白介素18及其基因多态性与冠心病的相关性研究
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摘要
背景
动脉粥样硬化是炎症相关疾病,与粥样硬化相关的细胞因子和细胞因子网络及其炎症瀑布的发现和功能性研究日益受到重视。白介素18(interleukin 18,IL-18)就是这些与粥样硬化相关的细胞因子之一。
IL-18具有固有性和适应性免疫细胞调节自然免疫能力,是一种多效促炎症细胞因子。它最初命名为干扰素y (interferon-gamma, IFN-γ)诱导因子,可刺激T淋巴细胞和自然杀伤细胞IFN-γ产生,这两者与粥样硬化斑块关系密切。IL-18可通过p38MAPK-NF-kappaB-PTEN信号系统和MMP-9依赖方式引起冠状动脉平滑肌细胞迁移,诱导内皮细胞凋亡,在内膜斑块形成中起重要作用,并加速粥样硬化的形成和斑块易损。
研究证实,血浆IL-18浓度在急性冠脉综合征患者中明显升高,并且可导致心肌功能受损,介导血管斑块易损和破裂,是冠状动脉事件的独立预后因素。在无症状患者中,IL-18不是粥样硬化的独立危险因素；但是与颈动脉稳定性斑块相比较,IL-18 mRNA在不稳定斑块患者中的表达明显增高。
合并2型糖尿病的冠心病患者高死亡率越来越受到人们的关注,研究发现,与不合并糖尿病的冠心病患者相比,合并2型糖尿病的男性和女性冠心病患者死亡率均明显增高,这类患者更易出现疾病再发、血管再狭窄及冠脉血运重建术后恶性心血管事件。有证据表明,炎症反应在动脉粥样硬化和2型糖尿病的发生发展中起着至关重要的作用。作为一种促炎症因子,IL-18可能参与了动脉粥样硬化和2型糖尿病的发生发展。
颈动脉粥样硬化(carotid atherosclerosis, CAS)作为全身动脉粥样硬化的一个表现,与冠状动脉粥样硬化有着密切的联系；研究证实,通过测定颈动脉IMT及斑块可间接诊断冠心病及其病变的范围和严重程度。
经皮冠状动脉介入治疗(percutaneous coronary intervention therapy, PCI)是目前冠心病患者临床上重要的治疗方法之一,PCI能迅速将急性冠脉综合征患者的梗死相关动脉或病变血管开通,恢复前向性血流,有效地降低死亡率,但由此引起的炎性反应以及不良心血管事件也日益受到广泛的关注。炎性反应对心脏有损伤与保护双重作用,也可能是PCI后再狭窄和发生其他心血管事件的重要机制。
近期研究发现IL-18基因变异可影响冠心病(coronary artery disease, CAD)患者血液中IL-18水平和临床结局,与年龄相关的心功能损害密切相关,并影响单核细胞IL-18的表达。已有研究证实IL-18基因启动子区-137G/C (RS187238)位点单核苷酸基因多态性(single nucleotide polymorphisms, SNPs)可影响IL-18和IFN-γ的表达。然而IL-18启动子单核苷酸基因多态性与冠心病的相关性并无定论。
目的
本研究以中国襄樊地区汉族人群中诊断或疑诊为冠心病,经冠状动脉造影确诊或排除冠心病者作为病例组或对照组。本研究旨在：
1.评价血清IL-18、肿瘤坏死因子a (TNFa)和白介素-10(IL-10)水平与急性冠脉综合征的关系及其临床意义；
2.评价冠心病合并2型糖尿病患者血清IL-18水平及其临床意义；
3.探讨冠心病患者颈动脉内膜-中层厚度(carotid artery intima-media thickness, IMT)及斑块与血清IL-18浓度的临床相关性；
4.观察经皮冠状动脉介入治疗(PCI)术前与术后血清白细胞介素18(IL-18)的变化,并分析其临床意义；
5.采用LDR-PCR技术,检测IL-18基因启动子区的一个功能性-137 G/C(rs187238)位点单核苷酸基因多态性,并分析其与血浆IL-18浓度的相关性,以及在冠心病中的临床价值。
方法
1.选取住我院心内科冠心病患者91例,非冠心病患者55例,根据临床表现分为急性冠脉综合征(ACS)组,稳定型心绞痛(SAP)组及对照组。评价冠状动脉狭窄程度至少需2次正投影摄片,以最大的狭窄程度确定粥样硬化的严重程度。狭窄节段直径和参照的正常血管测量后,狭窄严重度计算公式：%狭窄=(狭窄部位管腔直径／参照血管直径)×100%。狭窄<50%为对照组,狭窄在50%或以上为病例组(狭窄50%～69%为病例1组；70%～89%为病例2组；狭窄>90%或闭塞为病例3组)。冠状动脉造影前从穿刺动脉抽血。ELISA法测定血清IL-18、TNFa和IL-10浓度并分析。
