白细胞介素-1受体拮抗剂在糖尿病治疗中的作用

<正>目前认为糖尿病的发病与机体的炎症过程密切相关,已形成糖尿病的炎症发病学说。作为炎症过程的重要调节因子,细胞因子与糖尿病的关系日益引起重视。白细胞介素-1β(IL-1β)是由巨噬细胞、脂肪细胞和内皮细胞等产生和分泌的。IL-1β独立或介导的炎症过程所引起的β细胞功能损伤,是胰岛β细胞衰竭的重要原因。白细胞介素-1受体拮抗剂(IL-1Ra)是人体内天然存在的受体拮抗剂,通过与广泛存在各种组织和器官中表达的白细胞介     

白细胞介素1与阿尔茨海默病

目的:近年研究表明细胞因子作为免疫活性物质,在阿尔茨海默病的炎症反应中起着重要的调节作用,现就白细胞介素1在阿尔茨海默病病理生理过程中的作用的研究进展作一综述。资料来源:应用计算机检索Medline1995-08/2005-08的白细胞介素1与阿尔茨海默病相关的文章,检索词“interleukin1,Alzheimerdisease”,并限定文章语言种类为English。同时计算机检索CNKI1995-08/2005-08期间相关的文章,限定文章语言种类为中文,检索词“白细胞介素1,阿尔茨海默病”。资料选择:纳入标准:无论研究对象为动物还是患者全部纳入,实验研究要求设立对照组,其中研究内容相似的,以近3年且发表在较权威杂志者优先;排除标准:重复的临床或动物实验研究。资料提炼:就检索到的207篇文献进行筛选,选择白细胞介素1在阿尔茨海默病病理生理过程中的作用为主要研究内容的文献21篇,并按照白细胞介素1参与阿尔茨海默病病理生理过程分类,其中5篇为白细胞介素1基因多态性与阿尔茨海默病的关系,15篇与其作用于阿尔茨海默病不同的病理生理环节相关,1篇与其作用展望有关。排除186篇重复研究或无对照组文献。资料综合:①阿尔茨海默病患者血清中白细胞介素1β升高,提示白细胞介素1可能与阿尔茨海默病的发病有一定的相关性。②已经证实白细胞介素1A(-889)多态性与体内白细胞介素1α水平增高有关。白细胞介素1RN对白细胞介素1A、白细胞介素1B功能有调节作用,它们的相互作用可能在阿尔茨海默病发病中起作用。③白细胞介素1通过5'端非翻译区实现对淀粉样前体蛋白mRNA翻译的调控,还可以通过促进淀粉样前体蛋白降解,产生更多的淀粉样β蛋白。④在阿尔茨海默病脑中,许多白细胞介素1免疫阳性小胶质细胞围绕在病理改变脑区周围,它们在皮层的分布和淀粉样β蛋白分布是相关的。⑤白细胞介素1还可导致神经元纤维缠结形成、促进轴突增生过长等,从而参与整个阿尔茨海默病的病理生理过程。结论:白细胞介素1在阿尔茨海默病病理生理过程中具有重要的作用。针对它作用于阿尔茨海默病的各个过程寻找治疗靶点,如白细胞介素1Ra,可能为阿尔茨海默病的临床治疗提供新的思路。     

