高迁移率族蛋白B1在支气管哮喘中的研究进展

高迁移率族蛋白B1 (high-mobility group box 1,HMGB1)是一种保守的核蛋白,对维持核小体稳定、DNA重组、复制、修复及转录有着重要作用,其可由单核/巨噬细胞等固有免疫细胞在致炎细胞因子刺激下主动分泌,也可由坏死细胞被动释放.近年来的研究显示,HMGB1信号的活化与支气管哮喘(简称哮喘)的发生、发展密切相关,通过阻断和抑制HMGB1的作用可以减轻哮喘患者的炎症反应.该文拟对近年来HMGB1与哮喘相关的研究进展作一综述,以期为该疾病的诊断和治疗提供新的理论依据.     

高迁移率族蛋白-1与脑出血

高迁移率族蛋白(high mobility group box 1,HMGB1)是一种广泛分布于真核细胞中高度保守的非组DNA结合蛋白.它是一种重要的促炎性细胞因子,参与多种病理生理学过程,例如炎症和神经血管生成等.在脑出血早期,HMGB1可诱发炎性反应、神经元坏死、脑水肿等继发性脑损伤;在脑出血晚期,HMGB1可促进血管神经发生,进而改善神经功能.将来,HMGB1有可能成为脑出血的新治疗靶点.     

高迁移率族蛋白1和心血管疾病相关性的研究进展

胞内高迁移率族蛋白B1(HMGB1)作为一种重要的炎性介质和促炎细胞因子,可通过活化细胞的主动分泌和受损坏死细胞的被动释放进入胞外介导炎性反应。近年,HMGB1在心血管疾病中的作用受到关注。许多研究结果显示,HMGB1在动脉粥样硬化、心肌梗死及心脏缺血/再灌注损伤等发生发展过程中发挥着重要作用,本文综述相关的研究进展。     

高迁移率族蛋白B1与肝炎、肝癌关系的研究进展

高迁移率族蛋白B1(HMGB1)是一种非组蛋白染色体蛋白质,它在DNA重组、复制、修复和基因转录中起重要的辅助作用。细胞外HMGB1与细胞分化、细胞迁移、细胞增殖与凋亡、诱导炎性反应等密切相关。它既可以由坏死细胞被动释放,也可以由激活的巨噬细胞或单核细胞主动分泌到细胞外介导炎性反应。越来越多的研究表明,HMGB1可以作为缺血/再灌注损伤的实验模型,其拮抗剂可能对急性呼吸窘迫综合征、类风湿关节炎、败血症和肿瘤等疾病起治疗作用。但是有关HMGB1与肝脏疾病之间的关系以及研究进展的相关报道并不多见,此文就HMGB1与部分肝脏疾病之间的关系及其研究进展做一综述。     

高迁移率族蛋白B1与动脉粥样硬化

高迁移率族蛋白B1这一传统的非组DNA结合蛋白,与染色体的稳定性有关,并参与了细胞的转录等。近年研究发现,胞外高迁移率族蛋白1具有致炎细胞因子作用。胞内高迁移率族蛋白B1可通过活化细胞的主动分泌和坏死细胞的被动释放进入胞外,与细胞表面晚期糖基化终产物受体等配体结合后引发信号转导,诱导其他炎症介质的产生,扩大炎症反应。在动脉粥样硬化过程中,从炎症始发到斑块破裂及血栓形成的各个时期,高迁移率族蛋白B1均发挥重要的作用。     

高迁移率族蛋白B1与肺疾病的研究进展

高迁移率族蛋白B1(HMGB1)是一种普遍存在的高度保守的核蛋白,主要由巨噬细胞、单核细胞、垂体细胞等在炎症因子的刺激下主动释放,也可由坏死细胞被动释放,参与DNA 的转录、复制、修复以及炎症反应等.在呼吸系统中主要分布于支气管及肺泡上皮细胞,在细胞核、胞质及胞膜均可见.正常情况下,人类和大鼠气道内即有一定水平HMGB1表达,对呼吸系统正常功能的维持具有重要作用.HMGB1释放晚,维持时间长,对机体炎症反应的发生、发展、转归等均具有调控作用[1].HMGB1与肺损伤、肺癌、肺纤维化等疾病的发生发展密切相关,但其机制尚不清楚,本文对HMGB1与呼吸系统疾病的相关研究进行简要的综述.     