2.选取冠状动脉造影确诊的冠心病患者127例,根据是否合并2型糖尿病分为伴2型糖尿病组(42例)和不伴糖尿病组(85例),以冠状动脉造影排除冠心病者(55例)作为对照,ELISA法测定血清IL-18浓度。
3.选取126例经选择性冠状动脉造影检查的患者,依据狭窄程度分为冠心病组(狭窄50%或以上)及对照组(狭窄<50%),行颈动脉超声检查,测量颈动脉内膜中层厚度并观察粥样斑块发生情况；冠状动脉造影前抽取股动脉血,测血清IL-18水平。
4.检测87例冠心病患者经皮冠状动脉介入治疗术前及术后12h,术后2周血清IL-18变化,并随访术后12个月内的心血管事件,比较术前、术后以及发生不良心血管事件组与未发生组之间血清IL-18变化的差异。
5.用LDR-PCR技术检测并分析了中国襄樊地区汉族人群中241例冠状动脉造影证实的冠心病患者和145例对照组患者的IL-18基因启动子区-137G／C(RS187238)位点单核苷酸基因多态性,并检测各组IL-18水平。
结果
1.急性冠脉综合征(ACS)组和稳定性心绞痛(SAP)组血清IL-18和TNFa水平高于对照组,有统计学显著性差异(P<0.01),而血清IL-10低于对照组,有统计学显著性差异(P<0.01)。与稳定性心绞痛(SAP)组相比,急性冠脉综合征(ACS)组血清IL-18和TNFα水平明显升高,有统计学显著性差异(P<0.01),而血清IL-10水平则显著降低有统计学显著性差异(P<0.01)。随着冠脉狭窄程度的加重,IL-18水平逐渐增高,病例2组和病例3组均明显高于病例1组,均有统计学显著性差异(P<0.01),研究3组IL-18水平虽高于研究2组,但无统计学显著性差异(P>0.05)；不同狭窄程度的3组冠心病患者TNFα和IL-10水平无统计学显著性差异(P>0.05)。
2.冠心病合并2型糖尿病组患者血清IL-18水平高于不伴糖尿病组者,有统计学显著性差异(369.1±113.25 vs 275.9±85.74,P<0.01)。
3.冠心病组颈动脉内膜中层厚度、斑块发生率、血清炎性标记物IL-18均比对照组增高,两组间均有统计学显著性差异(P<0.05)。直线相关分析颈动脉内膜中层厚度与IL-18相关性,发现颈动脉内膜中层厚度与IL-18呈正相关,有统计学显著性差异(r=0.251,t=2.09,P=0.034)。冠心病组中颈动脉斑块多发生在颈动脉分叉部及其附近颈总动脉部位,少数发生在颈总动脉起始部或颈内动脉起始段。超声表现为软斑、硬班、钙化斑或复合性斑块,各组间比较,IL-18水平无统计学显著性差异(P>0.05)。
4.PCI组术前、术后12h和术后2周的IL-18水平全部明显高于冠脉造影组,有显著性统计学差异(P<0.01)；PCI组术后12h的IL-18水平明显高于术前水平,有显著性统计学差异(P<0.01)；PCI组术后2周的IL-18水平明显低于术后12h和术前的水平,有显著性统计学差异(P<0.01)；冠脉造影组造影前后IL-18水平无显著性统计学差异(P>0.05)。发生不良心血管事件组7例,其中短阵室速3例、室颤1例、II度-II型房室传导阻滞1例、Ⅲ度房室传导阻滞1例、急性左心衰1例；以上并发症经过相应处理后症状缓解。将该7例患者PCI前、术后12h IL-18的差值与发生不良心血管事件之间做相关分析,证实术前术后12h的IL-18差值与不良心血管事件的发生呈正相关,有统计学显著性意义(r=0.86,t=361,P<0.05)。
5.全部研究者中,基因型分布与高血压病(P=0.043)和体重指数(P=0.034)有统计学显著性差异(P<0.05),但是与其他冠心病的危险因素(年龄、性别、糖尿病、血脂异常、吸烟等)比较无统计学显著性差异(P>0.05)。病例组(CAD+)G等位基因频率(频率=0.90)与对照组(频率=0.83)比较有统计学显著性差异(P=0.004)；并且病例组GG基因型频率(频率=0.81)高于与对照组(频率=0.63),两组比较有统计学显著性差异(P=0.005)。多支病变(MVD)患者G等位基因频率或GG基因型频率与单支病变(SVD)比较无统计学显著性差异(P>0.05)。病例组(CAD+)含GG纯合子基因型的患者中,其IL-18蛋白浓度水平高于CG杂合子和CC纯合子合并后患者IL-18蛋白水平,有统计学显著性差异(P=0.000)；对于对照组(CAD-)同样如此。
结论