白细胞介素1与阿尔茨海默病

目的：近年研究表明细胞因子作为免疫活性物质，在阿尔茨海默病的炎症反应中起着重要的调节作用，现就白细胞介素1在阿尔茨海默病病理生理过程中的作用的研究进展作一综述。 资料来源：应用计算机检索Medline1995-08／2005-08的白细胞介素1与阿尔茨海默病相关的文章，检索词“interleukin 1，Alzheimer disease”，并限定文章语言种类为English。同时计算机检索CNKI 1995-08／2005-08期间相关的文章，限定文章语言种类为中文，检索词“白细胞介素1，阿尔茨海默病”。 资料选择：纳入标准：无论研究对象为动物还是患者全部纳入，实验研究要求设立对照组，其中研究内容相似的，以近3年且发表在较权威杂志者优先；排除标准：重复的临床或动物实验研究。 资料提炼：就检索到的207篇文献进行筛选，选择白细胞介素1在阿尔茨海默病病理生理过程中的作用为主要研究内容的文献21篇，并按照白细胞介素1参与阿尔茨海默病病理生理过程分类，其中5篇为白细胞介素1基因多态性与阿尔茨海默病的关系，15篇与其作用于阿尔茨海默病不同的病理生理环节相关，1篇与其作用展望有关。排除186篇重复研究或无对照组文献。 资料综合：①阿尔茨海默病患者血清中白细胞介素1β升高，提示白细胞介素1可能与阿尔茨海默病的发病有一定的相关性。②已经证实白细胞介素1A（-889）多态性与体内白细胞介素1α水平增高有关。白细胞介素1RN对白细胞介素1A、白细胞介素1β功能有调节作用，它们的相互作用可能在阿尔茨海默病发病中起作用。③白细胞介素1通过5′端非翻译区实现对淀粉样前体蛋白mRNA翻译的调控，还可以通过促进淀粉样前体蛋白降解，产生更多的淀粉样β蛋白。④在阿尔茨海默病脑中，许多白细胞介素1免疫阳性小胶质细胞围绕在病理改变脑区周围，它们在皮层的分布和淀粉样β蛋白分布是相关的。⑤白细胞介素1还可导致神经元纤维缠结形成、促进轴突增生过长等，从而参与整个阿尔茨海默病的病理生理过程。 结论：白细胞介素1在阿尔茨海默病病理生理过程中具有重要的作用。针对它作用于阿尔茨海默病的各个过程寻找治疗靶点，如白细胞介素1Ra，可能为阿尔茨海默病的临床治疗提供新的思路。     

急性脊髓损伤模型大鼠白细胞介素1β和核因子κB的表达

背景:在脊髓损伤后的继发性损伤过程中,白细胞介素1β参与刺激其他细胞因子和损伤介质的合成。目的:观察白细胞介素1受体拮抗剂对急性脊髓损伤模型大鼠损伤脊髓白细胞介素1β与核因子κB表达的影响。方法:采用改良Allen法建立SD大鼠急性脊髓损伤模型,造模后分别在损伤处敷含白细胞介素1受体拮抗剂或仅有生理盐水的明胶海绵,于脊髓损伤1,48,72h取损伤段脊髓标本,免疫组织化学染色检测白细胞介素1β与核因子κB的表达。结果与结论:经白细胞介素1受体拮抗剂治疗后,损伤脊髓组织白细胞介素1β和核因子κB的表达均显著降低。说明白细胞介素1受体拮抗剂可通过抑制白细胞介素1β和核因子κB的表达,减轻局部炎症反应,对急性脊髓损伤大鼠损伤段脊髓发挥保护作用。     

急性脊髓损伤模型大鼠白细胞介素1β和核因子κB的表达

背景：在脊髓损伤后的继发性损伤过程中,白细胞介素1β参与刺激其他细胞因子和损伤介质的合成。目的：观察白细胞介素1受体拮抗剂对急性脊髓损伤模型大鼠损伤脊髓白细胞介素1β与核因子κB表达的影响。方法：采用改良Allen法建立SD大鼠急性脊髓损伤模型,造模后分别在损伤处敷含白细胞介素1受体拮抗剂或仅有生理盐水的明胶海绵,于脊髓损伤1,48,72h取损伤段脊髓标本,免疫组织化学染色检测白细胞介素1β与核因子κB的表达。结果与结论：经白细胞介素1受体拮抗剂治疗后,损伤脊髓组织白细胞介素1β和核因子κB的表达均显著降低。说明白细胞介素1受体拮抗剂可通过抑制白细胞介素1β和核因子κB的表达,减轻局部炎症反应,对急性脊髓损伤大鼠损伤段脊髓发挥保护作用。     

