HMGB1作为整体在核内游动，与DNA非特异性结合的亲和力低，结合时间很短。与染色质的短暂结合，使HMGB1参与了基因转录、调控和蛋白翻译等生命活动。HMGB1除了在核内表达外，在一些细胞的细胞膜上也表达有HMGB1。膜相关HMGB1被作为两性物质，HMGB1参与介导神经轴突向外生长，对平滑肌细胞产生趋化作用和肿瘤细胞的转移。因此，HMGB1可以通过坏死细胞被动释放分布细胞外，或者从固有免疫细胞中主动分泌到细胞外。


HMGB1在细胞外的促炎作用
从20世纪90年代后期，人们对HMGB1蛋白的免疫生物学功能开始研究，使HMGB1的研究进入了一个文艺复兴时期。在寻求广泛的治疗窗口，用于脓毒症和内毒素血症的治疗中, Wang 等人用小鼠模型研究表明HMGB1是内毒素血症的晚期致炎物质。在试验中，用LPS、TNF-a和IL-1刺激单核-巨噬细胞随后主动分泌出HMGB1。体外研究表明用LPS刺激后，内毒素血症的早期致炎物质TNF-a和IL-1几分钟内被释放，而HMGB1在LPS刺激后18-24小时才被释放。同时，体外动力研究学表明，在内毒素血症实验模型中注射LPS 6-32小时后血清中HMGB1浓度维持较高水平。并且，使用抗HMGB1的抗体防御LPS介导致死率，这些研究都表明了HMGB1作为内毒素血症的晚期致炎物质。
近来研究表明，对小鼠盲肠进行结扎和穿孔的实验模型研究发现，HMGBI在脓毒症发病机制中也起了一个重要作用。这个研究包括对麻醉小鼠盲肠穿孔后实施盲肠结扎，诱导腹内感染和脓毒症发生。使用内源性分子HMGB1特异性拮抗剂（抗HMGB1的抗体或者重组体A box），即便腹膜炎诱导感染发生24小时才予以初始用药，也可以转变脓毒症的致死性。除此之外，乙基丙酮酸乙酯和烟碱也能有效抑制单核/巨噬细胞活化而释放HMGB1，从而提高重度脓毒症的存活率。用HMGB1的拮抗剂(抗HMGB1的抗体或者重组体A box)治疗比针对其它细胞因子的治疗获得较长窗口期。至今，还未发现脓毒症中以其它的致病性介质作为治疗靶点成功解救脓毒症的致死的动物。例如，用抗-TNF抗体在治疗小鼠盲肠结扎穿孔模型中反而提高了小鼠的死亡率，盲肠穿孔8h后，抗体对巨噬细胞迁移抑制因子的抑制作用是无效。这些研究表明，细胞外的HMGB1在介导全身炎症中起到很重要的作用，因此HMGB1成为潜在的治疗靶点。


HMGB1的细胞外释放
HMGB1分泌到细胞外环境有两个途径：一是坏死细胞的被动释放；二是有免疫细胞主动分泌。一旦细胞坏死，HMGBI的以可溶性分子扩散到细胞外环境中，在体内和体外引起炎症反应。坏死细胞分泌的HMGB1诱发单核细胞分泌出TNF，然而坏死的双阴性HMGB1细胞不能诱发单核细胞分泌出TNF。而且在急性肝坏死中，体内HMGB1的阻断减少了白细胞向受损部位的募集，表明HMGB1是坏死细胞诱导炎症反应的主要介质。急性损伤后的剧烈炎症反应对杀伤微生物、清除濒死的细胞和细胞碎片，为生长因子和细胞因子的释放起着关键的作用。不同细胞间协助作用有利于受损组织修复，执行保护性免疫应答。坏死细胞释放的HMGB1作为一种危险性信号分子传递给临近组织细胞，使其启动免疫应答，对受损部位进行组织修复反应。
除用LPS、TNF-α、IL-1等细胞因子或干扰素- 刺激活化单核-巨噬后主动分泌出HNGB1外，在垂体细胞中也发现有HMGB1。HMGB1是如何从细胞核分泌到细胞外的还不是很明确。HMGB1与染色质的快速结合与分离，并且不断的在细胞核与胞浆溶胶转运。随着对炎症刺激的进一步研究，表明赖氨酸残基乙酰化的结果使HMGB1从核内分泌到胞浆，并阻止其再进入细胞核。由于HMGB1缺乏信号肽，不能通过内质网/高尔基体途径分泌。在HMGB1释放到细胞外之前，先是由造血干细胞内的分泌溶酶体从核内分泌到胞浆。HMGB1如何被分泌性溶酶体摄取的目前尚不明确。一旦HMGB1被释放，HMGB1激活单核细胞分泌出细胞因子，包括TNF-α、IL-1。更有意义的是和经典的促炎刺激物LPS相比，HMGB1引起TNF-α的释放被推迟且分泌呈双相型。HMGB1不仅仅由活化后的巨噬细胞分泌，而且刺激，从新生成，延迟反应，因此对于维持和延长炎症反应起到重要作用。细胞外HMGB1的生物学功能除了从各种中细胞引导细胞因子和趋化因子产生外，它在诱导细胞增值和组织修复中细胞迁移发挥重要作用。
从坏死细胞被动释放的HMGB1与活化的巨噬细胞主动分泌的HMGB1存在着分子上差异，主动分泌的HMGB1分子需乙酰化修饰。HMGB1生物学活性的改变依赖于翻译后修饰。


