激活视黄醇类X受体对氧化型低密度脂蛋白诱导小鼠巨噬细胞系RAW264.7凋亡的影响

目的探讨激活视黄醇类X受体对氧化型低密度脂蛋白诱导巨噬细胞凋亡的影响及其机制。方法小鼠巨噬细胞系RAW264.7经氧化型低密度脂蛋白处理24h诱导凋亡,同时观察给予视黄醇类X受体特异性配体9-cisRA或SR11237对氧化型低密度脂蛋白诱导凋亡的干预作用,MTT法检测细胞活力,流式细胞仪PI单染法和DAPI染色检测细胞凋亡,CM-H2DCFDA荧光探针测定细胞内活性氧浓度。结果RAW264.7细胞经氧化型低密度脂蛋白(100mg/L)处理24h后细胞活力较对照组下降约60,细胞凋亡百分率较对照组升高约75,10-8mol/L和10-7mol/L9-cisRA及10-7mol/LSR11237能够显著抑制氧化型低密度脂蛋白诱导引起的细胞活力下降和凋亡(P<0.05)。给予氧化型低密度脂蛋白(100mg/L)4h后细胞内活性氧水平显著升高约17倍以上,如联合给予9-cisRA(10-7mol/L)或SR11237(10-6mol/L),平均荧光强度分别下降约52和28,较氧化型低密度脂蛋白单独处理组有显著性差异(P<0.05)。结论激活视黄醇类X受体能够抑制氧化型低密度脂蛋白诱导巨噬细胞凋亡,其机制可能与减轻细胞氧化应激损伤有关。     

血凝集素样氧化型低密度脂蛋白受体-1在氧化型低密度脂蛋白诱导的巨噬细胞氧化应激中的作用

目的：探讨血凝集素样氧化型低密度脂蛋白受体-1(LOX-1)在氧化型低密度脂蛋白（ox-LDL）诱导的巨噬细胞氧化应激中的作用。方法：将生长至对数增殖期的巨噬细胞随机分成对照组、空质粒对照组（pCon组）、ox-LDL组、LOX-1-小干扰RNA(siRNA)+ox-LDL组,分别测定各组丙二醛（MDA）含量及超氧化物歧化酶（SOD）活性,荧光显微镜及流式细胞仪检测各组巨噬细胞活性氧（ROS）水平,实时定量聚合酶链反应（PCR）及Western blot法检测各组还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）核心酶NOX2及亚组分p22phox的mRNA及蛋白表达水平。结果：（1）与对照组、pCon组比较,oxLDL组MDA含量明显升高,SOD活性明显下降;与ox-LDL组比较,LOX-1-siRNA+oxLDL组MDA含量明显下降,SOD活性明显升高。（2）荧光显微镜、流式细胞仪检测示oxLDL组巨噬细胞ROS平均荧光强度较正常对照组、pCon组显著增加,而LOX-1-siRNA+ox-LDL组较ox-LDL组显著降低,pCon组与对照组相比差异无统计学意义。（3）实时定量PCR及W...     

槟榔碱抑制氧化型低密度脂蛋白诱导的小鼠巨噬细胞炎症因子表达及其机制

目的 观察槟榔碱对氧化型低密度脂蛋白诱导的小鼠巨噬细胞炎症因子表达的影响,并探讨其作用机制.方法不同浓度槟榔碱(10-6、10-5、10-4和10-3moL/L)处理细胞24 h,台盼兰拒染法观察细胞活力;氧化型低密度脂蛋白诱导小鼠巨噬细胞,同时给予槟榔碱处理,采用逆转录聚合酶链反应检测肿瘤坏死因子α、白细胞介素6和细胞间黏附分子1 mRNA的表达以及过氧化体增殖物激活型受体γ mRNA的表达.结果 槟榔碱处理细胞24h后,10-3 mol/L组细胞活力下降(P<0.01),而10-6、10-5和10-4 mol/L组对细胞活力无明显影响;10-6、10-5和10-4 mol/L槟榔碱分别处理细胞24 h后,对肿瘤坏死因子α、白细胞介素6和细胞间黏附分子1 mRNA的表达无明显影响;10-6mol/L槟榔碱与氧化型低密度脂蛋白共同处理细胞24 h后,细胞肿瘤坏死因子α、白细胞介素6和细胞间黏附分子1 mRNA的表达无显著改变,而10-5和10-4mol/L槟榔碱明显抑制氧化型低密度脂蛋白诱导的小鼠巨噬细胞肿瘤坏死因子α、白细胞介素6和细胞间黏附分子1 mRNA的表达,且10-5mol/L槟榔碱使氧化型低密度脂蛋白诱导的细胞内过氧化体增殖物激活型受体γ mRNA的表达增加(P<0.01).结论 槟榔碱抑制氧化型低密度脂蛋白诱导的巨噬细胞炎症因子表达,其作用机理可能是通过过氧化体增殖物激活型受体γ起作用.     