细胞因子中白细胞介素受体的平衡

目的:探讨白细胞介素受体的结构、信号转导及临床意义。资料来源:应用计算机检索Medline 1994-01/2006-01关于白细胞介素及其受体的文章,检索词为“Interleukin recepertor”并限定语言为英文,同时计算机检索万方数据库2004-04/2006-04关于白细胞介素受体的文章,限定语种为中文,检索词为“白细胞介素受体”。资料选择:对资料进行初审,选取与白细胞介素受体有关的文章,删除明显无关文献或相关性不强的文献,对剩余文献查找全文,进一步明确其相关性。纳入标准:随机对照研究;实验或临床研究包含平行对照组。排除标准:重复性研究和综述类文章。资料提炼:共收集到74篇有关白细胞介素及其受体的文章,31个实验或临床研究纳入标准。排除重复性研究及综述类文章。资料综合:31个研究包括1600例患者和432只动物,分别阐述了白细胞介素受体的结构,信号转导及作用机制,白细胞介素受体与临床疾病如变态反应性、自身免疫性、肿瘤、炎症等的关系。①白细胞介素受体的结构:白细胞介素受体均为跨膜糖蛋白结构,其N端位于细胞外,C端进入胞内,跨膜区为数目不等的氨基酸组成的肽链。②白细胞介素受体的信号转导:包括JAK-STAT途径、Ras-MAPK级联反应途径和p13k途径。③白细胞介素受体与疾病:白细胞介素受体与炎症、自身免疫性疾病、肿瘤、器官移植、骨质疏松及某些心肌病变的发生、发展有密切关系。结论:白细胞介素作为一种重要的细胞因子,其作用的发挥主要是通过其受体完成,白细胞介素受体与疾病的发生、发展有密切关系。对白细胞介素受体的信号转导及作用机制的研究,有助于阐明多种疾病的发病机制,尤其对临床疾病的诊断、治疗、预后判断等方面有重要的意义。     

骨关节炎与白细胞介素17的关系

目的:综合分析骨关节炎与细胞因子白细胞介素17的关系。资料来源:应用计算机检索Pubmed1995-01/2005-12有关细胞因子白细胞介素17与骨关节炎关系的文章,检索词“osteoarthritis,IL-17”,并限定文章语言种类为English;同时应用计算机检索中国期刊全文数据库1995-01/2005-02有关细胞因子白细胞介素17与骨关节炎关系的文章,检索词“骨关节炎,白细胞介素17”,并限定文章语言种类为中文。资料选择:对检索到的白细胞介素17、骨关节炎方面的相关信息进行整理,选取针对性强的文章。同一领域的文献则选择近期发表或权威杂志的文章。资料提炼:共检索到44篇相关文献,其中16篇文章符合要求。排除28篇,其中16篇系重复同一研究,12篇为临床报道。资料综合:白细胞介素17通过与其受体结合发挥生物学作用,其可能通过增加关节软骨细胞诱导性一氧化氮合酶表达和一氧化氮产量,增强软骨细胞基质金属蛋白酶(MMP-1/3/13)的表达,增强蛋白聚糖酶和胶原酶活性,促进软骨蛋白多糖及胶原降解,并增强单核细胞对软骨基质的破坏,从而诱导和加速骨关节炎的发生和发展。结论:白细胞介素17在骨关节炎疾病发生和发展中所起的作用已基本肯定,但其作用途径以及其与症状的关系等尚未完全明确。从分子水平阐明骨关节炎的发病途径以及针对该途径的免疫治疗都有待于进一步探索。     

运动和营养补充对白细胞介素的影响

目的:采用文献法总结白细胞介素1、白细胞介素2、白细胞介素6的作用,运动与白细胞介素的关系以及营养补充对运动后白细胞介素水平的影响,为了解运动、营养和免疫的关系提供一定的理论依据和参考。资料来源:通过计算机检索Springer数据库1990-01/2005-09关于白细胞介素和运动相关的文章,检索词主要为“Interleukin,exercise”,并限定文章语言为English;同时检索中文期刊全文数据库1995-01/2005-05关于白细胞介素、细胞因子和运动相关的文章,检索词为“白细胞介素,细胞因子,运动,免疫”,限定语言种类为中文。资料选择:对资料进行初审。选择与白细胞介素1、白细胞介素2、白细胞介素6与运动有关的文章以及营养补剂与白细胞介素有关的文章。纳入标准:白细胞介素1、白细胞介素2、白细胞介素6与运动及营养补剂与白细胞介素有关的文章。排除标准:重复性研究和综述。资料提炼:共搜集到与标准相符的文章65篇,排除重复性研究25篇,纳入40篇。其中运动和白细胞介素1有关的文章13篇,运动和白细胞介素2有关的文章10篇,运动和白细胞介素6有关的文章12篇,营养补剂对白细胞介素水平的影响5篇。资料综合:白细胞介素是一类介导机体体液免疫和细胞免疫功能的重要细胞因子。不同运动方式、运动强度和运动时间对白细胞介素1、白细胞介素2和白细胞介素6的产生均有不同的影响。结论:食用合适的营养补剂能有效减轻运动性免疫抑制,调节白细胞介素的分泌和释放,从而起到调节机体免疫功能的作用。     