高迁移率族蛋白B1与心血管疾病的关系

<正> 高迁移率族蛋白B1(HMGB1)是一种高度保守的核蛋白,主要由坏死或损伤的细胞被动释放及对内源性和外源性炎性刺激发生反应的单核和(或)巨噬细胞主动分泌。释放后,与晚期糖基化终末产物(RAGE)受体或Toll样受体结合,激活血管内皮细胞及单核和(或)巨噬细胞,表达其他促炎性因子。近年发现HMGB1参与冠心病等心血管疾病的     

高迁移率族蛋白B1在脑出血炎症损伤和修复中的作用研究进展

综述脑出血后高迁移率族蛋白B1(HMGB1)在脑出血急性期炎症损伤和恢复期促进神经血管再生的作用。提示HMGB1可以由活化的免疫细胞主动分泌或者通过损伤及坏死细胞被动释放至细胞外,并作为损伤相关分子的模式(DAMP)启动和维持下游炎症反应,从而发挥其化学趋化因子和促炎性因子的作用,而炎症反应是脑出血继发性损伤的主要机制之一。脑出血急性期,HMGB1作为一种早期的促炎细胞因子触发炎症反应促进病情的进展。然而,脑出血恢复期,HMGB1可以介导有益神经血管修复作用,细胞外HMGB1蛋白特殊的双重生物学特性可能与半胱氨酸残基的氧化还原状态有关。     

高迁移率族蛋白-1在实验性急性肝衰竭中的作用

高迁移率族蛋白-1（HMGB1）是广泛存在于真核细胞内高度保守的非组蛋白染色体蛋白。研究表明HMGB1可由巨噬细胞等主动分泌或由坏死细胞被动释放到细胞外基质内。作为晚期炎症因子参与脓毒症、关节炎等病理生理反应过程，并认为它有可能是肿瘤坏死因子α（TNFα）、白细胞介素-1（IL-1）的下游因子。急性肝衰竭（AHF）往往导致严重的肠源性内毒素血症，并介导TNFα等细胞因子释放。但HMGB1在急性肝衰竭中是否参与其病理生理过程，目前尚不清楚。本实验通过D-氨基半乳糖和内毒素诱导的大鼠急性肝损伤模型，探讨了HMGB1在AHF中的变化和意义。     

高迁移率族蛋白B-1及其在肝损伤合并内毒素血症中的作用

高迁移率族蛋白B-1(high mobility group box 1 protein, HMGB 1)是早在30年前就发现的一种核内结构蛋白,它在DNA重组、修复、复制和基因转录中起重要作用。近年研究发现:它可以由坏死细胞被动释放,也可以由被激活的巨噬细胞     

HMGB1 is a potent trigger of arthritis

Rheumatoid arthritis is a chronic inflammatory disease characterized by synovial inflammation and structural damage of joints. Although the cause of rheumatoid arthritis (RA) remains unknown, the excessive production of proinflammatory cytokines such as tumour necrosis factor (TNF) and interleukin-1 (IL-1) by intra-articular macrophages occupies a critical pathogenic role in the development and progression of the disease. High mobility group box chromosomal protein 1 (HMGB1) is a recently identified mediator of interest in human and experimental arthritides. HMGB1 can either be actively secreted from macrophages or passively released from necrotic cells of all kinds. Activated macrophages and unprogrammed cell death caused by ischaemia or activated complement are all prominent features of chronic arthritis, contributing to the persistent synovial inflammation. HMGB1 is cytoplasmically and extracellularly overexpressed in inflammatory synovial tissue in human RA as well as experimental collagen-induced arthritis. Elevated levels of HMGB1 are also present in synovial fluid samples from RA patients. Synovial tissue from rats with experimental arthritis exhibits aberrant deposition of HMGB1 preceding the onset of clinical signs of arthritis, and the expression becomes prominent after the onset of clinical disease. The synovial levels of HMGB1 are comparable with those of TNF and IL-1beta at the peak of manifest disease. HMGB1-targeted intervention with either neutralizing antibodies or the antagonistic A box domain of HMGB1 ameliorates collagen-induced arthritis both in mice and rats, and inhibits the local overexpression of IL-1beta in the joints. It is thus conceivable that therapeutic HMGB1 blockade may contribute to future treatment of human chronic arthritis.     