与HMGB1结合的受体
膜相关的HMGB1与RAGE（晚期糖基化终末产物受体）具有高亲和力，并且增加了成神经细胞瘤细胞中RAGE表达。RAGE是免疫球蛋白超家族的成员，属于一种跨膜蛋白，广泛表达于单核/巨噬细胞、树突状细胞、内皮细胞和血管平滑肌细胞。此外在一些慢性退化疾病和癌症的发病机制中RAGE也起着重要作用。RAGE作为一种粘附在内皮细胞上受体，促进白细胞募集反应。实验表明：RAGE的缺失降低了脓毒症小鼠的致死率，RAGE的阻断抑制了巨噬细胞和内皮细胞中HMGB1促炎症反应的效果。但是这种抑制并不是完全的，说明除了RAGE受体外，还有与HMGB1结合的一些其它受体，如巨噬细胞表达的TLR2、TLR4受体。用TLR2和TLR4的负相表型结构转染小鼠的巨噬细胞，结果表明这种转染降低了HMGB1刺激活化作用。然而，TLR2敲除的小鼠巨噬细胞和野生型的巨噬细胞对HMGB1的反应是相类似的。所以，认为RAGE受体与HMGB1结合要比TLRs和其它受体与HMGB1结合相对重要，这个结论不能被完全解释。HMGB1刺激活化的各种信号传导途径，包括活化GTP酶、MAPK1激酶（p38、ERK1/2），加强蛋白激酶和转录因子NF-KB，这些信号传导途径进一步证实了各种细胞中与HMGB1结合的受体的功能。RAGE受体与TLRs受体所识别抗原决定族表位不同。HMGB1与不同蛋白结合的能力主要通过与HMGB1结合的DNA结合域或通过酸性羧基末端，HMGB1蛋白分子中和受体结合的部位位于150－183之间的氨基酸序列中，正好在酸性羧基末端前面。不同结合部位可以结合不同的受体。