白细胞介素18和前列腺素E2与骨关节炎

目的:回顾近年来国内外有关白细胞介素18和前列腺素E2在骨关节炎发病机制中作用的研究,分析白细胞介素18和前列腺素E2在骨关节炎发病机制中的作用进展。资料来源:应用计算机检索Medline1995-01/2005-02相关白细胞介素18和前列腺素E2与骨关节炎的文献,检索词“Interleukin-18,prostaglandinE2,cytokines,Osteoarthritis”,并限定文献语言种类为Eng-lish,同时计算机检索清华同方中国医院1995-01/2005-02相关白细胞介素18和前列腺素E2与骨关节炎,部分为细胞因子与骨关节炎的文献,检索词为“白细胞介素18,前列腺素E2,细胞因子,骨关节炎”。资料选择:对资料进行初选,选取包含白细胞介素18、前列腺素E2、细胞因子与骨关节炎的文献,开始查找与全文。纳入标准:①白细胞介素18与骨关节炎。②前列腺素E2与骨关节炎。③细胞因子与骨关节炎。④白细胞介素18,前列腺素E2与骨关节炎。排除标准:①细胞因子,炎症介质与类风湿性、风湿性关节炎。②骨关节炎的治疗。③重复的综述文献与研究,Meta分析类文章。资料提炼:共收集了有关白细胞介素18和前列腺素E2与骨关节炎,部分为细胞因子与骨关节炎的文献212篇,纳入65篇。其中2篇阐述了白细胞介素18和前列腺素E2在骨关节炎中的共同作用。将文献进行综合评价。资料综合:骨关节炎是人体活动关节中最常见的一种疼痛和退行性变疾病,其发病机制尚未完全阐明。其中细胞因子和炎症介质起着重要作用。新发现致炎因子白细胞介素18是骨关节炎发病机制中重要的一种炎症前因子,能诱导炎症介质前列腺素E2的产生。从免疫、病理、动物试验进行研究,揭示白细胞介素18,前列腺素E2在骨关节炎发病机制中的作用。结论:白细胞介素18与前列腺素E2参与了骨关节炎的发病机制,白细胞介素18的增高可能引起前列腺素E2含量的增高,从而在骨关节炎的发病机制中发挥重要作用。     

骨关节炎与白细胞介素17的关系

目的：综合分析骨关节炎与细胞因子白细胞介素17的关系。资料来源：应用计算机检索Pubmed 1995—01／2005—12有关细胞因子白细胞介素17与骨关节炎关系的文章，检索词“osteoarthritis，IL-17”，并限定文章语言种类为English；同时应用计算机检索中国期刊全文数据库1995—01／2005—02有关细胞因子白细胞介素17与骨关节炎关系的文章，检索词“骨关节炎，白细胞介素17”，并限定文章语言种类为中文。资料选择：对检索到的白细胞介素17、骨关节炎方面的相关信息进行整理，选取针对性强的文章。同一领域的文献则选择近期发表或权威杂志的文章。资料提炼：共检索到44篇相关文献，其中16篇文章符合要求。排除28篇，其中16篇系重复同一研究，12篇为临床报道。资料综合：白细胞介素17通过与其受体结合发挥生物学作用，其可能通过增加关节软骨细胞诱导性一氧化氮合酶表达和一氧化氮产量，增强软骨细胞基质金属蛋白酶（MMP-1／3／13）的表达，增强蛋白聚糖酶和胶原酶活性，促进软骨蛋白多糖及胶原降解，并增强单核细胞对软骨基质的破坏，从而诱导和加速骨关节炎的发生和发展。结论：白细胞介素17在骨关节炎疾病发生和发展中所起的作用已基本肯定，但其作用途径以及其与症状的关系等尚未完全明确。从分子水平阐明骨关节炎的发病途径以及针对该途径的免疫治疗都有待于进一步探索。     

