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。     

骨关节炎软骨细胞对白细胞介素18的炎症应答

目的探讨IL-18 对骨关节炎软骨细胞的作用。方法取骨关节炎患者的膝关节软骨,进行原代细胞培养。不同浓度的IL-18（0,50,150,300 ng/mL）刺激软骨细胞,RT-PCR检测TNFα和COX-2 mRNA的表达,ELISA检测TNFα、PGE2的水平。应用IL-1 受体阻断剂（IL-1Ra）+IL-18 干预软骨细胞,检测软骨细胞COX-2 的表达量和培养液中PGE2的水平。提取软骨细胞RNA,测定IL-18受体的表达。结果对于COX-2和TNFα,300 ng/mL组和150 ng/mL组mRNA的表达量显著高于对照组（P<0.01,P<0.05）。50、300 ng/mL组的PGE2水平显著高于对照组（P<0.05）。150、300 ng/mL组的TNFα蛋白的浓度显著高于对照组（P<0.05）,IL-1Ra 组的PGE2浓度高于对照组（P<0.01）,但是低于IL-18 组（P<0.01）。软骨细胞能够检测到IL-18 受体的表达。结论IL-18诱导软骨细胞产生炎症应答,这种作用和IL-1β有关但不完全依赖IL-1β。      

白细胞介素-18与系统性红斑狼疮活动性关系探讨

目的进一步证实系统性红斑狼疮(SLE)患者血清中IL-18的水平与SLE活动性的关系。方法采用酶联免疫吸附试验(ELISA)检测了38例SLE患者在活动期和治疗后稳定期及30例对照血清中IL-18的水平,观察IL-18与SLE疾病活动指数标准(SLEDAI)及其它疾病活动指标[血沉(ESR),抗双链-DNA(ds-DNA)抗体,补体C3和C4及总补体CH50]的相关性。结果(1)活动期和治疗后稳定期SLE患者血清中IL-18水平[分别为(754.2±314.8)pg/ml,(311.5±256.7)pg/ml]显著高于健康对照组[(108.4±12.6)pg/ml];活动期SLE患者血清中IL-18水平显著高于稳定期患者(P<0.05)。(2)在活动期SLE患者,血清中IL-18水平分别与抗ds-DNA抗体滴度和SLEDAI评分呈现显著的正相关(均P<0.05)。与ESR,C3,C4和CH50等其它实验室指标无显著相关性(均P>0.05)。而活动期SLEDAI评分分别与C3、CH50和抗ds-DNA抗体滴度呈显著的相关性(均P<0.05)。(3)活动期和治疗后稳定期SLE患者血清中IL-18水平变化结果与SLEDAI评分变化结果呈现显著相关性(r=0.46,P<0.05)。结论IL-18水平在SLE中升高,与SLE活动性呈现显著正相关,检测IL-18可以作为诊断SLE活动性的有效的指标之一。     

白细胞介素在骨关节炎发病机制中的作用研究进展

骨关节炎(OA)又称退行性关节炎或增生性OA,是一种临床常见的关节疾病,而对于其病因、发病机制以及治疗尚无明确有效的手段。随着一些基础学科的发展,OA的发病机制越来越成为研究热点,并试图从该病的发生和进展过程中找到控制以及治疗的可能。OA的发病机制是一个复杂的过程,多种病理机制参与其中。经研究发现,OA进行性退变的各个环节均有细胞因子的参与:细胞因子通过影响软骨细胞基质的合成、分解与代谢的平衡在OA的病程中起到了至关重要的作用,此外,关节滑膜细胞分泌的细胞因子也可部分解释OA的病理过程。在关节组织中发现的能影响软骨细胞和滑膜细胞功能的细胞因子主要包括:白细胞介素、生长因子、趋化因子和肿瘤坏死因子等。本文就白细胞介素在OA发病机制中的作用作一综述。     

白藜芦醇调控体外培养人骨关节炎滑膜细胞白细胞介素18的表达

背景：白藜芦醇可在体外抑制软骨细胞的凋亡。目的：观察白藜芦醇对体外培养人骨关节炎滑膜细胞中白细胞介素18、白细胞介素1β和肿瘤坏死因子α表达的影响。方法：对兔以白藜芦醇临床等效剂量灌胃后,制备含10%,20%,40%白藜芦醇含药血清,与人骨关节炎滑膜细胞共培养,以正常兔血清培养细胞为对照。结果与结论：ELISA检测及免疫细胞化学检测结果显示,不同浓度白藜芦醇含药血清组体外培养滑膜细胞白细胞介素18、白细胞介素1β、肿瘤坏死因子α分泌量较正常兔血清组明显降低（P〈0.01）,并随白藜芦醇浓度的增加,白细胞介素18、白细胞介素1β、肿瘤坏死因子α分泌量逐渐降低（P〈0.01或P〈0.05）。白细胞介素1β、肿瘤坏死因子α水平依次与白细胞介素18水平呈正相关。表明白藜芦醇能够显著下调白细胞介素18、白细胞介素1β、肿瘤坏死因子α在骨关节炎滑膜细胞中的表达,减轻滑膜炎症反应。     

