019热休克蛋白70在免疫中的作用及应用

热休克蛋白(heat shock protein,hsp)是生物体在应激条件下产生的一组蛋白,在正常细胞中也广泛存在.其中hsp70具有多种功能,在免疫中机体对hsp70有4种作用模式;hsp70不仅可作为免疫佐剂、抗原载体,而且在基因疫苗中也显示出诱人的前景.     

热休克蛋白70的功能及其在寄生虫生长发育中的作用

热休克蛋白（heat shock protein,HSP）也称应激蛋白,具有分子伴侣活性。外源性HSP70能被宿主抗原提呈细胞（antigen presenting cell,APC）识别,引起前炎症反应及获得性免疫应答,而自体HSP70则具有抗炎效应。在最近的研究中还发现HSP70具有佐剂功效,能增强机体对其他抗原肽的免疫应答反应。HSP70在寄生虫的生长发育过程中也起着重要作用。     

外周血单个核细胞在不同介质中HSP70形成的研究

目的研究外周血单个核细胞（PBMC）在不同介质中热休克蛋白（Heat shock protein HSP）70的表达。方法抽取16例健康志愿者外周血，应用密度梯度法分离单个核细胞，在不同介质中42℃热休克0．5、1h，免疫组化染色测定热休克蛋70的形成。结果PBMC在不同介质中热休克蛋白70形成与空白相比有明显差异（P〈0．01）；在1640培养液和血清中热休克0.5h，热休克蛋白70的表达差异明显（P〈0．01）；在1640培养液中热休克0．5h和1h间无显著差别（P〉0．05）。结论热休克蛋白的形成与介质密切相关，只有当变性蛋白质达到一定的量才能启动热休克蛋白基因的转录、合成。     

Hsp70的研究进展及其在类风湿关节炎中的作用北大核心

热休克蛋白70(heat shock protein 70,Hsp70)是一类高度保守的蛋白,在机体应激状态下表达增多,可介导一系列的细胞基本生理功能。Hsp70在自身免疫性疾病的发生和发展中起到了重要作用。Hsp70可以改善类风湿关节炎(rheumatoid arthritis,RA)疾病模型中的炎症损伤。该文就Hsp70的免疫功能及其在RA中的生物学机制方面予以综述。     

热休克因子1与恶性肿瘤

热休克因子1 (heat shock factor 1,HSF1) 是调控真核生物热休克反应的主要转录因子。HSF1的作用远不止诱导热休克蛋白（heat shock protein, HSP）表达, 也是肿瘤发生的一个有力调节因子,对肿瘤的起始和维持是必需的。HSF1在肿瘤发生中的可能机制是：作为转录因子诱导HSP90和抑制雌激素反应元件调节的基因和XAF1基因的表达;HSF1作为非转录因子诱导细胞有丝分裂停止和基因组不稳定性。     

热休克蛋白抑制慢性心理应激引起的焦虑样行为增加

目的：采用HSFI基因敲除小鼠模型探讨热休克蛋白（heat shock protein，HSP）对慢性心理应激引起的焦虑样行为增加的抑制作用。方法：将热休克因子1（heat shock factor 1）基因野生型小鼠（HSFI＋／＋）和热休克因子1基因敲除小鼠（HSF1-／-）暴露于2个月的慢性心理应激，部分小鼠在暴露于慢性心理应激前给予热休克预处理，2个月后采用高架十字迷宫和旷场实验检测各组小鼠焦虑样行为，Western blots检测和比较HSP72，HSC70表达，采用多因素析因设计方差分析对各组小鼠焦虑样行为进行比较。结果：慢性心理应激引起焦虑样行为增加．HSF1基因敲除导致焦虑样行为增加更加明显。热休克预处理使野生型小鼠海马组织中HSP70。HSC70明显升高，并明显减轻了心理应激所致的焦虑样行为的增加。HSF1基因敲除废除了热休克所致的HSP诱导表达及其对心理应激所致焦虑样行为增加的抑制作用。结论：诱导型HSP在抑制心理应激引起的焦虑样行为增加中起着重要的作用。     

GRP78与乳腺癌的研究进展

热休克蛋白(heat shock protein，HSP)是一类应激蛋白，与肿瘤发生、发展、增殖、分化以及耐药密切相关，实体肿瘤细胞中存在HSP异常表达。葡萄糖调节蛋白78(glucose regulated protein，GRP78)是HSP家族的重要组成部分。近年来研究发现GRP78在乳腺癌的增殖、转移、抗凋亡、耐药以及新的治疗靶点中占据重要作用，现就GRP78在乳腺癌中的研究做一综述。     