Neurokinin-1 receptor resensitization precedes receptor recycling

Following agonist binding, neurokinin-1 receptors undergo rapid desensitization followed by internalization and recycling. Desensitization requires receptor phosphorylation but does not require internalization, whereas resensitization is thought to require internalization and recycling. Our previous data, however, have suggested that, following activation and desensitization, the return of responsiveness to the neurokinin-1 agonist substance P (termed "resensitization") occurs hours before internalized receptors are recycled back to the plasma membrane. To further investigate this novel mechanism of neurokinin-1 receptor resensitization, we have studied the time courses of neurokinin-1 receptor responsiveness, recycling, and dephosphorylation by measuring cellular Ca(2+) responses, ligand-receptor binding, and receptor phosphorylation, respectively. Concentration-response curves and competition binding curves were obtained at various times following desensitization. The effects of the nonhydrolyzable GTP analog Gpp(NH)p on substance P binding were also studied to assess receptor-G protein coupling. After receptor activation and desensitization, Ca(2+) signaling in response to substance P occurred within 90 min, whereas the return of receptor binding required 240 min. Receptor dephosphorylation was greater than 90% complete 20 min after agonist washout. In addition, the return of substance P responsiveness coincided with a return in sensitivity of substance P binding to Gpp(NH)p, indicating a return in receptor-G protein coupling. These data show that the resensitization of responsiveness to substance P precedes receptor recycling. This may result from a conversion of nonfunctional neurokinin-1 receptors to functional receptors at the plasma membrane.     

Serotonin1c receptor reserve in choroid plexus masks receptor subsensitivity

This paper tests the hypothesis that spare serotonin 5-HT1c receptors are present in the rat choroid plexus and explores the possible influence of such sites on the adaptive regulation of the 5-HT1c receptor. The consequences of partial receptor inactivation were compared for the natural agonist 5-HT and the putative partial agonists trifluoromethylphenylpiperazine (TFMPP) and (+)-lysergic acid diethylamide (LSD). These studies showed approximately 50% reserve of 5-HT1c receptors in the rat choroid plexus. The calculated KA for 5-HT obtained by partial irreversible inactivation was 36 nM. Phenoxybenzamine reduced the maximum response elicited by TFMPP and LSD, without shifting the EC50 values, consistent with the interpretation that TFMPP and LSD are partial agonist at the 5-HT1c receptor in rat choroid plexus. The KA of TFMPP and LSD was 0.16 microM and 9 nM, respectively. Quantitative analysis of percentage of receptor occupancy vs. percentage of maximum response showed that 5-HT occupied only 70% of the receptors to give a maximum response, whereas a linear relationship between percentage of occupancy and response was found for TFMPP. These differences had functional consequences as demonstrated in studies of regulation of the 5-HT1c receptor. Chronic administration of the 5-HT agonist quipazine produced a 32% loss of 5-HT1c binding sites in the choroid plexus, with no change in the 5-HT-induced phosphoinositide hydrolysis response. This dissociation between binding and function is likely explained by the receptor reserve that exists for the 5-HT1c receptors. Consistent with this interpretation, the TFMPP-induced phosphoinositide hydrolysis signal was reduced to the same extent as the loss of binding sites. These results show that the 5-HT1c receptor in the choroid plexus adapts predictably to chronic receptor activation and suggest the possibility that the paradoxical regulation that has been described for other 5-HT receptors might be explained partially by the unrecognized existence of receptor reserve.     