葡萄糖和厄贝沙坦对单核巨噬细胞系凝集素样氧化型低密度脂蛋白受体表达的影响

目的研究不同浓度葡萄糖和厄贝沙坦对人单核巨噬细胞系(THP-1)凝集素样氧化型低密度脂蛋白受体mRNA及蛋白表达的影响,并探讨其可能的机制。方法 THP-1细胞经0.16μmol/L佛波酯诱导分化72 h后,将细胞分为对照组、不同浓度葡萄糖组(5、8、12和15 mmol/L)和厄贝沙坦干预组,葡萄糖组将不同浓度葡萄糖与诱导分化的巨噬细胞孵育24 h,厄贝沙坦干预组用厄贝沙坦预先孵育2 h后,再加入15 mmol/L葡萄糖共同孵育24 h。用荧光定量PCR和细胞酶联免疫法检测凝集素样氧化型低密度脂蛋白受体mRNA和蛋白的表达。结果与对照组相比,5 mmol/L葡萄糖组凝集素样氧化型低密度脂蛋白受体mRNA及蛋白表达差异无显著性(P>0.05),其余高糖组该受体mRNA和蛋白表达明显增加(P<0.05),并且其表达呈浓度依赖性;厄贝沙坦可显著抑制此作用,使该受体表达明显降低。结论高糖以浓度依赖方式上调凝集素样氧化型低密度脂蛋白受体mRNA和蛋白的表达,这可能是导致动脉粥样硬化发生的机制之一;厄贝沙坦可显著抑制这一作用,可能在抗动脉粥样硬化中起作用。     

孤儿核受体Nur77抑制小鼠巨噬细胞脂质沉积

目的 探讨孤儿核受体Nur77对巨噬细胞脂质沉积的影响及其机制.方法 建市稳定表达绿色荧光蛋白(GFP)和GFP-Nur77质粒cDNA的小鼠巨噬细胞RAW264.7单克隆细胞系,40 μg/ml氧化型低密度脂蛋白(ox-LDL)刺激24 h后,用油红O染色定性观察细胞内脂质沉积,液相色谱-质谱联用法定量检测细胞内胆固醇酯,用荧光实时定量PCR(RT-PCR)检测CD36和腺苷三磷酸结合盒转运体A1(ABCA1)mRNA水平的变化,用流式细胞仪检测CD36蛋白表达,Western blot方法检测ABCA1蛋白表达.结果 Nur77能够显著减少ox-LDL诱导引起的巨噬细胞内脂质沉积.ox-LDL诱导前,GFP-RAW264.7组和GFP-Nur77-RAW264.7组细胞内总胆固醇含量分别为(38.66±0.13)μg/mg蛋白和(36.25±0.48)μg/mg蛋白,细胞内胆固醇酯含量为(18.85±0.03)μg/mg蛋白和(17.79±0.86)μg/mg蛋白.ox-LDL诱导24h后,GFP-RAW264.7组和GFP-Nur77-RAW264.7组细胞内总胆固醇含量分别为(68.98±1.68)μg/mg蛋白和(50.94±1.63)μg/mg蛋白,细胞内胆同醇酯含量为(35.92±2.28)μg/mg蛋白和(24.81±2.92)μg/mg蛋白.同时伴随CD36的mRNA及蛋白表达下降和ABCAI的mRNA及蛋白表达上调.结论 孤儿核受体Nur77通过减少脂质摄取和增加脂质排出而减轻巨噬细胞内脂质沉积,这可能是其抗动脉粥样硬化的重要机制之一.     