IL-18、TNFa和IL-10可以反映动脉粥样硬化斑块的严重程度和稳定性状态,可作为监测病情的临床生化指标。合并2型糖尿病的冠心病患者血清IL-18水平高,可能是其易发生致死性心血管事件的重要原因,对这类人群需积极采取措施进行二级预防。颈动脉内膜中层厚度、斑块发生率、血清IL-18水平的检测可作为定量检测冠状动脉粥样硬化,进而判断冠心病危险度的良好指标。冠状动脉介入治疗术后存在炎性反应,IL-18是反映介入治疗后早期炎性反应的敏感指标,它的变化程度对不良心血管事件的发生可能具有预测价值,介入治疗加剧了局部炎症反应,并随着血管开通炎症反应逐渐减弱。IL-18基因启动子区-137G／C单核苷酸基因多态性可影响血浆中IL-18蛋白水平和冠心病的发生,表明IL-18可能参与动脉粥样硬化及其并发症的发生和发展。
总之,IL-18与冠心病关系密切,是冠心病诊治过程中极有前景的靶点。
Background
Atherosclerosis is clearly an inflammatory disease and does not result simply from the accumulation of lipids. The discovery and functional assessment of cytokines and cytokine networks involved in the inflammatory cascade are receiving growing emphasis.
Interleukin 18 (IL-18) is a pleiotropic proinflammatory cytokine that has immunomodulatory effects on both the innate and the adaptive immune systems. Originally identified as an interferon-gamma inducing factor, it stimulates interferon-gamma production in T lymphocytes and natural killer cells, both of which are essential for atherosclerotic plaque progression and stability. IL-18 plays a critical role for in neointimal formation, induces endothelial cell apoptosis via activating p38MAPK-NF-kappaB-PTEN signal transduction pathway and human coronary artery smooth muscle cell migration in matrix metalloproteinase-9-dependent manner, and accelerates atherosclerosis and plaque vulnerability. Plasma IL-18 concentrations are increased in patients with acute coronary syndromes and correlate with the severity of myocardial dysfunction, and plasma IL-18 levels are an independent predictor of coronary events, which suggest that IL-18 mediates later events in plaque unstability and eventual disruption. IL-18 is not an independent risk factors for atherosclerosis in asymptomatic individuals, but IL-18 mRNA is expressed at higher levels in unstable human carotid plaques compared with stable plaques.
Among the risk factors for coronary artery disease, diabetes mellitus has a privileged position. Cardiovascular complications are the leading cause of mortality in patients with diabetes mellitus. Diabetes mellitus is a strong independent predictor for both death and myocardial infarction (MI).