Complement receptor 1/CD35 is a receptor for mannan-binding lectin

Mannan-binding lectin (MBL), a member of the collectin family, is known to have opsonic function, although identification of its cellular receptor has been elusive. Complement C1q, which is homologous to MBL, binds to complement receptor 1 (CR1/CD35), and thus we investigated whether CR1 also functions as the MBL receptor. Radioiodinated MBL bound to recombinant soluble CR1 (sCR1) that had been immobilized on plastic with an apparent equilibrium dissociation constant of 5 nM. N-acetyl-d-glucosamine did not inhibit sCR1-MBL binding, indicating that the carbohydrate binding site of MBL is not involved in binding CR1. C1q inhibited MBL binding to immobilized sCR1, suggesting that MBL and C1q might bind to the same or adjacent sites on CR1. MBL binding to polymorphonuclear leukocytes (PMNs) was associated positively with changes in CR1 expression induced by phorbol myristate acetate. Finally, CR1 mediated the adhesion of human erythrocytes to immobilized MBL and functioned as a phagocytic receptor on PMNs for MBL-immunoglobulin G opsonized bacteria. Thus, MBL binds to both recombinant sCR1 and cellular CR1, which supports the role of CR1 as a cellular receptor for the collectin MBL.     

The inhibitory activity of human interleukin-1 receptor antagonist is enhanced by type II interleukin-1 soluble receptor and hindered by type I interleukin-1 soluble receptor.

Interleukin-1 (IL-1) is a major proinflammatory cytokine produced by monocytes/macrophages. At the inflammatory site, IL-1 is a potent inducer of the production of prostaglandin E2 (PGE2) and metalloproteinases on fibroblast-like cells, thus triggering tissue damage. The biological activity of IL-1 is counterbalanced by two types of inhibitors: the IL-1 receptor antagonist (IL-1Ra) which competitively binds IL-1 receptor without inducing signal transduction; and IL-1 soluble receptors (IL-1sR) which bind IL-1 and diminish the free concentration of soluble cytokine, thus hampering its binding to the cell surface receptor. Since IL-1sR can also bind IL-1Ra, we studied the simultaneous effects of both inhibitors on the production of interstitial collagenase (C'ase) and PGE2 by human dermal fibroblasts and synovial cells stimulated by either IL-1 alpha or IL-1 beta. IL-1Ra inhibited fibroblast and synovial cell stimulation by approximately 90%, with the exception of C'ase production by synovial cells which was inhibited by approximately 55%. Type I IL-1sR (IL-1sRI) preferentially inhibited IL-1 alpha, whereas type II IL-1sR (IL-1sRII) mainly inhibited IL-1 beta. When IL-1Ra was used simultaneously with IL-1sRI, the final inhibition was lower than that of either of the inhibitors. The simultaneous presence of IL-1Ra and IL-1sRII abolished the IL-1-induced production of PGE2 and C'ase on both dermal fibroblasts and synovial cells, demonstrating that concurrently these two inhibitors are able to abolish most of the inflammatory response. To our knowledge, this is the first example of two types of inhibitors that abolish each other's effects, one of which acts at the receptor level and the other at the ligand level, thus leaving ligand activity unimpaired.     

Angiotensin AT1 receptor over-expression in hypercholesterolaemia

Angiotensin II mediates most of the biological effects of the renin-angiotensin system (RAS), such as vasoconstriction and cell proliferation, via stimulation of the angiotensin II type 1 (AT1) receptor. The AT1 receptor plays a central role in the pathogenesis of atherosclerosis and hypertension. In parallel, hypercholesterolaemia is a major risk factor for the development and progression of cardiovascular diseases. The underlying molecular events, however, are understood only partially. An important mechanism may be the interaction between hypercholesterolaemia and AT1 receptor expression in vascular tissue. Low-density lipoprotein (LDL) cholesterol leads to a profound increase in AT1 receptor expression in cultured vascular smooth muscle cells as well as in hypercholesterolaemic rabbits. This up-regulation is associated with an enhanced functional response upon stimulation with angiotensin II. Over-expression of the vascular AT1 receptor can also be observed in hypercholesterolaemic men and is prevented by treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. These findings may explain why hypercholesterolaemia is frequently associated with hypertension and why blockade of the RAS attenuates the progression of atherosclerosis.