HMGB1介导树突状细胞成熟与功能
树突状细胞在启动和调控适应性免疫应答的过程中起到关键作用。树突状细胞在由未成熟向成熟成长的过程中可以识别病原体且产生应答，这个过程使其迁移到次级淋巴器官并活化抗原特异性T细胞。然而，在没有细菌刺激情况下免疫应答也能产生。属于细胞死亡发生在体内这种情况的有：濒死细胞释放的内源性细胞因子，包括有尿酸和热休克蛋白，通过激活的树突状增强了他们的免疫源性。细胞外HMGB1促炎反应的效果和HMGB1在细胞内的含量表明，HMGB1能够警报树突状细胞周围有细胞死亡，以便使其启动免疫应答。实际上，从坏死细胞释放的HMGB1作为一种内源性免疫佐剂。在体外，HMGB1的抗体和重组体A box减弱了坏死细胞上清液诱导的树突状细胞的成熟。而从双阴性HMGB1细胞中制备的上清组织不能诱导树突状细胞的成熟。然而，在体内，从坏死细胞和重组蛋白衍生出来的HMGB1提高了直接抑制外源性可溶抗原的IgG抗体的滴度，并且对致瘤性淋巴瘤产生了长期保护性免疫应答。
在体外，内源性分子HMGB1诱导的持续效应使重组体激活了人类单核细胞衍生来的树突状细胞。重组体HMGB1的B box结构域诱导的树突状细胞表型成熟。除此之外，B box诱导促炎因子IL-12的分泌，IL-12诱导Th细胞向Th1细胞的分化。尽管重组体B box是引起HMGB1炎症反应的部位，但是这个部位缺少与RAGE（糖基化末端产物受体）的结合序列。所以，潜在的机理还不是十分明确。RAGE存在于未成熟的树突状细胞的表面，且通过RAGE的下游区信号传导使B box激活了NF- B。这表明了HMGB1对树突状细胞的效应是通过RAGE介导的。通过活化的NK细胞分泌的HMGB1诱导了树突状细胞的成熟使得NK细胞和树突状细胞之间的干扰。
实验发现HMGB1从树突状细胞核内转运到胞浆中，随后在活化作用下使HMGB1从胞浆被分泌到细胞外环境。HMGB1的分泌对信号转导起到决定性作用，即维护了树突状细胞的成熟又对T细胞起到功能调控作用。这表明在自分泌-旁分泌形成的环中，树突状细胞阻断内源性核内分子HMGB1进入它们的成熟阶段，从而增强了免疫应答。因此，在多数情况下，树突状细胞倾向于模拟从坏死细胞分泌的外源性分子HMGB1的促炎效应。


针对HMGB1的靶向治疗
HMGB1可以由受损细胞分泌且可作为警报信号使受损组织周围的细胞启动免疫应答，因此，HMGB1在疫苗、自身免疫和炎症反应方面有着潜在的应用。
针对HMGB1在急慢性炎症疾病的发病过程中发挥重要作用，人们将开始了以HMGB1为靶向的药物治疗。脓毒症是在潜在的致命性急性炎症条件和HMGB1的释放形成的恶性循环中的一个典型例子。脓毒症病人血清中HMGB1的升高，预示着不良的后果。HMGB1的拮抗剂（抗HMGB1抗体或重组体A box），在脓毒症治疗试验中提供相对较宽的窗口，为临床治疗提供广阔的前景。
象失血性休克这种不是由微生物引起的急性炎症，血清中HMGB1的含量水平也比较高，这种疾病也逐渐得到治疗。在小鼠模型中，用抗-HMGB1抗体治疗由HMGB1介导的急性失血引起的肺损伤明显改善了肺损伤症状的严重度。
在慢性炎症条件下，以HMGB1为靶点对类风湿性关节炎也提供潜能治疗。HMGB1促进了实验性关节炎的发病机制的研究。从胶原辅助剂诱导关节炎的小鼠滑液组织分析揭示了HMGB1在细胞外有表达且在巨噬细胞和滑膜细胞的细胞浆中也有表达。另外，在小鼠模型的关节内注射HMGB1也可以诱导关节炎的发生。抗HMGB1抗体和重组体A box减弱胶原质诱导的关节炎症状。在类风湿性关节炎病人的滑液组织和滑液标本测的关节内HMGB1的水平也是升高。
在成人癌症自然病变中都涉及到炎症反应和细胞坏死。一些结肠、胸腺和前列腺恶性肿瘤中HMGB1都是过表达的，且在神经胶质瘤小鼠模型中RAGE受体或HMGB1传导信号的阻断抑制了肿瘤生长和转移。肿瘤中常有白细胞的渗透可以通过自发的或药物诱导肿瘤细胞的死亡来表征。濒死的肿瘤细胞和渗透的噬菌细胞中HMGB1的相互作用为癌症治疗提供了有价值的靶点。
随HMGB1分子生物学功能的各个方面深入研究，细胞外的HMGB1作为炎症信号的发现，为HMGB1诱导的疾病的治疗提供了了一些新的途径。抗HMGB1抗体、重组体A box或HMGB1受体RAGE的缺失都证明了在炎症疾病治疗中成效。用丙酮酸乙酯或烟碱抑制HMGB1的分泌和HMGB1诱导细胞内的信号传导途径将为炎症控制提供另外药理学工具。


