白细胞介素-18:一种预测冠心病新的重要标记物

动脉粥样硬化斑块的形成不仅由血管内皮被动损伤后脂质浸润引起,而且活动性炎症在动脉粥样硬化形成中可能起到了更为重要的作用。白细胞介素(IL)-18作为一种促炎症因子在细胞因子网络中起着重要作用,它参与了动脉粥样硬化斑块发生、发展乃至破裂的整个过程。1IL-18与冠心病血脂     

肿瘤坏死因子α与2型糖尿病血管并发症发病关系的研究

2003年6月在美国旧金山召开的第62届美国糖尿病学术年会上,炎症学说在2型糖尿病发病机制中的作用已得到广泛的认可,并明确2型糖尿病也是一种炎症性疾病,试验也证实了糖尿病患者胰岛β细胞周围大量存在白介素(IL-2、IL-4、IL-6等)、肿瘤坏死因子α(TNFα)、C反应蛋白(CRP)、转化生长因子(TGF)等细胞因子.而血管疾病如动脉粥样硬化等近年来也认为与炎症有关,作为2型糖尿病并发的血管疾病更有其特点,有证据表明细胞因子与2型糖尿病血管并发症的发生密切相关,其中TNFα受到更广泛的关注,现将其研究现状综述如下:     

肿瘤坏死因子α与2型糖尿病血管并发症发病关系的研究

2003年6月在美国旧金山召开的第62届美国糖尿病学术年会上,炎症学说在2型糖尿病发病机制中的作用已得到广泛的认可,并明确2型糖尿病也是一种炎症性疾病,试验也证实了糖尿病患者胰岛β细胞周围大量存在白介素（IL-2、IL-4、IL-6等）、肿瘤坏死因子α（TNFα）、C反应蛋白（CRP）、转化生长因子（TGF）等细胞因子.而血管疾病如动脉粥样硬化等近年来也认为与炎症有关,作为2型糖尿病并发的血管疾病更有其特点,有证据表明细胞因子与2型糖尿病血管并发症的发生密切相关,其中TNFα受到更广泛的关注,现将其研究现状综述如下：     

炎性细胞因子在细菌感染中的作用

炎症是最基本的病理变化之一,包括感染性与非感染性炎症。在炎症发生发展过程中,细胞因子起着重要的作用,主要表现为促炎和抗炎细胞因子之间相互促进相互制约作用,前者主要有肿瘤坏死因子-α、干扰素-γ、白细胞介素（IL）-2、IL-6及IL-17、IL-23等,后者主要包括IL-4、IL-10、IL-13、转化生长因子-β等,两者的动态变化决定炎症的发展及结局。研究炎症尤其是感染性炎症中的炎性细胞因子对可能取得彻底治愈炎性疾病的突破有重要意义。本文对在细菌感染中起重要作用的主要促炎与抗炎细胞因子作一综述。     

冠心病与血清白细胞介素-18关系的研究

已有研究发现炎症反应的激活可能是导致动脉粥样硬化（AS）斑块不稳定的主要因素，有多种炎性细胞和炎性细胞因子参与了AS和急性冠脉综合征（ACS）的过程，其中促炎性细胞因子白细胞介素-18（IL-18）、白细胞介素-6（IL-6）与抗炎症细胞因子白细胞介素-10（IL-10）之间的平衡失调可能是促使AS斑块不稳定的重要原因之一．并且IL-18的水平可一定程度的反映AS炎症的强弱和冠状动脉粥样硬化斑块的稳定性。本文通过检测冠心病患者血清IL-18的水平，旨在探讨其与冠心病发生发展的关系。     

白介素-12家族在冠状动脉粥样硬化中的研究进展

近年来研究发现炎症的持续性和免疫应答失衡在动脉粥样硬化的发生和发展中起到关键作用。多种炎症细胞及其分泌的细胞因子参与到冠状动脉粥样硬化的过程中。而白介素(IL)-12家族作为重要的炎症细胞因子,其家族成员包括IL-12、IL-23、IL-27、IL-35、IL-39和IL-Y,在冠心病的疾病过程中产生的促进或抑制作用已成为近年来国内外心血管领域的研究热点。现主要阐述IL-12家族各细胞因子对冠状动脉粥样硬化作用的研究现状,可能为冠心病的病情评估和治疗提供新的思路。     