白藜芦醇调控体外培养人骨关节炎滑膜细胞白细胞介素18的表达

背景:白藜芦醇可在体外抑制软骨细胞的凋亡。目的:观察白藜芦醇对体外培养人骨关节炎滑膜细胞中白细胞介素18、白细胞介素1β和肿瘤坏死因子α表达的影响。方法:对兔以白藜芦醇临床等效剂量灌胃后,制备含10%,20%,40%白藜芦醇含药血清,与人骨关节炎滑膜细胞共培养,以正常兔血清培养细胞为对照。结果与结论:ELISA检测及免疫细胞化学检测结果显示,不同浓度白藜芦醇含药血清组体外培养滑膜细胞白细胞介素18、白细胞介素1β、肿瘤坏死因子α分泌量较正常兔血清组明显降低(P<0.01),并随白藜芦醇浓度的增加,白细胞介素18、白细胞介素1β、肿瘤坏死因子α分泌量逐渐降低(P<0.01或P<0.05)。白细胞介素1β、肿瘤坏死因子α水平依次与白细胞介素18水平呈正相关。表明白藜芦醇能够显著下调白细胞介素18、白细胞介素1β、肿瘤坏死因子α在骨关节炎滑膜细胞中的表达,减轻滑膜炎症反应。     

白细胞介素18与急性肾损伤

急性肾损伤（AKI）是一种常见的急、危重疾病,病死率较高,部分患者如不及时救治可转为慢性肾衰竭。白细胞介素18（IL-18）是巨噬细胞产生的促炎症因子,其生物学特性和功能在急性肾损伤中有重要的作用。在特定人群的急性肾损伤中,血清、尿液中的IL-18含量均有一定变化,对其深入的研究可为今后早期预测、诊断AKI,预测AKI死亡率及预后,从而为早期干预和治疗急性肾损伤提供依据。     

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。     

白细胞介素18研究进展

白细胞介素18,以前称IFN-γ诱导因子,是一种新发现的细胞因子.在结构上与IL-1相似,在功能上与IL-12相似.它可刺激T细胞增殖,增强Th1及NK细胞毒活性,参与细胞因子的生成和骨的重塑,并具有抗肿瘤和抗微生物感染的作用.还可引起内毒素诱导的肝损害,并与变态反应性疾病及非肥胖性糖尿病有关,是一个多功能的值得进一步研究的细胞因子.     

白细胞介素-18与急性胰腺炎

急性胰腺炎(AP)是一种常见的急腹症，也是一种具有潜在威胁的疾病，它的发病率较高，总死亡率为10％。临床上根据病情的严重度将其分为轻型急性胰腺炎(MAP)和重症急性胰腺炎(SAP)，其中MAP具有自限性，预后较好，而SAP波及邻近组织并可并发远隔脏器的损害，导致多脏器功能不全综合征(MODS)的发生，预后差，死亡率高达20％～：30％。近些年来的研究表明，     

Interleukin-1 regulation of prostaglandin E2 synthesis by the papillary collecting duct

Interleukin-1 (IL-1) has been demonstrated to cause a natriuresis and diuresis in experimental animals. This effect is associated with an increase in prostaglandin E2 (PGE2) excretion and is prevented by pretreatment with cyclooxygenase inhibitors. Micropuncture studies have shown IL-1 inhibition of sodium reabsorption by the rat papillary collecting duct (PCD), a nephron segment capable of abundant PGE2 synthesis. The current study examined the effect of IL-1 on PGE2 synthesis by cultured PCD cells and the mechanism by which such regulation occurs. IL-1 markedly increased PCD cell PGE2 synthesis within 15 minutes of exposure in a dose-dependent manner. Preincubation with saturating concentrations of arachidonic acid abolished IL-1 stimulation of PGE2 synthesis. PCD cells labeled with tritiated arachidonic acid released significantly more arachidonic acid within 5 minutes of exposure to IL-1 as compared to control cells. These data demonstrate that IL-1 directly stimulates PGE2 synthesis by PCD cells and that this effect occurs by enhancement of arachidonic acid release.     