结论
从移动的核内蛋白到有效的细胞外因子，HMGB1被认识发现到作为靶点治疗经历了漫长过程。HMGB1作为炎症因子，在组织受损部位介导了组织修复和免疫防护。尽管生物学特性已被揭示，但是许多问题仍不清楚，如控制HMGB1的释放的机制，细胞表面外的受体特性，下游区信号传导途径，主动分泌与被动分泌HMGB1的生物学活性区别，以及HMGB1在促炎反应中的生理学调节机制尚不明确，若以上问题得已解决的话，将为解决炎症反应和疾病治疗提供一个较好机制。

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TRENDS in Immunology Vol.26 No.7 July 2005

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肝脏缺血所致TLR4依赖的活性氧分子产生和钙粒子介导的信号诱导HMGB1释放

 

Allan Tsung, John R. Klune, Xianghong Zhang, Geetha Jeyabalan1, Zongxian Cao, Ximei Peng, Donna B. Stolz, David A. Geller, Matthew R. Rosengart, and Timothy R. Billiar
Department of Surgery and 2 Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15213


Ischemic tissues require mechanisms to alert the immune system of impending cell damage. The nuclear protein high-mobility group box 1 (HMGB1) can activate inflammatory pathways when released from ischemic cells. We elucidate the mechanism by which HMGB1, one of the key alarm molecules released during liver ischemia/reperfusion (I/R), is mobilized in response to hypoxia. HMGB1 release from cultured hepatocytes was found to be an active process regulated by reactive oxygen species (ROS). Optimal production of ROS and subsequent HMGB1 release by hypoxic hepatocytes required intact Toll-like receptor (TLR) 4 signaling. To elucidate the downstream signaling pathways involved in hypoxia-induced HMGB1 release from hepatocytes, we examined the role of calcium signaling in this process. HMGB1 release induced by oxidative stress was markedly reduced by inhibition of calcium/calmodulin-dependent kinases (CaMKs), a family of proteins involved in a wide range of calcium-linked signaling events. In addition, CaMK inhibition substantially decreased liver damage after I/R and resulted in accumulation of HMGB1 in the cytoplasm of hepatocytes. Collectively, these results demonstrate that hypoxia-induced HMGB1 release by hepatocytes is an active, regulated process that occurs through a mechanism promoted by TLR4-dependent ROS production and downstream CaMK-mediated signaling.

 

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The Journal of Experimental Medicine, Vol. 204, No. 12, 2913-2923

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细胞对危险信号HMGB1的反应迁移到组织损伤部位需要NFkB的活化

 

Roberta Palumbo, Beatriz G. Galvez, Tobias Pusterla, Francesco De Marchis, Giulio Cossu, Kenneth B. Marcu4, and Marco E. Bianchi1

Chromatin Dynamics Unit and 2 Stem Cell Research Institute, Istituto Scientifico San Raffaele, 20132 Milan, Italy


Tissue damage is usually followed by healing, as both differentiated and stem cells migrate to replace dead or damaged cells. Mesoangioblasts (vessel-associated stem cells that can repair muscles) and fibroblasts migrate toward soluble factors released by damaged tissue. Two such factors are high mobility group box 1 (HMGB1), a nuclear protein that is released by cells undergoing unscheduled death (necrosis) but not by apoptotic cells, and stromal derived factor (SDF)–1/CXCL12. We find that HMGB1 activates the canonical nuclear factor {kappa}B (NF-{kappa}B) pathway via extracellular signal-regulated kinase phosphorylation. NF-{kappa}B signaling is necessary for chemotaxis toward HMGB1 and SDF-1/CXCL12, but not toward growth factor platelet-derived growth factor, formyl-met-leu-phe (a peptide that mimics bacterial invasion), or the archetypal NF-{kappa}B–activating signal tumor necrosis factor {alpha}. In dystrophic mice, mesoangioblasts injected into the general circulation ingress inefficiently into muscles if their NF-{kappa}B signaling pathway is disabled. These findings suggest that NF-{kappa}B signaling controls tissue regeneration in addition to early events in inflammation.

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2007. J. Cell Biol..