孤儿核受体Nur77参与AopE-/-小鼠颈动脉易损斑块的形成

目的:研究孤儿核受体Nur77在AopE-/-小鼠动脉粥样硬化易损斑块形成中的作用。方法:AopE-/-小鼠左肾动脉和左颈总动脉联合部分结扎建立颈动脉易损斑块模型,采用HE染色观察斑块病理学改变,免疫荧光染色结合激光扫描共聚焦显微镜技术观察斑块中Nur77蛋白的表达。同时,体外培养小鼠巨噬细胞系RAW264.7,在氧化低密度脂蛋白(oxLDL)及其主要成分7-酮胆固醇(7-ketocholesterol,7-KC)或者游离胆固醇(FC),以及炎症介质(LPS、IL-1β)等条件刺激下,应用蛋白免疫印迹技术(Western blot)检测Nur77蛋白表达变化。结果:AopE-/-小鼠颈动脉易损斑块局部有Nur77蛋白高表达,而oxLDL及其组成成分(7-KC和FC)以及某些炎症介质(如LPS、IL-1β等)均能在RAW264.7细胞中诱导Nur77蛋白表达上调。结论:孤儿核受体Nur77可能在动脉粥样硬化易损斑块发展进程中发挥着重要作用。     

氧化型低密度脂蛋白对小鼠腹腔巨噬细胞胆固醇蓄积的影响及可能机制

研究氧化型低密度脂蛋白对小鼠腹腔巨噬细胞胆固醇蓄积的影响 ,并探讨其与组织蛋白酶活性之间的关系。用 10 0mg/L的乙酰化低密度脂蛋白和氧化型低密度脂蛋白处理小鼠腹腔巨噬细胞 2 4h ,分别测定巨噬细胞胞浆和溶酶体中胆固醇的含量以及溶酶体中组织蛋白酶的活性。结果发现 ,乙酰化低密度脂蛋白和氧化型低密度脂蛋白均可引起细胞胆固醇含量增加 (分别为 2 2 .2± 0 .4 μg和 2 2 .5 5± 0 .15 μg比对照组的 7.0± 0 .4 μg ,P <0 .0 1) ,但蓄积部位和形式完全不同 ,前者蓄积部位主要在胞浆并以胆固醇酯为主 (胞浆与溶酶体分别为 18.9± 0 .4 μg和3.3± 0 .2 μg ,游离胆固醇与胆固醇酯分别为 0 .73± 0 .0 5 μg和 18.1± 0 .4 μg) ,后者主要在溶酶体并以游离胆固醇为主 (胞浆与溶酶体分别为 3.6 5± 0 .14 μg和 18.90± 0 .15 μg ,游离胆固醇与胆固醇酯分别为 14 .13± 0 .14 μg和 4 .77±0 .33μg) ;前者不引起溶酶体组织蛋白酶的活性改变和蛋白含量增加 (组织蛋白酶L和D分别为 99.5± 3.4和 2 8.0± 2 .4 ,对照组分别为 10 2 .3± 8.2和 2 7.3± 1.6 ,P >0 .0 5 ;蛋白含量为 8.8± 0 .4 μg ,对照组为 9.0± 0 .3μg,P >0 .0 5 ) ;后者则造成溶酶体组织蛋白酶活性的明显降低和蛋白蓄积 (组织     

氧化型低密度脂蛋白诱导巨噬细胞内源性大麻素系统激活

目的 探讨氧化型低密度脂蛋白刺激能否诱导巨噬细胞内源性大麻素系统激活.方法 体外常规培养RAW264.7小鼠巨噬细胞,加入氧化型低密度脂蛋白或溶媒孵育24 h,用高效液相色谱分析技术检测巨噬细胞内源性大麻素Anandamide和2-arachidonoylglycerol水平,以实时定量PCR技术和免疫印迹法对大麻素CB1、CB2受体和血小板活化因子受体mRNA和蛋白的表达进行分析.结果 内源性大麻素2-arachidonoylglycerol水平在6mg/L和12 mg/L氧化型低密度脂蛋白刺激时分别升高了2.4倍和4.8倍,而Anandamide水平无明显变化.3～12mg/L氧化型低密度脂蛋白刺激时,RAW264.7巨噬细胞大麻素CB1和CB2受体及血小板活化因子受体mRNA和蛋白的表达均明显上调(P＜0.01).结论 首次证实氧化型低密度脂蛋白通过激活血小板活化因子受体诱导巨噬细胞内源性大麻素系统激活,提示氧化型低密度脂蛋白致动脉粥样硬化过程中可能涉及该系统的激活.     