细胞因子与胰岛素抵抗及2型糖尿病的关系

过去几十年里积累的大量有效证据证明,炎症标志物及其他细胞因子与胰岛素抵抗综合征的组分有关.最近,慢性亚临床性炎症作为胰岛素抵抗综合征的一部分被提出.论述炎症标志物预示糖尿病和糖代谢紊乱发展的流行病学证据也开始出现.基于上述观点,现将TNF-α、IL-6、NF-κB与胰岛素抵抗及2型糖尿病的关系略做讨论.1 IL-6在胰岛素抵抗和2型糖尿病中的作用IL-6是由多种不同细胞产生的多功能的细胞因子,这些细胞包括免疫细胞、内皮细胞、纤维母细胞、肌细胞和脂肪组织,具有介导炎症和应激反应的作用.     

细胞因子与胰岛素抵抗及2型糖尿病的关系

过去几十年里积累的大量有效证据证明,炎症标志物及其他细胞因子与胰岛素抵抗综合征的组分有关.最近,慢性亚临床性炎症作为胰岛素抵抗综合征的一部分被提出.论述炎症标志物预示糖尿病和糖代谢紊乱发展的流行病学证据也开始出现.基于上述观点,现将TNF-α、IL-6、NF-κB与胰岛素抵抗及2型糖尿病的关系略做讨论.1 IL-6在胰岛素抵抗和2型糖尿病中的作用IL-6是由多种不同细胞产生的多功能的细胞因子,这些细胞包括免疫细胞、内皮细胞、纤维母细胞、肌细胞和脂肪组织,具有介导炎症和应激反应的作用.     

核转录因子-κB及其相关因子与糖尿病血管并发症

核转录因子(NF)-κB作为具有多向转录调节活性的蛋白质,在介导免疫、炎症反应过程中发挥了重要作用。近年的研究表明,在糖尿病发病机制中存在多种炎症细胞因子的活化,动脉粥样硬化是糖尿病尤其是2型糖尿病最常见的大血管并发症,是一个以慢性炎症反应为特征的病理生理过程,NF-κB及其相关的上游激活物和下游靶分子共同参与了糖尿病大血管并发症的发生发展。     

白细胞介素-6、白细胞介素-10与冠心病关系的研究进展

随着分子生物学技术的发展和临床应用,炎症在冠心病(CHD)发病机制中的作用日益引起重视.而炎性因子在其中起到了不可忽视的作用.冠心病的病理基础是冠状动脉粥样硬化,大量的研究表明动脉粥样硬化(AS)是一种慢性炎症性疾病,炎症和感染过程参与了AS及其并发症的发生和发展,而炎性因子在机体的免疫应答、炎症反应等方面起着关键作用,炎性因子介导的系统或局部的炎症反应导致AS斑块的形成.近年来促炎与抗炎之间的平衡失调导致粥样斑块病变的假说引起了人们的注意.白细胞介素-6(IL-6)在炎症反应中起核心调节作用,是炎症免疫反应的重要介质,其与疾病的活动性相关,是冠心病的一个重要的危险因子,参与动脉粥样硬化的形成和发展.白细胞介素-10(IL-10)是近年来研究的最为广泛的一种抗炎因子之一,其有抑制粥样斑块形成、稳定斑块的作用.本文就与冠心病关系较为密切的细胞因子IL-6和IL-10的研究进展作一综述.     

Interleukin-10 and coronary disease

Understanding of the pathophysiology of atherosclerosis has changed markedly over the past few decades. It is now widely accepted that inflammation plays a fundamental role in the genesis and development of atherosclerosis. Inflammatory mechanisms also appear to determine clinical presentation and disease outcome. Atherosclerotic lesions have high concentrations of inflammatory cells (T lymphocytes and activated macrophages) as well as an abundance of pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-8, interferon-gamma, tumor necrosis factor-alpha, etc.] that modulate local inflammatory responses. These may also alter plaque stability and facilitate the development of acute cardiovascular events. The role of anti-inflammatory cytokines in this context remains to be studied. IL-10 is an anti-inflammatory cytokine synthesised by T-lymphocytes and macrophages and has other anti-inflammatory effects. IL-10 expression within human atherosclerotic plaques has been demonstrated and animal experiments have shown that low levels of IL-10 lead to the development of extensive and unstable atherosclerotic lesions. Currently available evidence suggests a potential protective role for IL-10 in atherosclerosis. This new perspective on coronary disease as a chronic inflammatory process may open new avenues for the management of ischemic heart disease.     