Increased carotid artery intima-media thickness is a marker of coronary vascular disease which can be measured non-invasively and may be used as a biological marker of coronary artery disease. In addition, an increased carotid artery intima-media thickness may have considerable importance as a screening tool for coronary atheroma.
Recently, variations within the IL-18 gene have been shown to influence circulating levels of IL-18 and clinical outcome in subjects with coronary artery disease and play an active role in age-related functional impairment, as well as to affect IL-18 production capability by monocytes. It has been identified single nucleotide polymorphisms (SNPs) in the promoter of IL-18 gene at the position-137G/C (RS187238) can influence the expression of IL-18 and also potentially of IFN-gamma. However, the relationship between the functional promoter polymorphism and coronary artery disease has not been clearly defined.
Objectives
1 To study the relations of the levels of serum interleukin-18, tumor necrosis factor-a and interleukin 10 with acute coronary syndrome and their clinical significance.
2 To investigate the expression and significance of interleukin-18 in coronary heart disease patients with type 2 diabetes mellitus.
3 To investigate the clinical relationship of carotid artery intima-media thickness, atherosclerotic plaque and serum interleukin-18 levels in patients with coronary heart diseases.
4 To investigate the changes of serum interleukin-18 before and after percutaneous coronary intervention therapy for exploring the Clinical significance.
5 To investigate the clinical significance of the single nucleotide polymorphisms (SNPs) in promoter of IL-18 gene at the position-137G/C (RS187238) in patients with coronary artery disease, using the ligase detection reaction-polymerase chain reaction (LDR-PCR) method. Subjects studied in this research are Chinese Han population in Xiangfan region.
Methods
1 Patient:Cases of coronary artery disease and Control Cases were identified by coronary angiography. Assessment of coronary stenosis requires in at least two orthogonal projections. Lesion severity was then assessed in the projection revealing the greatest extent of narrowing. The diameter of the narrowed segment and reference vessel may be measured by digital and stenosis severity calculated as: %stenosis= (lumen diameter at stenosis site/reference diameter)×100. Diameter narrowing of more than 50% was considered to be Patients Group. The degree of severity is commonly classified into one of the following categories:(1), Normal coronary arteries; (2), Irregularities; (3),< 50% stenosis; (4),50%-69% stenosis; (5),70%-89% stenosis; (6),> or= 90% stenosis; (7), Occlusion. Categories (1), (2), and (3) were belonged to the Control Cases; Category 4) defined as Patients Group 1 (50%～69%stenosis); Category (5) defined as Patients Group 2 (70%～89% stenosis); Categories (6) and (7) were defined as Patients Group 3 (> or= 90% stenosis and Occlusion). Blood was collected from the arteriae femoralis for detection of the serum levels of IL-18 before selective coronary angiography. The concentration of serum IL-18, TNFaand IL-10 was measured with ELISA in patients with acute coronary syndrome (including unstable angina pectoris and acute myocardial infarction), patients with stable angina pectoris and control cases. The relations of the levels of serum interleukin-18, tumor necrosis factor-a and interleukin 10 between groups were analyzed.
2 Patients with coronary heart disease were divided in two groups based on the presence or absence of type 2 diabetes mellitus. Diabetes mellitus was considered present if the fasting glucose level was at least 7 mmol/L, or if the patient had been informed of the diagnosis and treatment had been prescribed with a special diet, oral antidiabetic drugs or insulin. The concentration of serum IL-18 was measured with ELISA. The relations of the levels of serum interleukin-18 between groups were analyzed.
3 Ultrasonography was performed to measure the carotid artery intima-media thickness and to observe the incidence rate of carotid atheromatous plaque in patients who had been examined by selective coronary angiography. The concentration of serum IL-18 was measured.
4 The levels of serum IL-18 in patients with coronary artery disease before percutaneous coronary intervention (PCI) and 12 hours and 2 weeks after percutaneous coronary intervention therapy were measured, changes of IL-18 were analyzed. The cardiovascular events were followed up 12 months after therapy.
5 The functional-137 G/C polymorphism (rs187238) in the promoter region of IL-18 gene was genotyped using the ligase detection reaction-polymerase chain reaction. Case patients of coronary artery disease and control patients were identified by coronary angiography and the plasma IL-18 concentrations were measured. Correlation between plasma IL-18 protein levels and genotypes of IL-18 polymorphism in studied population were analyzed.