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在凋亡介导的致死性败血症中HMGB1的作用

Shixin Qin, Haichao Wang, Renqi Yuan, et al

Critical Therapeutics, Inc., Lexington, MA 02421


Severe sepsis, a lethal syndrome after infection or injury, is the third leading cause of mortality in the United States. The pathogenesis of severe sepsis is characterized by organ damage and accumulation of apoptotic lymphocytes in the spleen, thymus, and other organs. To examine the potential causal relationships of apoptosis to organ damage, we administered Z-VAD-FMK, a broad-spectrum caspase inhibitor, to mice with sepsis. We found that Z-VAD-FMK–treated septic mice had decreased levels of high mobility group box 1 (HMGB1), a critical cytokine mediator of organ damage in severe sepsis, and suppressed apoptosis in the spleen and thymus. In vitro, apoptotic cells activate macrophages to release HMGB1. Monoclonal antibodies against HMGB1 conferred protection against organ damage but did not prevent the accumulation of apoptotic cells in the spleen. Thus, our data indicate that HMGB1 production is downstream of apoptosis on the final common pathway to organ damage in severe sepsis.

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J. Exp. Med., Jul 2006; 203: 1637 - 1642.

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TLR和RAGE受体信号途径通过HMGB1而整合和放大

 

Judy R. van Beijnum Wim A. Buurman Arjan W. Griffioen

 

Sustained proinflammatory responses in rheumatoid arthritis, atherosclerosis, and diabetic retinopathy, as well as in cancer, are often associated with increased angiogenesis that contributes to tissue disruption and disease progression. High mobility group B1 (HMGB1) has been recognized as a proinflammatory cytokine and more recently, as a proangiogenic factor. HMGB1 can either be passively released from necrotic cells or actively secreted in response to angiogenic and inflammatory signals.
HMGB1 itself may signal through the receptor for advanced glycation end products (RAGE), and via toll-like receptors, TLR2 and TLR4. Activation of these receptors results in the activation of NFjB, which induces the upregulation of leukocyte adhesion molecules and the production of proinflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. Interestingly, HMGB1 seems to be involved in a positive feedback mechanism, that may help to sustain inflammation and angiogenesis in several pathological conditions, thereby contributing to disease progression. Endothelial cells express HMGB1, as well as the receptors RAGE, TLR2, and TLR4, and in diverse pathologies HMGB1 and its receptors are overexpressed.
Furthermore, HMGB1-induced signaling can activate NFkB, which can subsequently induce the expression of HMGB1 receptors. Thus, HMGB1 can mediate amplification of inflammation and angiogenesis through increased secretion of HMGB1 and increased expression of the receptors it can interact with. In this review, we discuss signaling cascades that HMGB1 can induce via TLRs and RAGE, as well as its contribution to pathologies involving endothelial cells.

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Angiogenesis (2008) 11:91–99

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严重败血症患者中HMGB1作为器官功能障碍和愈后的一个指标

Sari Karlsson Ville Pettil? Jyrki Tenhunen et al

 

Objective: To study the predictive value of high mobility group box-1 protein (HMGB1) and hospital mortality in adult patients with severe sepsis. Study design:Prospective observational cohort study in 24 ICUs in Finland. Patients: Two hundred and fortyseven adult patients with severe sepsis. Measurements and main results: Blood samples for HMGB1 analyses were drawn from 247 patients at baseline and from 210 patients 72 h later. The mean APACHE II and SAPS II scores were 24 (SD 9) and 44 (SD 17), respectively. The hospital mortality was 26%. The serum HMGB1 concentrations were measured first by semi-quantitative Western immunoblotting (WB) analysis. The median HMGB1 concentration on day 0 was 108% (IQR 98.5-119) and after 72 h 107% (IQR 98.8-120), which differed from healthy controls (97.5%, IQR 91.3-106.5; p = 0.028 and 0.019,
respectively). The samples were reanalyzed by ELISA (in a subgroup of 170 patients) to confirm the results by WB. The median concentration in healthy controls was 0.65 ng/ml (IQR 0.51-1.0). This was lower than in patients with severe sepsis (3.6 ng/ml, IQR 1.9-6.5, p < 0.001). HMGB1 concentrations (WB and ELISA) did not differ between hospital survivors and non-survivors. In ROC analyses for HMGB1 levels (WB) on day 0 and 72 h with respect to hospital mortality, the areas under the curve were 0.51 and 0.56 (95% CI 0.40-0.61 and 0.47-0.65). Conclusions: Serum HMGB1 concentrations were elevated in patients with severe sepsis, but did not differ between survivors and
non-survivors and did not predict hospital mortality

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Intensive Care Med

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HMGB1内源性危险信号

 