The predictive value of TNF-α and IL-6 and the incidence of macrovascular complications in patients with type 2 diabetes

Some inflammation factors have been shown to accelerate type 2 diabetes macrovascular complication (T2DMC). The study investigates the variation of TNF-α and IL-6 levels during the progression of T2DMC to explore their predictive value in the incidence of T2DMC. All participants were divided into two groups, type 2 diabetes mellitus (T2DM) and non-diabetes (ND) group. TNF-α and IL-6 were analyzed with enzyme immunoassay. All participants were followed up by carotid Doppler, Doppler of lower extremities, head CT and 64-row multislice spiral CTA. The incidence of macrovascular atherosclerosis in T2DM was significantly higher than that in ND group (P < 0.05). The levels of TNF-α and IL-6 in both groups with atherosclerosis increased annually. In patients who had atherosclerosis with diabetes, measured levels of TNF-α and IL-6 were significantly higher than those in patients with atherosclerosis without diabetes (P < 0.05). The levels of TNF-α and IL-6 in T2DMC and ND group with atherosclerosis was significantly higher than that in two groups without atherosclerosis (P < 0.05). Patients with T2DM were divided into four groups according to their HbA1C level. There was a strong positive correlation between the levels of TNF-α and IL-6 and HbA1C (P > 0.05). The TNF-α and IL-6 levels can be used as predictors for atherosclerosis development. Compared with non-diabetic atherosclerosis, TNF-α and IL-6 have stronger predictive value in diabetic atherosclerosis development. One reason for hyperglycemia increasing atherosclerosis is to activate inflammatory cells and relives of inflammatory factors. Hyperglycemia can trigger inflammation, which is a quality–effect relationship reaction.     

Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages

Inflammation is emerging as an important mechanism for micro- and macrovascular complication of diabetes. The macrophage plays a key role in the chronic inflammatory response in part by generating particular cytokines. IL-1beta, IL-6, IL12, IL-18, TNFalpha, and interferon-gamma are produced primarily in macrophages and have been associated with accelerated atherosclerosis and altered vascular wall function. In this study, we evaluated the effect and mechanism of high glucose (HG) on gene expression of these cytokines in mouse peritoneal macrophages (MPM). HG led to a 2-fold increase in the mRNA expression of these cytokines, with IL-12 showing the highest activation (5.4-fold) in a time-dependent (3-12 h) and dose-dependent (10, 17.5, and 25 mmol/liter) manner. The effects were specific to HG because mannitol and 3-O-methyl-glucose had no effect on cytokine mRNA expression. HG also increased IL-12 protein accumulation from MPM. We also explored the role of induced and spontaneous diabetes on inflammatory cytokine expression in MPM. Increases in expression in MPM of multiple inflammatory cytokines, including a 20-fold increase in IL-12 mRNA, were observed in streptozotocin-induced type 1 diabetic mice as well as type 2 diabetic db/db mice, suggesting that cytokine gene expression is increased by hyperglycemia in vivo. We next explored potential mechanisms of HG-induced increases in IL-12 mRNA. HG increased the activity of protein kinase C, p38 MAPK (p38), c-Jun terminal kinase, and inhibitory-kappaB kinase in MPM. Furthermore, inhibitors of these signaling pathways significantly reduced HG-induced IL-12 mRNA expression in MPM. These results provide evidence for a potentially important mechanism linking elevated glucose and diabetes to inflammation.     

糖原合成酶激酶-3在炎症反应中的研究

糖原合成酶激酶-3（GSK3）是一种丝/苏氨酸磷酸激酶,在原发性和继发性免疫系统均发挥重要作用,其增加促进炎症因子（IL-1β、IL-2、IL-6等）的产生,抑制GSK3活性后可减轻炎症反应同时保护机体免受免疫介导的病理损伤.GSK3活化与阿尔茨海默病、糖尿病、急性肾衰竭等疾病发生、发展有一定的相关性.本文就GSK3在不同免疫系统及其参与相关疾病的研究进展作一综述.     

Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging cardiovascular risk marker. To explore the biologic role of Lp-PLA2 in atherosclerosis, we examined its expression and contribution to leukocyte activation under proatherogenic conditions. METHODS AND RESULTS: Following the induction of diabetes and hypercholesterolemia in a porcine model, a rapid increase in plasma Lp-PLA2 activity was observed at 1 month. This was accompanied by upregulated Lp-PLA2 mRNA expression by peripheral blood mononuclear cells (PBMC) at 3 months, and elevated Lp-PLA2 mRNA expression in coronary arteries at 6 months. These changes were paralleled by increased inflammatory responses by circulating PBMC (ICAM-1, IL-6), in coronary tissues (ICAM-1, VCAM-1), and the subsequent accumulation of inflammatory cells. In human PBMC, proinflammatory mediators augmented the synthesis and release of functional Lp-PLA2. Furthermore, lysophosphatidylcholine (lysoPC), a product of Lp-PLA2 activity, induced an increase in several inflammatory cytokines (IL-1beta, IL-6, TNF-alpha) in a concentration-dependent manner. In contrast, Lp-PLA2 inhibition (SB677116; 1 microM) abrogated the inflammatory response elicited by oxidized LDL. CONCLUSIONS: In an experimental model of diabetes and hypercholesterolemia, leukocyte activation was associated with augmented Lp-PLA2 expression. In vitro, Lp-PLA2 activity mediated leukocyte activation and inflammatory responses, whereas Lp-PLA2 inhibition abolished inflammatory responses induced by oxidized LDL. Collectively, these observations support a proatherogenic role for Lp-PLA2.     

Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1

The mechanisms that promote an inflammatory environment and accelerated atherosclerosis in diabetes are poorly understood. We show that macrophages isolated from two different mouse models of type 1 diabetes exhibit an inflammatory phenotype. This inflammatory phenotype associates with increased expression of long-chain acyl-CoA synthetase 1 (ACSL1), an enzyme that catalyzes the thioesterification of fatty acids. Monocytes from humans and mice with type 1 diabetes also exhibit increased ACSL1. Furthermore, myeloid-selective deletion of ACSL1 protects monocytes and macrophages from the inflammatory effects of diabetes. Strikingly, myeloid-selective deletion of ACSL1 also prevents accelerated atherosclerosis in diabetic mice without affecting lesions in nondiabetic mice. Our observations indicate that ACSL1 plays a critical role by promoting the inflammatory phenotype of macrophages associated with type 1 diabetes; they also raise the possibilities that diabetic atherosclerosis has an etiology that is, at least in part, distinct from the etiology of nondiabetic vascular disease and that this difference is because of increased monocyte and macrophage ACSL1 expression.     

2型糖尿病患者血清炎性因子与颈动脉粥样硬化的相关性研究

目的 研究2型塘尿病患者血清炎性因子水平与颈动脉粥样硬化的关系.方法 选择124例2型糖尿病患者,采用酶联免疫吸附法测定血清内皮细胞猫附分子1（ICAM-1）、血管细胞黏附分子1（VCAM-1）,E选择素、白细胞介素6（IL-6）和C反应蛋白（CRP）水平;按颈动脉超声检查结果将糖尿病患者分为颈动脉正常组（38例）、颈动脉增厚组（40例）和颈动脉斑块组（46例）.选择40例健康体检者作为对照组,比较各组血清炎性因子水平.结果 ①颈动脉正常组血清ICAM-1,IL-6及CRP较对照组升高,颈动脉增厚组ICAM-1、VCAM-1、IL-6及CRP水平高于颈动脉正常组,颈动脉斑块组ICAM-1、VCAM-1、E选择素高于颈动脉增厚组,上述指标各组差异均有统计学意义,P 〈0.05,或P〈0.01.②相关性分析显示,颈动脉内-中膜厚度（IMT）增厚程度与糖化血红蛋白（HbAlc）（r=0.472）、ICAM-1（r=0.501）、VCAM-1（r = 0.484）、E选择素（r＝0.289）、IL-6（r=0.425）及CRP（r=0.381）呈正相关.患者HbAlc与ICAM-1、VCAM-1、IL-6及CRP呈正相关.ICAM-1、VCAM-1、E选择素、IL-6、CRP间呈正相关,均P〈0.01或P〈0.05.结论 炎性反应参与了2型糖尿病患者颈动脉粥样硬化的发病过程,血清炎性因子水平可以在一定程度上反映糖尿病患者的颈动脉粥样硬化程度.     

Exercise reduces plasma levels of the chemokines MCP-1 and IL-8 in subjects with the metabolic syndrome.