氧化型低密度脂蛋白诱导肝窦内皮细胞植物血凝素样氧化型低密度脂蛋白受体1的表达

目的：探讨植物血凝素样氧化型低密度脂蛋白（ox-LDL）受体1（LOX-1）在肝窦内皮细胞（HSECs）中的表达和ox-LDL对其表达的调控作用。方法使用实时定量聚合酶链反应（RT-PCR）和Western blotting法从基因和蛋白水平检测未经处理HSECs 中LOX-1的表达。应用不同浓度ox-LDL（0、20、40、60、80和100 mg/L）对HSECs作用24 h并应用80 mg/L ox-LDL对HSECs作用不同时间（0、12、24和48 h）,作用后实时定量PCR检测HSECs内LOX-1 mRNA的表达水平,Western blotting法检测细胞内LOX-1蛋白表达。给予80 mg/L ox-LDL干预组多聚肌苷酸250 mg/L作用24 h后,测定LOX-1 mRNA和蛋白的表达。采用单因素方差分析及t检验进行数据分析。结果 LOX-1 mRNA和蛋白在HSECs中均有表达。20～80 mg/L ox-LDL组HSECs中LOX-1 mRNA、蛋白表达水平随ox-LDL剂量增加而升高,与剂量有明显相关性（F＝38.7、3.43,均P＜0.05）。与80 mg/L ox-LDL组相比,100 mg/L ox-LDL 组 LOX-1 mRNA、蛋白表达下降,差异有统计学意义（ t ＝23.75、18.26, P ＜0.05）。80 mg/L ox-LDL对HSECs作用时间在0～24 h时,随着时间延长,LOX-1 mRNA、蛋白表达递增,与ox-LDL作用时间有明显相关性（F＝2.36、0.33,均P＜0.05）。与作用24 h相比,作用48 h组HSECs中LOX-1 mRNA、蛋白表达下降（t＝69.21、36.27,均P＜0.05）。与80 mg/L ox-LDL组相比,多聚肌苷酸组中LOX-1 mRNA和蛋白表达降低,两组差异均有统计学意义（ t＝54.93、28.19,均P＜0.05）。结论LOX-1存在于HSECs。在一定浓度和时间范围内,ox-LDL对HSECs LOX-1的调控作用具有时间和浓度依赖性,而多聚肌苷酸可部分抑制这种效应。     

普罗布考抑制氧化低密度脂蛋白上调巨噬细胞清道夫受体CD36的表达

背景 普罗布考是一降脂药,同时具有抗氧化特性,近年来的研究表明其可以通过多种机制抑制动脉粥样硬化的形成,降低经皮冠状动脉成形术后再狭窄的发生.目的 探讨普罗布考对氧化低密度脂蛋白(Ox-LDL)刺激巨噬细胞后清道夫受体CD36表达的抑制效应.方法 用不同浓度的Ox-LDL刺激人单核细胞系THP-1源性巨噬细胞及用不同浓度普罗布考和核因子κBp65(NF-κBp65)特异性抑制剂(PDTC)预处理细胞后再用氧化低密度脂蛋白刺激,半定量RT-PCR方法检测CD36和NF-κBp65的mRNA的表达,Western-blot检测CD36和细胞核NF-κBp65蛋白表达水平.结果 THP-1单核细胞分化成巨噬细胞后,CD36和NF-κBp65 mRNA和蛋白的表达上调;不同浓度的Ox-LDL刺激后,CD36 mRNA和蛋白的表达呈浓度依赖性增加,同时伴NF-κBp65 mRNA和蛋白的表达增加;PDTC和普罗布考干预后,NF-κBp65和CD36的mRNA和蛋白表达下调.结论 Ox-LDL可以通过NF-κBp65途径上调巨噬细胞CD36的表达;而普罗布考则可以抑制CD36的表达,这种作用与抑制NF-κBp65有关.     

Melatonin stabilizes rupture‐prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORα‐dependent manner

Rupture of vulnerable plaques is the main trigger of acute cardio‐cerebral vascular events, but mechanisms responsible for transforming a stable atherosclerotic into a vulnerable plaque remain largely unknown. Melatonin, an indoleamine hormone secreted by the pineal gland, plays pleiotropic roles in the cardiovascular system; however, the effect of melatonin on vulnerable plaque rupture and its underlying mechanisms remains unknown. Here, we generated a rupture‐prone vulnerable carotid plaque model induced by endogenous renovascular hypertension combined with low shear stress in hypercholesterolemic ApoE^?/? mice. Melatonin (10 mg/kg/d by oral administration for 9 weeks) significantly prevented vulnerable plaque rupture, with lower incidence of intraplaque hemorrhage (42.9% vs. 9.5%, P = 0.014) and of spontaneous plaque rupture with intraluminal thrombus formation (38.1% vs. 9.5%, P = 0.029). Mechanistic studies indicated that melatonin ameliorated intraplaque inflammation by suppressing the differentiation of intraplaque macrophages toward the proinflammatory M1 phenotype, and circadian nuclear receptor retinoid acid receptor‐related orphan receptor‐α (RORα) mediated melatonin‐exerted vasoprotection against vulnerable plaque instability and intraplaque macrophage polarization. Further analysis in human monocyte‐derived macrophages confirmed the role of melatonin in regulating macrophage polarization by regulating the AMPKα‐STATs pathway in a RORα‐dependent manner. In summary, our data provided the first evidence that melatonin‐RORα axis acts as a novel endogenous protective signaling pathway in the vasculature, regulates intraplaque inflammation, and stabilizes rupture‐prone vulnerable plaques.     