Effect of ciprofloxacin-induced prostaglandin E2 on interleukin-18-treated monocytes

Ciprofloxacin, a fluorinated 4-quinolone, is useful for the clinical treatment of infections due to its antibacterial properties and also modulates the immune response of monocytes isolated from human peripheral blood mononuclear cells. In the present study, we found that ciprofloxacin induced the production of prostaglandin E(2) in monocytes in a concentration-dependent manner regardless of the presence of interleukin-18 by enhancing the expression of cyclooxygenase-2 protein and that this in turn led to the elevation of intercellular cyclic AMP in monocytes via the stimulation of prostaglandin receptors. The prostaglandin E(2) and cyclic AMP production increased by ciprofloxacin was inhibited by indomethacin, a nonselective cyclooxygenase-2 inhibitor, and NS398, a selective cyclooxygenase-2 inhibitor. In addition, ciprofloxacin suppressed the interleukin-18-induced production of tumor necrosis factor alpha, gamma interferon, and interleukin-12 in peripheral blood mononuclear cells by inhibiting the expression of intercellular adhesion molecule 1, B7.1, B7.2, and CD40 on monocytes, and this effect could be reversed by the addition of indomethacin or NS398. These results indicate that ciprofloxacin exerts immunomodulatory activity via the production of prostaglandin E(2) and imply therapeutic potential of ciprofloxacin for the treatment of systemic inflammatory responses initiated by interleukin-18.     

Licofelone suppresses prostaglandin E2 formation by interference with the inducible microsomal prostaglandin E2 synthase-1

The anti-inflammatory drug licofelone [=ML3000; 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid], currently undergoing phase III trials for osteoarthritis, inhibits the prostaglandin (PG) and leukotriene biosynthetic pathway. Licofelone was reported to suppress the formation of PGE(2) in various cell-based test systems, but the underlying molecular mechanisms are not entirely clear. Here, we examined the direct interference of licofelone with enzymes participating in PGE(2) biosynthesis, that is, cyclooxygenase (COX)-1 and COX-2 as well as microsomal PGE(2) synthase (mPGES)-1. Licofelone concentration-dependently inhibited isolated COX-1 (IC(50) = 0.8 microM), whereas isolated COX-2 was less affected (IC(50) > 30 microM). However, licofelone efficiently blocked the conversion of PGH(2) to PGE(2) mediated by mPGES-1 (IC(50) = 6 microM) derived from microsomes of interleukin-1beta-treated A549 cells, being about equipotent to 3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK-886), a well recognized mPGES-1 inhibitor. In intact interleukin-1beta-treated A549 cells, licofelone potently (IC(50) < 1 microM) blocked formation of PGE(2) in response to calcimycin (A23187) plus exogenous arachidonic acid, but the concomitant generation of 6-keto PGF(1alpha), used as a biomarker for COX-2 activity, was not inhibited. We conclude that licofelone suppresses inflammatory PGE(2) formation preferentially by inhibiting mPGES-1 at concentrations that do not affect COX-2, implying an attractive and thus far unique molecular pharmacological dynamics as inhibitor of COX-1, the 5-lipoxygenase pathway, and of mPGES-1.     

急性冠脉综合征患者血浆白介素18、白介素10及其比值的变化和意义

目的：观察急性冠脉综合征患者血浆白介素（IL）-18、IL-10及其比值的变化,探讨其在急性冠脉综合征发生中的意义。方法：采用酶联免疫吸附（ELISA）法检测66例急性冠脉综合征患者和48例稳定型心绞痛患者血浆IL-18、IL-10等浓度变化。结果：急性冠脉综合征患者血浆IL-18、IL-10水平及其比值明显高于稳定性心绞痛患者（P〈0.01）;IL-18/IL-10比值与急性冠脉综合征的发生显著相关（OR=5.567,P〈0.01）。结论：急性冠脉综合征患者炎症反应比稳定型心绞痛明显;IL-18/IL-10比值与急性冠脉综合征的发生明显相关,提示了IL-18/IL-10对预测急性冠脉综合征的发生有一定价值。     