Results
1 The serum levels of IL-18 and TNF-awere higher, and level of IL-10 was lower in than patients with coronary heart disease than those in control cases (P< 0.01). The levels of IL-18 and TNF-awere higher, and level of IL-10 was lower in acute coronary syndrome (including unstable angina pectoris and acute myocardial infarction) than patients with stable angina pectoris (P< 0.01). The level of IL-18 in Patients Group 2 (70%～90%stenosis) and Patients Group 3 (> 90% stenosis and Occlusion) was higher than Patients Group 1 (50%～70% stenosis) respectively. There were no significant differences in the levels of TNF-αand IL-10 between these groups.
2 The coronary heart disease patients with type 2 diabetes mellitus were similar to the non-diabetic coronary heart disease patients with respect to age, BMI and lipid (P> 0.05). The serum level of IL-18 in patients with coronary heart disease was higher than that with control patients (P< 0.01). Concentration of IL-18 was higher in patients with diabetes mellitus than patients with non-diabetes mellitus.
3 Carotid artery intima-media thickness in coronary disease group was significantly greater than control group (0.93mm±0.26mm vs 0.65mm±0.13mm, P< 0.01). The incidence rate of an carotid atherosclerotic plaques in coronary disease group was significantly higher than control group (97.65% vs 6.9%, P< 0.01). The serum level of IL-18 was in coronary disease group was higher than control group (316.5 pg/ml±94.2 pg/ml vs 36.38 pg/ml±18.99 pg/ml, P< 0.01).
4 The concentration of IL-18 12 hours after percutaneous coronary intervention therapy in patients with coronary artery disease was significantly increased than that before therapy (423.5 pg/ml±298.7 pg/ml vs.316.5 pg/ml±274.2 pg/ml, P<0.01), but 2 weeks later it was decreased significantly than that before therapy (286.7 pg/ml±256.9 pg/ml vs.316.5 pg/ml±274.2 pg/ml, P<0.01).
5 A significant increase of G allele or GG-genotype was observed in 241 case patients compared to 145 control individuals (frequency of G allele= 0.90 vs 0.83, P=0.004; frequency of GG-genotype= 0.81 vs 0.68, P= 0.005). In case patients, G allele carriers in multi-vessel disease patients had a higher occurrence rate when compared to single-vessel disease patients, but no significant difference was detected (frequency of G allele= 0.92 vs 0.88, P=0.107; frequency of GG-genotype = 0.84 vs 0.75, P= 0.089). IL-18 protein concentration of the-137GG genotype was much higher than concentration of CG and CC genotype (case patients:229.1±131.5 vs 122.7±73.6 pg/ml, P< 0.001; control patients:65.9±31.6 vs 42.4±19.5 pg/ml, P< 0.001).
Conclusions
IL-18 and TNF-a are suggested to play a role in atherogenesis and atheromatous plaque rupture leading to the coronary artery disease. Conversely, the anti-inflammatory cytokine IL-10 seems to have an atheroprotective role. Patients of type 2 diabetes mellitus predispose to a higher serum level of IL-18, which may explain their vulnerability to fatal cardiovascular events. Carotid artery intima-media thickness, the incidence rate of carotid atheromatous plaque and the serum levels of IL-18 can be used as a satisfactory index to quantitatively detect carotid artery atherosclerosis, and further to judge the risk factors of coronary heart disease. There is inflammation after percutaneous coronary intervention therapy. IL-18 are sensitive to reflect early inflammation and the changing degree of IL-18 may be one of predictors for cardiovascular events after coronary intervention therapy. IL-18 promoter-137G/C polymorphism influences IL-18 levels and the occurrence of coronary artery disease, suggesting that IL-18 is causally involved in the development of atherosclerosis. In summary, IL-18 and Coronary Artery Disease are closely related.