AIMS: Inflammation plays an essential role in the atherosclerotic process, and chemokines such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) seem to play a pivotal role in the pathogenesis of atherosclerosis. A possible common inflammatory basis for the pathogenesis of type 2 diabetes, metabolic syndrome and atherosclerosis has been suggested. In this study we investigated the effect of physical exercise and the HMG-CoA reductase inhibitor pravastatin on peripheral markers of inflammation in subjects with the metabolic syndrome. METHODS: The study was an unmasked randomized 2x2 factorial trial of 12 weeks duration. RESULTS: In the combined exercise groups there was a significant reduction in MCP-1 and IL-8 of 48 pg/ml (P=0.04) and 1.0 pg/ml (P=0.007), respectively, as compared to the combined non-exercise groups. There was also a significant reduction vs baseline of 50 pg/ml (33%) (P=0.002) and 0.35 pg/ml (13%) (P=0.03) for MCP-1 and IL-8, respectively. Changes in MCP-1 were significantly correlated to changes in visceral fat (r=0.41, P=0.02). CONCLUSION: The protective effect of exercise might in part be due to suppression of the inflammatory process.     

Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-Dihydroxyvitamin D(3) works as anti-inflammatory

The exact factors contributing to the pathogenesis of type 2 diabetes remain elusive. Lately, it was suggested that inflammation and activation of the innate immune system could be linked to type 2 diabetes pathogenesis and also to the development of common diabetic complications, mainly atherosclerosis. The aim of this study was to investigate the role of monocytes in this sub-clinical inflammatory state and test 1,25-dihydroxyvitamin D(3), the active form of Vitamin D, as an anti-inflammatory agent. For this purpose, monocytes from type 2 diabetic patients were compared to monocytes from healthy controls and type 1 diabetic patients. The expression profile of inflammatory markers in freshly isolated and immune-stimulated monocytes was measured by quantitative real-time RT-PCR. Type 2 diabetic patients showed significantly higher expression levels of TNF-alpha, IL-6, IL-1, IL-8, COX-2, ICAM-1 and B7-1 compared to controls and type 1 diabetic patients. 1,25-Dihydroxyvitamin D(3) was able to down-regulate the expression of TNF-alpha, IL-6, IL-1, and IL-8, confirming its immunomodulatory properties. From these data we concluded that monocytes from type 2 diabetic patients have a pro-inflammatory profile. In addition, 1,25-dihydroxyvitamin D(3) was able to modulate inflammation in these monocytes.     

Effects of rosiglitazone on postprandial leukocytes and cytokines in type 2 diabetes

OBJECTIVE: We postulated that in type 2 diabetes, the postprandial phase is a pro-inflammatory state that can be modulated by PPAR-gamma agonists. For this purpose, we determined the effects of rosiglitazone (8 mg/d) on postprandial leukocyte counts and pro-inflammatory cytokines (IL-6 and IL-8) in patients with type 2 diabetes. METHODS AND RESULTS: A randomized, 8-week, cross-over, placebo-controlled, double-blind clinical trial was performed in 19 patients with type 2 diabetes. Standardized 6-h oral fat-loading tests were performed after each treatment period. During placebo treatment, blood leukocytes increased to a maximum 6-h postprandially, due to significant increases in neutrophils and lymphocytes. Concomitant postprandial increases were observed for IL-6 and IL-8, the major chemokines responsible for leukocyte recruitment. Rosiglitazone reduced the incremental area under the curves (dAUCs) for IL-6 (-63%, p<0.01) and IL-8 (-16%, p<0.05). The dAUC for leukocytes decreased with 37% (p<0.05), due to a specific reduction of neutrophils (-39%, p<0.05). CONCLUSIONS: Rosiglitazone attenuated the postprandial increases of neutrophils, IL-6 and IL-8 in patients with type 2 diabetes. Since inflammation is a major force driving atherosclerosis, and man lives in a postprandial period most part of the day, a reduced inflammatory response after a meal may delay progression of atherosclerosis. CONDENSED ABSTRACT: We postulated that in type 2 diabetes, the postprandial phase is a pro-inflammatory state that can be modulated by PPAR-gamma agonists. Rosiglitazone attenuated the postprandial increases of neutrophils, IL-6 and IL-8 in patients with type 2 diabetes. These effects may contribute to cardiovascular risk reduction.