Novel protective role of the circadian nuclear receptor retinoic acid‐related orphan receptor‐α in diabetic cardiomyopathy

Diabetic cardiomyopathy is a major complication that significantly contributes to morbidity and mortality in diabetics with few therapies. Moreover, antidiabetic drugs reported inconsistent or even adverse cardiovascular effects, suggesting that it is important to exploit novel therapeutic targets against diabetic cardiomyopathy. Here, we observed that the nuclear melatonin receptor, the retinoic acid‐related orphan receptor‐α (RORα), was downregulated in diabetic hearts. By utilizing a mouse line with RORα disruption, we demonstrated that RORα deficiency led to significantly augmented diastolic dysfunction and cardiac remodeling induced by diabetes. Microscopic and molecular analyses further indicated that the detrimental effects of RORα deficiency were associated with aggravated myocardial apoptosis, autophagy dysfunction, and oxidative stress by disrupting antioxidant gene expression. By contrast, restoration of cardiac RORα levels in transgenic mice significantly improved cardiac functional and structural parameters at 8 weeks after diabetes induction. Consistent with genetic manipulation, pharmacological activation of RORα by melatonin and SR1078 (a synthetic agonist) showed beneficial effects against diabetic cardiomyopathy, while the RORα inhibitor SR3335 significantly exacerbated cardiac impairments in diabetic mice. Collectively, these findings suggest that cardiac‐targeted manipulation of nuclear melatonin receptor RORα may hold promise for delaying diabetic cardiomyopathy development.     

SF-1在内分泌领域的研究进展

孤儿核受体类固醇生成因子-1(SF-1)是核受体超家族的成员之一,具有与其他核受体不同的特征性结构域,广泛参与诸如细胞色素P450类固醇羟化酶、黄体生成素和芳香化酶等众多基因的表达与调控。研究证实SF-1与内分泌器官的生长、发育密切相关,它参与了下丘脑—垂体—性腺轴的形成,是肾上腺类固醇合成、性别分化和代谢中的一个关键调节因子。     

New therapeutic target in inflammatory disease: macrophage migration inhibitory factor

The cytokine macrophage migration inhibitory factor (MIF) participates in fundamental events in innate and adaptive immunity. The profile of activities of MIF in vivo and in vitro is strongly suggestive of a role for MIF in the pathogenesis of many inflammatory diseases, including rheumatoid arthritis (RA), and hence antagonism of MIF is suggested as a potential therapeutic strategy in inflammatory disease. The best developed case for therapeutic antagonism of MIF is in RA. In RA, MIF is abundantly expressed in serum and synovial tissue. MIF induces synovial expression of key pro-inflammatory genes, regulates the function of endothelial cells and leucocytes, and is implicated in the control of synoviocyte proliferation and apoptosis via direct effects on the expression of the tumour suppressor protein p53. In animal models of RA, anti-MIF antibodies or genetic MIF deficiency are associated with significant inhibition of disease. A similar case has been made, for example using MIF-deficient mice, in models of atheroma, colitis, multiple sclerosis and other inflammatory diseases. The relationship with p53 also means MIF may be important in the link between inflammatory disease and cancer, such as is seen in RA or colitis. MIF also has a unique relationship with glucocorticoids, in that despite antagonizing their effects, the expression of MIF is in fact induced by glucocorticoids. Thus, MIF functions as a physiological counter-regulator of the anti-inflammatory effects of glucocorticoids. This may be entrained by selective activation of mitogen-activated protein kinases rather than nuclear factor kappa B. Therapeutic MIF antagonism may therefore provide a specific means of 'steroid sparing'. Exploitation of antibody, soluble receptor or small molecule technologies may soon lead to the ability to test in the clinic the importance of MIF in human inflammatory diseases.     