动脉粥样硬化是炎症相关疾病,与粥样硬化相关的细胞因子和细胞因子网络及其炎症瀑布的发现和功能性研究日益受到重视。白介素18(interleukin 18,IL-18)就是这些与粥样硬化相关的细胞因子之一。
IL-18具有固有性和适应性免疫细胞调节自然免疫能力,是一种多效促炎症细胞因子。它最初命名为干扰素y (interferon-gamma, IFN-γ)诱导因子,可刺激T淋巴细胞和自然杀伤细胞IFN-γ产生,这两者与粥样硬化斑块关系密切。IL-18可通过p38MAPK-NF-kappaB-PTEN信号系统和MMP-9依赖方式引起冠状动脉平滑肌细胞迁移,诱导内皮细胞凋亡,在内膜斑块形成中起重要作用,并加速粥样硬化的形成和斑块易损。
研究证实,血浆IL-18浓度在急性冠脉综合征患者中明显升高,并且可导致心肌功能受损,介导血管斑块易损和破裂,是冠状动脉事件的独立预后因素。在无症状患者中,IL-18不是粥样硬化的独立危险因素；但是与颈动脉稳定性斑块相比较,IL-18 mRNA在不稳定斑块患者中的表达明显增高。
合并2型糖尿病的冠心病患者高死亡率越来越受到人们的关注,研究发现,与不合并糖尿病的冠心病患者相比,合并2型糖尿病的男性和女性冠心病患者死亡率均明显增高,这类患者更易出现疾病再发、血管再狭窄及冠脉血运重建术后恶性心血管事件。有证据表明,炎症反应在动脉粥样硬化和2型糖尿病的发生发展中起着至关重要的作用。作为一种促炎症因子,IL-18可能参与了动脉粥样硬化和2型糖尿病的发生发展。
颈动脉粥样硬化(carotid atherosclerosis, CAS)作为全身动脉粥样硬化的一个表现,与冠状动脉粥样硬化有着密切的联系；研究证实,通过测定颈动脉IMT及斑块可间接诊断冠心病及其病变的范围和严重程度。
经皮冠状动脉介入治疗(percutaneous coronary intervention therapy, PCI)是目前冠心病患者临床上重要的治疗方法之一,PCI能迅速将急性冠脉综合征患者的梗死相关动脉或病变血管开通,恢复前向性血流,有效地降低死亡率,但由此引起的炎性反应以及不良心血管事件也日益受到广泛的关注。炎性反应对心脏有损伤与保护双重作用,也可能是PCI后再狭窄和发生其他心血管事件的重要机制。
近期研究发现IL-18基因变异可影响冠心病(coronary artery disease, CAD)患者血液中IL-18水平和临床结局,与年龄相关的心功能损害密切相关,并影响单核细胞IL-18的表达。已有研究证实IL-18基因启动子区-137G/C (RS187238)位点单核苷酸基因多态性(single nucleotide polymorphisms, SNPs)可影响IL-18和IFN-γ的表达。然而IL-18启动子单核苷酸基因多态性与冠心病的相关性并无定论。
目的
本研究以中国襄樊地区汉族人群中诊断或疑诊为冠心病,经冠状动脉造影确诊或排除冠心病者作为病例组或对照组。本研究旨在：
1.评价血清IL-18、肿瘤坏死因子a (TNFa)和白介素-10(IL-10)水平与急性冠脉综合征的关系及其临床意义；
2.评价冠心病合并2型糖尿病患者血清IL-18水平及其临床意义；
3.探讨冠心病患者颈动脉内膜-中层厚度(carotid artery intima-media thickness, IMT)及斑块与血清IL-18浓度的临床相关性；
4.观察经皮冠状动脉介入治疗(PCI)术前与术后血清白细胞介素18(IL-18)的变化,并分析其临床意义；
5.采用LDR-PCR技术,检测IL-18基因启动子区的一个功能性-137 G/C(rs187238)位点单核苷酸基因多态性,并分析其与血浆IL-18浓度的相关性,以及在冠心病中的临床价值。
方法