HSP90对低氧诱导因子的调节作用

低氧诱导因子（hypoxia-inducible factor 1,HIF-1）是一种调节细胞和机体氧稳态的转录因子。在低氧时，HIF-1蛋白得以稳定，并活化一系列基因如促红细胞生成素、血管内皮生长因子、糖酵解酶等来增强细胞供能供氧能力，促使细胞在低氧环境下存活或增殖。在这一过程中，热休克蛋白90（heat shock protein 90, HSP90）对HIF-1起着重要的调节作用，它能与活化蛋白激酶C受体竞争结合HIF-1α，使其免于非氧依赖方式的降解从而维持其稳定，并影响低氧时HIF-1α的核转位、与HIF-1β的异二聚化及转录活性等。此外，HIF-1也能通过增强热休克因子的转录水平来上调热休克蛋白家族，进而加强自身的稳定。     

结核菌感染中热休克蛋白对巨噬细胞的影响

热休克蛋白(heat shock protein,HSP)是生物界普遍存在的一种高度保守的蛋白质,对维持细胞生存和内环境的稳定起重要作用。在结核菌感染过程中机体或病原体的HSP被激活,影响巨噬细胞的自噬、凋亡和极化等作用。本文综述了结核菌感染中,能影响巨噬细胞功能的主要HSP的相关研究进展。     

热休克蛋白60和免疫反应

热休克蛋白(heat shock protein/hsp)是一类高度保守的蛋白，在新生蛋白的正确折叠、转运、定位及降解上具有重要的作用，因此又叫分子伴侣。近十年研究发现hsp90、hsp70、hsp60以及gp96都可以作为一个危险信号触发机体的先天免疫反应，尤其是hsp60，在先天免疫中可以强烈的活化APC，促进DC的成熟以及诱导前炎症因子、细胞因子和趋化因子的释放。本文综述了10年来HSP60和免疫系统关系的研究进展。     

Stress proteins in CNS inflammation

Stress proteins or heat shock proteins (HSPs) are ubiquitous cellular components that have long been known to act as molecular chaperones. By assisting proper folding and transport of proteins, and by assisting in the degradation of aberrant proteins, they play key roles in cellular metabolism. The frequent accumulation of insoluble protein aggregates during chronic neurodegenerative disorders suggests failure of HSP functions to be a common denominator among such diseases. Recent developments have clarified that functions of HSPs extend well beyond their role in protein folding and degradation alone. Stress-inducible HSPs also regulate apoptosis, antigen presentation, inflammatory signalling pathways and, intriguingly, also serve as extracellular mediators of inflammation. Several receptors have been identified for extracellular HSPs, which control inflammatory pathways similar to those activated by cytokines and chemokines. In this review, both the traditional and the exciting novel functions of HSPs are discussed, with a focus on their relevance for neurodegeneration and neuroinflammation. Recent advances in this field suggest that HSPs represent attractive novel targets as well as therapeutic entities for CNS disorders.     

Heat shock proteins and high mobility group box 1 protein lack cytokine function

In search of the etiology and pathophysiology for autoimmune and chronic inflammatory diseases, many molecules have been identified as endogenous damage-associated molecules with proinflammatory cytokine functions that may be responsible for the sterile inflammation leading to tissue injuries observed in these disorders. HSPs and HMGB1 are intracellular molecular chaperones for peptides and DNAs, respectively. They are released extracellularly upon cellular injury or activation. In vitro studies revealed that HSPs and HMGB1 were capable of inducing the release of proinflammatory cytokines by monocytes and macrophages and the activation and maturation of DCs. These cytokine effects were reported to be mediated by TLR2 and TLR4 signal transduction pathways. Thus, they were called endogenous ligands of TLR2 and TLR4 and might serve as danger signals, alarmins, or damage-associated molecules to the host immune system. It has been suggested that HSPs provide a link between innate and adaptive immune systems, and HMGB1 functions at the cross-road between innate and adaptive immunity. However, recent evidence suggests that highly purified HSPs and HMGB1, although retaining their biological activities, do not have cytokine effects. Thus, HSPs and HMGB1 do not meet the definition of endogenous ligands of TLRs, danger signals, alarmins, or damage-associated molecules. In contrast, HSPs and HMGB1 are found to bind a number of pathogen-associated molecules, such as LPS and bacterial lipopeptides, and enhance the cytokine effects of these molecules. The significance of these cytokine-enhancing effects of HSPs and HMGB1 needs further investigation.     