表皮生长因子受体及增殖细胞核抗原在胃癌中的表达及意义

为探讨表皮生长因子受体 ( EGFR)及增殖细胞核抗原 ( PCNA)在胃癌中的表达 ,应用免疫组织化学技术 ,对胃癌和胃良性肿瘤组织中 EGFR和 PCNA分别进行定性和半定量检测 ,分析其与临床病理参数的关系。结果显示 1在胃良性肿瘤组织中 EGFR的表达率为 2 3 .0 8% ,PCNA L I为 2 7.80± 12 .2 0 ,明显低于胃癌组织中的表达率 ( 49.0 9% ,PCNA L I5 2 .73± 12 .2 5 ,P<0 .0 1)。2胃癌组织中 EGFR和 PCNA的表达与患者性别、年龄、病变部位、分型、组织学类型及分化程度无关 ( P均 >0 .0 5 ) ,而与临床分期、浸润深度及淋巴结转移情况相关 ( P <0 .0 5 ) ,表明联合检测 EGFR和 PCNA可作为判断胃癌恶性程度、预测淋巴结转移、制定合理治疗方案及评估预后的重要指标     

Role of receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1-alpha (MIP-1a) in monoclonal gammopathy of undetermined significance (MGUS)

The aim of this study was to evaluate the role of markers of bone remodelling, and osteoclast activation/function in patients with monoclonal gammopathy of undetermined significance (MGUS). We have measured serum levels of soluble RANKL (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein-1alpha (MIP-1alpha), markers of bone resorption [N-telopeptide of collagen type-I (NTX), and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)] and bone formation [bone-alkaline phosphatase (bALP)] in 40 MGUS patients. These parameters were compared with those of 42 newly diagnosed myeloma patients, and 45 healthy, gender- and age-matched controls. MGUS patients had elevated levels of NTX, sRANKL, and sRANKL/OPG ratio compared with controls (P < 0.0001). Furthermore, TRACP-5b, MIP-1alpha and NTX were decreased in patients with MGUS compared with myeloma patients (P < 0.001), while OPG and bALP were increased (P < 0.001). Serum levels of MIP-1alpha, as well as TRACP-5b, and sRANKL/OPG ratio were reduced, while bALP was increased in MGUS patients, even when compared with myeloma patients who had stage I/II disease. These results demonstrate that increased osteoclastogenesis leading to increased bone resorption is present in MGUS but seems to be compensated for by normal bone formation, which is absent in MM. Furthermore MIP-1alpha, bALP, and sRANKL/OPG may be useful tools for distinguishing between cases of MGUS and early myeloma.     

Serum levels of macrophage inflammatory protein-1 alpha (MIP-1alpha) correlate with the extent of bone disease and survival in patients with multiple myeloma

The role of serum macrophage inflammatory protein-1 alpha (MIP-1alpha) in bone disease and survival was evaluated in 85 newly diagnosed multiple myeloma (MM) patients. MIP-1alpha was elevated in MM patients and correlated with the extent of bone disease, bone resorption markers and levels of soluble receptor activator of nuclear factor-kappaB (RANK) ligand. MIP-1alpha was also associated with survival; the 3-year probability of survival was 85% and 44% for MIP-1alpha levels below and above 48 pg/ml respectively (P = 0.021). This suggests that MIP-1alpha contributes to the pathogenesis of bone disease in MM and possibly in tumour growth, as reflected by its impact on survival.     

Circulating levels of granulocyte macrophage colony-stimulating factor in patients with the systemic inflammatory response syndrome

OBJECTIVES: Granulocyte-macrophage colony stimulating factor (GM-CSF) is a key regulator cytokine that modulates the proliferation and maturation of polymorphonuclear and mononuclear progenitors. This study was designed to investigate and clarify the role of GM-CSF in 52 critically ill patients with systemic inflammatory response syndrome (SIRS). METHODS: Serum levels of GM-CSF were detected by an immunoenzyme assay. RESULTS: Our results clearly show that the serum concentrations of GM-CSF were significantly elevated in patients with infectious and noninfectious SIRS (33.2+/-45.7pg/ml, controls: 17.2+/-9.8pg/ml; p=0.0303). In addition, GM-CSF levels significantly decreased in patients with SIRS, particularly in patients with infectious SIRS, 5 and 7 days later. There was a clear tendency toward higher levels of GM-CSF in patients with poor, as compared with those having a good outcome of the disease. CONCLUSION: These results show that GM-CSF may play an important role in patients with infectious and noninfectious SIRS, and that GM-CSF levels progressively and significantly decrease in patients with infectious SIRS.