Activated protein C inhibits high mobility group box 1 signaling in endothelial cells

A pathogenic role for high-mobility group box 1 (HMGB1) protein has been postulated in severe sepsis. Activated protein C (APC) is the only drug approved by the Food and Drug Administration for severe sepsis; however, its effect on HMGB1 signaling has never been investigated. Here, we monitored the effect of APC on the lipopolysaccharide-mediated release of HMGB1 and the HMGB1-mediated modulation of proinflammatory responses in HUVECs. APC potently inhibited the release of HMGB1 and down-regulated the adhesion of the monocytic cell line, THP-1, to HMGB1-activated endothelial cells. HMGB1 up-regulated proinflammatory responses by interacting with 3 pathogen-related pattern recognition receptors: TLR2 and TLR4 and the receptor for advanced glycation end products. APC not only inhibited HMGB1 release but also down-regulated the cell surface expression of all 3 HMGB1 receptors in endothelial cells. The protective effects of APC were mediated through endothelial cell protein C receptor (EPCR) and protease-activated receptor 1 (PAR-1). Interestingly, a thrombin derivative containing the Gla-domain of APC recapitulated all protective effects of APC with a 20- to 50-fold higher efficacy. These results suggest that the EPCR- and PAR-1-dependent protective effects of APC in severe sepsis may partially be mediated through the inhibition of HMGB1 signaling and that the chimeric thrombin mutant has potential therapeutic utility for severe sepsis.     

Overexpression of HMGB1 A-box reduced lipopolysaccharide-induced intestinal inflammation via HMGB1/TLR4 signaling in vitro

AIM: To investigate the inhibitory effects and mechanism of high mobility group box(HMGB)1 A-box in lipopolysaccharide(LPS)-induced intestinal inflammation.METHODS: Overexpression of HMGB1 A-box in human intestinal epithelial cell lines(SW480 cells) was achieved using the plasmid p EGFP-N1. HMGB1 A-box-overexpressing SW480 cells were stimulated with LPS and co-culturing with human monocyte-like cell lines(THP-1 cells) using a Transwell system, compared with another HMGB1 inhibitor ethyl pyruvate(EP). The m RNA and protein levels of HMGB1/toll-like receptor(TLR) 4 signaling pathways [including HMGB1, TLR4, myeloid differentiation factor88(MYD88), Phosphorylated Nuclear Factor κB(p NF-κB) p65] in the stimulated cells were determined by realtime polymerase chain reaction and Western blotting. The levels of the proinflammatory mediators [including HMGB1, interleukin(IL)-1β, IL-6 and tumor necrosis factor(TNF)-α] in the supernatants of the stimulated cells were determined by ELISA.RESULTS: EP downregulated the m RNA and protein levels of HMGB1, inhibited the TLR4 signaling pathways(TLR4, MYD88 and p NF-κB p65) and reduced the secretion of proinflammatory mediators(HMGB1, IL-1β, IL-6 and TNF-α) in the SW480 and THP-1 cells activated by LPS but not in the unstimulated cells. Activated by LPS, the overexpression of HMGB1 A-box in the SW480 cells also inhibited the HMGB1/TLR4 signaling pathways and reduced the secretion of these proinflammatory mediators in the THP-1 cells but not in the transfected and unstimulated cells. CONCLUSION: HMGB1 A-box, not only EP, can reduce LPS-induced intestinal inflammation through inhibition of the HMGB1/TLR4 signaling pathways.     

Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1)

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 NFκB, 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 NFκB, 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.     

人高迁移率族蛋白B1在风湿免疫性疾病中的研究进展

人高迁移率族蛋白B1(HMGB1)是细胞核内典型的非组蛋白。HMGB1在细胞和组织中分布十分广泛,受到炎症刺激后能从坏死或损伤细胞被动释放,并可诱导树突状细胞上调其成熟的表面抗原。本文详细介绍了HMGB1的结构、功能特点及HMGB1在系统性红斑狼疮、类风湿关节炎、肌炎、系统性硬化症、干燥综合征等风湿免疫性疾病中的表达情况。随着对HMGB1研究的不断深入,HMGB1在风湿性疾病诊断、治疗等中的潜力将进一步得到发展。     

Lupus antibodies to the HMGB1 chromosomal protein: epitope mapping and association with disease activity

The high mobility group box 1 (HMGB1) protein is a non-histone chromosomal protein that acts as a potent proinflammatory cytokine when actively secreted from LPS- or TNF-activated macrophages, monocytes, and other cells. Anti-HMGB1/2 antibodies have been previously identified in sera from a high proportion of patients with autoimmune diseases. In this study, we examined anti-HMGB1 antibody titers in sera of patients with systemic rheumatic diseases and the correlations between the presence of anti-HMGB1 antibodies and disease activity in systemic lupus erythematosus (SLE) patients by enzyme-linked immunosorbent assay and western blotting. We detected increases in both the levels and the frequency of anti-HMGB1 antibodies in sera from SLE and polymyositis/dermatomyositis (PM/DM) patients, and observed that the presence of anti-HMGB1 antibodies positively correlates with SLE disease activity index. Through epitope mapping, we found that multiple HMGB1 epitopes were recognised in SLE sera, with the major epitope mapping to box A. Another epitope, the joiner region of HMGB1, was preferentially recognized by SLE sera, but not by PM/DM sera. Collectively, these observations suggest that the presence of anti-HMGB1 antibodies correlates with disease activity in SLE patients.     

PRRSV Induces HMGB1 Phosphorylation at Threonine-51 Residue to Enhance Its Secretion

Porcine reproductive and respiratory syndrome virus (PRRSV) induces secretion of high mobility group box 1 (HMGB1) to mediate inflammatory response that is involved in the pulmonary injury of infected pigs. Our previous study indicates that protein kinase C-delta (PKC-delta) is essential for HMGB1 secretion in PRRSV-infected cells. However, the underlying mechanism in HMGB1 secretion induced by PRRSV infection is still unclear. Here, we discovered that the phosphorylation level of HMGB1 in threonine residues increased in PRRSV-infected cells. A site-directed mutagenesis study showed that HMGB1 phosphorylation at threonine-51 was associated with HMGB1 secretion induced by PRRSV infection. Co-immunoprecipitation (co-IP) of HMGB1 failed to precipitate PKC-delta, but interestingly, mass spectrometry analysis of the HMGB1 co-IP product showed that PRRSV infection enhanced HMGB1 binding to ribosomal protein S3 (RPS3), which has various extra-ribosomal functions. The silencing of RPS3 by siRNA blocked HMGB1 secretion induced by PRRSV infection. Moreover, the phosphorylation of HMGB1 at threonine-51 was correlated with the interaction between HMGB1 and RPS3. In vivo, PRRSV infection also increased RPS3 levels and nuclear accumulation in pulmonary alveolar macrophages. These results demonstrate that PRRSV may induce HMGB1 phosphorylation at threonine-51 and increase its interaction with RPS3 to enhance HMGB1 secretion. This finding provides insights into the pathogenesis of PRRSV infection.