Heat shock proteins: Cellular and molecular mechanisms in the central nervous system

Emerging evidence indicates that heat shock proteins (HSPs) are critical regulators in normal neural physiological function as well as in cell stress responses. The functions of HSPs represent an enormous and diverse range of cellular activities, far beyond the originally identified roles in protein folding and chaperoning. HSPs are now understood to be involved in processes such as synaptic transmission, autophagy, ER stress response, protein kinase and cell death signaling. In addition, manipulation of HSPs has robust effects on the fate of cells in neurological injury and disease states. The ongoing exploration of multiple HSP superfamilies has underscored the pluripotent nature of HSPs in the cellular context, and has demanded the recent revamping of the nomenclature referring to these families to reflect a re-organization based on structure and function. In keeping with this re-organization, we first discuss the HSP superfamilies in terms of protein structure, regulation, expression and distribution in the brain. We then explore major cellular functions of HSPs that are relevant to neural physiological states, and from there we discuss known and proposed HSP impacts on major neurological disease states. This review article presents a three-part discussion on the array of HSP families relevant to neuronal tissue, their cellular functions, and the exploration of therapeutic targets of these proteins in the context of neurological diseases.     

Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy

Stress or heat shock proteins (HSPs) are the most conserved proteins present in both prokaryotes and eukaryotes. Their expression is induced in response to a wide variety of physiological and environmental insults. These proteins play an essential role as molecular chaperones by assisting the correct folding of nascent and stress-accumulated misfolded proteins, and preventing their aggregation. HSPs have a dual function depending on their intracellular or extracellular location. Intracellular HSPs have a protective function. They allow the cells to survive lethal conditions. Various mechanisms have been proposed to account for the cytoprotective functions of HSPs. Several HSPs have also been demonstrated to directly interact with various components of the tightly regulated programmed cell death machinery, upstream and downstream of the mitochondrial events. On the other hand, extracellular located or membrane-bound HSPs mediate immunological functions. They can elicit an immune response modulated either by the adaptive or innate immune system. This review will focus on HSP27, HSP70, and HSP90. We will discuss the dual role of these HSPs, protective vs. immunogenic properties, making a special emphasis in their utility as targets in cancer therapy.     

Distribution of heat shock proteins in kidneys of rats after immunosuppressive treatment with cyclosporine A

Cyclosporine A (CsA), a fungal undecapeptide, is the most common immunosuppressive drug used in organ transplantation and auto-immune diseases. However, it has severe side effects mainly on renal structures and functions. Therefore, nephrotoxicity is the major limiting side effect. Heat shock proteins (HSPs) are molecular chaperones, that are induced or expressed at high levels in mammalian cells due to a variety of adverse effects. HSPs have beneficial roles in protein processing and protection against cell injury. In the present study, we examined immunohistochemically levels of expression and localization patterns of various HSPs in rat kidneys after administration of a therapeutic CsA dose during 30 days. After CsA treatment, both constitutive HSP 25 and alpha B-crystallin immunoreactivity became stronger in glomeruli, proximal tubules and collecting ducts. Nuclear translocation of these proteins was detected in renal tubules. HSP 47 was detected in the interstitial space between tubules, vascular smooth muscle and medullary rays. Finally, HSP 72 was induced in the cytoplasm of epithelial cells of proximal and distal tubules, and in the cytoplasm of epithelial cells of Henle limbs and collecting ducts. These data demonstrate that CsA clearly induces increased immunoreactivity of HSPs in defined structures of rat kidneys. These findings suggest that these proteins are functionally involved in the defence against renal cellular damage caused by prolonged drug treatment in rat.     

Heat-Shock Stress-Response Proteins in Endocrine Pathology

Heat-shock proteins (HSPs), also known as stress-response proteins, represent an evolutionarily conserved class of glycoproteins; members of this protein family are also known as "molecular chaperones." HSPs are constitutively expressed, and most are overproduced in response to a nonlethal thermal shock or other stressful conditions. They are implicated in several cell functions; they likely act in association with steroid receptors at the level of receptor-DNA interactions. Various types of HSPs have been found in endocrine glands, hormone-dependent tissues, and neoplasms. At present, their exact role remains obscure. HSPs may serve as tumor markers of prognostic significance; they may also have diagnostic and therapeutic uses.     