Hemodynamic roles of thromboxane A2 and prostaglandin E2 in glomerulonephritis

Eicosanoid metabolites may play a role in the pathophysiology of nephrotoxic serum nephritis (NSN), a model of immune renal disease. Our purpose was to determine the relative importance of vasoconstrictor [thromboxane A2 (TX)A2] and vasodilator [prostaglandin E2 (PG)E2] eicosanoids as mediators of hemodynamic and renal functional changes. Glomerular filtration rate (GFR; inulin clearance), and renal plasma flow (RPF; para-aminohippurate clearance/extraction) were measured in rats on day 1 and day 14 of NSN. Specific inhibitors of TXA2 synthesis and receptor binding, and cyclooxygenase inhibitors were used to determine the relative roles of TXA2 and PGE2. In vitro glomerular production of radioimmunoassayable PGE2 and TXB2 were measured after clearances. At 1 day GFR is decreased compared to control, 1.9 +/- 0.2 vs. 2.6 +/- 0.2 ml/min. RPF is numerically increased, 10.0 +/- 1.0 vs. 7.0 +/- 0.6 ml/min. By 14 days GFR is normal, 2.2 +/- 0.2 ml/min, as a consequence of significantly increased RPF, 11.7 +/- 1.0 ml/min. Glomerular production of PGE2 and TXB2 was increased 11- and 15-fold respectively at both 1 and 14 days. Pretreatment with OKY-1581, or acute treatment with UK-38,485, both inhibitors of TXA2 synthesis, had no effect on GFR or RPF in NSN rats. Addition of EP 092, a TXA2 receptor antagonist was similarly without effect. In contrast, acute treatment with the cyclooxygenase inhibitors meclofenamate or indomethacin resulted in a 50% decrease in both RPF and GFR; these inhibitors had no effect in control rats. We conclude that PGE2 (vasodilator) is of greater relative significance than TXA2 (vasoconstrictor) with respect to renal function in the NSN rat at 1 and 14 days.     

IL-6、IL-18与心房颤动的关系研究胡耀明

目的：研究心房颤动患者血清IL-6、IL-18水平与心房颤动的关系。方法：入选71个房颤患者进行试验,及年龄与性别相匹配的30名健康志愿者做对照组。酶联免疫吸附法测定血清IL-6、IL-18水平,.超声心动图测定左心房内径。结果： 1. 永久性房颤组血清IL-6、IL-18水平分别高于持续性房颤组, 持续性房颤组水平高于阵发性房颤组,阵发性房颤组水平高于对照组;2房颤患者左心房内径均大于对照组;永久性房颤组大于持续性房颤组;持续性房颤组大于阵发性房颤组。IL-18水平 与LAD成正相关r = 0.26, P < 0.01。IL-6水平与LAD成正相关r = 0.31, P < 0.01。IL-18、与IL-6水平成正相关r = 0.34, P < 0.01。结论：房颤患者IL-6和IL-18水平升高。房颤患者左心房内径增大。细胞因子IL-6和IL-18在AF的发病机制中可能具有重要的作用。     

Interleukin-4 adenoviral gene therapy reduces production of inflammatory cytokines and prostaglandin E2 by rheumatoid arthritis synovium ex vivo.

BACKGROUND: The rheumatoid arthritis (RA) joint is characterized by an inflammatory synovial pannus which mediates tissue destruction. Interleukin (IL)-4 reduces the production of many proinflammatory cytokines, particularly by activated macrophages. Therefore, we examined the ability of adenovirally delivered IL-4 for the treatment of human RA to reduce the secretion of proinflammatory molecules. METHODS: Adenoviral vectors encoding the genes for human IL-4 (AxCAIL-4) and bacterial beta-galactosidase (AxCAlacZ) were generated and examined for appropriate production and biological activity. RA synovial tissue (ST) explants or fibroblasts were infected with AxCAIL-4 or a beta-galactosidase producing vector, as a control, and conditioned medium (CM) was collected for ELISA analysis. RESULTS: AxCAIL-4 decreased the production of the inflammatory cytokines IL-1 beta and tumor necrosis factor-alpha in RA ST explant CM. IL-8 levels were significantly reduced by 71%, 88%, and 82% at 24, 48, and 72 hours, respectively, in RA ST explant CM. In the same CM, monocyte chemotactic protein-1 (MCP-1) levels decreased 60% at 48 hours. In contrast, RA synovial fibroblast CM levels of MCP-1 were increased by AxCAIL-4. Epithelial neutrophil activating peptide-78 levels produced by RA ST explants were significantly decreased by AxCAIL-4 by 88%, 92%, and 93% at 24, 48, and 72 hours, respectively. Growth related gene product-alpha levels were likewise decreased in RA ST explant CM. In ST explants as well as RA synovial fibroblasts, IL-4 treatment decreased prostaglandin E2 (PGE2) production. CONCLUSIONS: Increased expression of IL-4 via gene therapy may decrease RA-associated inflammation by reducing proinflammatory cytokines and PGE2.