John R. Klune, Rajeev Dhupar, Jon Cardinal et al


While foreign pathogens and their products have long been known to activate the innate immune system, the recent recognition of a group of endogenous molecules that serve a similar function has provided a framework for understanding the overlap between the inflammatory responses activated by pathogens and injury. These endogenous molecules, termed alarmins, are normal cell constituents that can be released into the extracellular milieu during states of cellular stress or damage and subsequently activate the immune system. One nuclear protein, High mobility group box -1 (HMGB1) has received particular attention as fulfilling the functions of an alarmin by being involved in both infectious and non-infectious inflammatory conditions. Once released, HMGB1 signals through various receptors to activate immune cells involved in the immune process. Although initial studies demonstrated HMGB1 as a late mediator of sepsis, recent findings indicate HMGB1 to have an important role in models of non-infectious inflammation, such as autoimmunity, cancer, trauma, and ischemia reperfusion injury. Furthermore, in contrast to its pro-inflammatory functions, there is evidence that HMGB1 also has restorative effects leading to tissue repair and regeneration. The complex functions of HMGB1 as an archetypical alarmin are outlined here to review our current understanding of a molecule that holds the potential for treatment in many important human conditions.

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Mol Med.

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在自身免疫病发病机制中细胞死亡的作用：HMGB1和微粒作为细胞间炎症的介导者

Ardoin SP, Pisetsky DS.


Cell death is critical to normal homeostasis, although this process, when increased aberrantly, can lead to the production of pro-inflammatory mediators promoting autoimmunity. Two novel intercellular mediators of inflammation generated during cell death are high mobility group box 1 (HMGB1) protein and microparticles (MPs). HMGB1 is a nuclear protein that functions in transcription when inside the nucleus but takes on pro-inflammatory properties when released during cell death. Microparticles are small, membrane-bound structures that extrude from cells when they die and contain cell surface proteins and nuclear material from their parent cells. MPs circulate widely throughout the vasculature and mediate long-distance communication between cells. Both MPs and HMGB1 have been implicated in the pathogenesis of a broad spectrum of inflammatory diseases, including the prototypic autoimmune conditions systemic lupus erythematosus and rheumatoid arthritis. Given their range of activity and association with active disease, both structures may prove to be targets for effective therapy in these and other disorders.

 

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Mod Rheumatol. 2008 Apr 17

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RAG1/2裂解活性的HMG盒区刺激是金属粒子依赖性的


Kriatchko AN, Bergeron S, Swanson PC.

 

BACKGROUND: RAG1 and RAG2 initiate V(D)J recombination by assembling a synaptic complex with a pair of antigen receptor gene segments through interactions with their flanking recombination signal sequence (RSS), and then introducing a DNA double-strand break at each RSS, separating it from the adjacent coding segment. While the RAG proteins are sufficient to mediate RSS binding and cleavage in vitro, these activities are stimulated by the architectural DNA binding and bending factors HMGB1 and HMGB2. Two previous studies (Bergeron et al., 2005, and Dai et al., 2005) came to different conclusions regarding whether only one of the two DNA binding domains of HMGB1 is sufficient to stimulate RAG-mediated binding and cleavage of naked DNA in vitro. Here we test whether this apparent discrepancy is attributed to the choice of divalent metal ion and the concentration of HMGB1 used in the cleavage reaction. RESULTS: We show here that single HMG-box domains of HMGB1 stimulate RAG-mediated RSS cleavage in a concentration-dependent manner in the presence of Mn2+, but not Mg2+. Interestingly, the inability of a single HMG-box domain to stimulate RAG-mediated RSS cleavage in Mg2+ is overcome by the addition of partner RSS to promote synapsis. Furthermore, we show that mutant forms of HMGB1 which otherwise fail to stimulate RAG-mediated RSS cleavage in Mg2+ can be substantially rescued when Mg2+ is replaced with Mn2+. CONCLUSION: The conflicting data published previously in two different laboratories can be substantially explained by the choice of divalent metal ion and abundance of HMGB1 in the cleavage reaction. The observation that single HMG-box domains can promote RAG-mediated 23-RSS cleavage in Mg2+ in the presence, but not absence, of partner RSS suggests that synaptic complex assembly in vitro is associated with conformational changes that alter how the RAG and/or HMGB1 proteins bind and bend DNA in a manner that functionally replaces the role of one of the HMG-box domains in RAG-HMGB1 complexes assembled on a single RSS.

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Journal of Pharmacological Sciences
Vol. 106 (2008) , No. 3 pp.332-335

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HMGB1信号途径


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