Gut microbiota imbalance and chaperoning system malfunction are central to ulcerative colitis pathogenesis and can be counteracted with specifically designed probiotics: a working hypothesis

In this work, we propose that for further studies of the physiopathology and treatment for inflammatory bowel diseases, an integral view of the conditions, including the triad of microbiota–heat shock proteins (HSPs)–probiotics, ought to be considered. Microbiota is the complex microbial flora that resides in the gut, affecting not only gut functions but also the health status of the whole body. Alteration in the microbiota’s composition has been implicated in a variety of pathological conditions (e.g., ulcerative colitis, UC), involving both gut and extra-intestinal tissues and organs. Some of these pathologies are also associated with an altered expression of HSPs (chaperones) and this is the reason why they may be considered chaperonopathies. Probiotics, which are live microorganisms able to restore the correct, healthy equilibrium of microbiota composition, can ameliorate symptoms in patients suffering from UC and modulate expression levels of HSPs. However, currently probiotic therapy follows ex-adiuvantibus criteria, i.e., treatments with beneficial effects but whose mechanism of action is unknown, which should be changed so the probiotics needed in each case are predetermined on the basis of the patient’s microbiota. Consequently, efforts are necessary to develop diagnostic tools for elucidating levels and distribution of HSPs and the microbiota composition (microbiota fingerprint) of each subject and, thus, guide specific probiotic therapy, tailored to meet the needs of the patient. Microbiota fingerprinting ought to include molecular biology techniques for sequencing highly conserved DNA, e.g., genes encoding 16S RNA, for species identification and, in addition, quantification of each relevant microbe.     

Differential expression of heat shock protein mRNAs under in vivo glutathione depletion in the mouse retina

Heat shock proteins (HSPs) are highly conserved proteins playing a protective role under deleterious conditions caused by a wide variety of pathophysiological, including environmental stresses. Glutathione (GSH) is known to play a critical role in the cellular defense against unregulated oxidative stress in mammalian cells including neurons. We previously demonstrated that GSH depletion induced cell death in the retina, but the mechanism(s) of cellular protection were not clear. Unregulated oxidative stress was induced by depletion of intracellular GSH by systematic administration of buthionine sulphoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. After 0, 1, 4 and 7 days of BSO administration, we examined expression of both large and small HSP mRNAs (hsp90alpha, hsp90beta, hsp70, hsp60 and hsp25) in oxidative-stressed mouse retina. Of large HSPs, only hsp70 expression was significantly decreased from 1 day after BSO injection, whereas expression of other large hsps was not changed on day 1. Expression of hsp60 decreased on 4 days, whereas expression of hsp90 decreased on 7 days after BSO administration. Different from large HSPs, a small HSP, hsp25 increased its expression to a great extent from 1 day after BSO administration. Taken together, our results show that unregulated oxidative stress could induce differential expression of HSPs, which, in turn, may play distinct roles in the cellular defense. Targeting HSPs, therefore, may provide novel tools for treatment of retinal degenerative diseases such as glaucoma, retinopathy or age-related macular degeneration.     

Multiple centrosomes: together they stand, divided they fall

Cells with extra centrosomes rely entirely on centrosome clustering mechanisms to assemble a bipolar spindle and to divide in a bipolar fashion. To identify the pathways involved in suppression of multipolarity, Kwon, Godinho, and colleagues (pp. 2189-2203) have set up a genome-wide screen in Drosophila S2 cells. Surprisingly, they found that efficient clustering requires a large number of proteins associated with a variety of cellular functions.     

Uncoupling protein homologs may provide a link between mitochondria, metabolism and lifespan

Uncoupling proteins (UCPs), which dissipate the mitochondrial proton gradient, have the ability to decouple mitochodrial respiration from ATP production. Since mitochondrial electron transport is a major source of free radical production, it is possible that UCP activity might impact free radical production. Free radicals can react with and damage cellular proteins, DNA and lipids. Accumulated damage from oxidative stress is believed to be a major contributor to cellular decline during aging. If UCP function were to impact mitochondrial free radical production, then one would expect to find a link between UCP activity and aging. This theory has recently been tested in a handful of organisms whose genomes contain UCP1 homologs. Interestingly, these experiments indicate that UCP homologs can affect lifespan, although they do not support a simple relationship between UCP activity and aging. Instead, UCP-like proteins appear to have a variety of effects on lifespan, and on pathways implicated in lifespan regulation. One possible explanation for this complex picture is that UCP homologs may have tissue-specific effects that complicate their effects on aging. Furthermore, the functional analysis of UCP1 homologs is incomplete. Thus, these proteins may perform functions in addition to, or instead of, mitochondrial uncoupling. Although these studies have not revealed a clear picture of UCP effects on aging, they have contributed to the growing knowledge base for these interesting proteins. Future biochemical and genetic investigation of UCP-like proteins will do much to clarify their functions and to identify the regulatory networks in which they are involved.