1.选取住我院心内科冠心病患者91例,非冠心病患者55例,根据临床表现分为急性冠脉综合征(ACS)组,稳定型心绞痛(SAP)组及对照组。评价冠状动脉狭窄程度至少需2次正投影摄片,以最大的狭窄程度确定粥样硬化的严重程度。狭窄节段直径和参照的正常血管测量后,狭窄严重度计算公式：%狭窄=(狭窄部位管腔直径／参照血管直径)×100%。狭窄<50%为对照组,狭窄在50%或以上为病例组(狭窄50%～69%为病例1组；70%～89%为病例2组；狭窄>90%或闭塞为病例3组)。冠状动脉造影前从穿刺动脉抽血。ELISA法测定血清IL-18、TNFa和IL-10浓度并分析。
2.选取冠状动脉造影确诊的冠心病患者127例,根据是否合并2型糖尿病分为伴2型糖尿病组(42例)和不伴糖尿病组(85例),以冠状动脉造影排除冠心病者(55例)作为对照,ELISA法测定血清IL-18浓度。
3.选取126例经选择性冠状动脉造影检查的患者,依据狭窄程度分为冠心病组(狭窄50%或以上)及对照组(狭窄<50%),行颈动脉超声检查,测量颈动脉内膜中层厚度并观察粥样斑块发生情况；冠状动脉造影前抽取股动脉血,测血清IL-18水平。
4.检测87例冠心病患者经皮冠状动脉介入治疗术前及术后12h,术后2周血清IL-18变化,并随访术后12个月内的心血管事件,比较术前、术后以及发生不良心血管事件组与未发生组之间血清IL-18变化的差异。
5.用LDR-PCR技术检测并分析了中国襄樊地区汉族人群中241例冠状动脉造影证实的冠心病患者和145例对照组患者的IL-18基因启动子区-137G／C(RS187238)位点单核苷酸基因多态性,并检测各组IL-18水平。
结果
1.急性冠脉综合征(ACS)组和稳定性心绞痛(SAP)组血清IL-18和TNFa水平高于对照组,有统计学显著性差异(P<0.01),而血清IL-10低于对照组,有统计学显著性差异(P<0.01)。与稳定性心绞痛(SAP)组相比,急性冠脉综合征(ACS)组血清IL-18和TNFα水平明显升高,有统计学显著性差异(P<0.01),而血清IL-10水平则显著降低有统计学显著性差异(P<0.01)。随着冠脉狭窄程度的加重,IL-18水平逐渐增高,病例2组和病例3组均明显高于病例1组,均有统计学显著性差异(P<0.01),研究3组IL-18水平虽高于研究2组,但无统计学显著性差异(P>0.05)；不同狭窄程度的3组冠心病患者TNFα和IL-10水平无统计学显著性差异(P>0.05)。
2.冠心病合并2型糖尿病组患者血清IL-18水平高于不伴糖尿病组者,有统计学显著性差异(369.1±113.25 vs 275.9±85.74,P<0.01)。
3.冠心病组颈动脉内膜中层厚度、斑块发生率、血清炎性标记物IL-18均比对照组增高,两组间均有统计学显著性差异(P<0.05)。直线相关分析颈动脉内膜中层厚度与IL-18相关性,发现颈动脉内膜中层厚度与IL-18呈正相关,有统计学显著性差异(r=0.251,t=2.09,P=0.034)。冠心病组中颈动脉斑块多发生在颈动脉分叉部及其附近颈总动脉部位,少数发生在颈总动脉起始部或颈内动脉起始段。超声表现为软斑、硬班、钙化斑或复合性斑块,各组间比较,IL-18水平无统计学显著性差异(P>0.05)。
4.PCI组术前、术后12h和术后2周的IL-18水平全部明显高于冠脉造影组,有显著性统计学差异(P<0.01)；PCI组术后12h的IL-18水平明显高于术前水平,有显著性统计学差异(P<0.01)；PCI组术后2周的IL-18水平明显低于术后12h和术前的水平,有显著性统计学差异(P<0.01)；冠脉造影组造影前后IL-18水平无显著性统计学差异(P>0.05)。发生不良心血管事件组7例,其中短阵室速3例、室颤1例、II度-II型房室传导阻滞1例、Ⅲ度房室传导阻滞1例、急性左心衰1例；以上并发症经过相应处理后症状缓解。将该7例患者PCI前、术后12h IL-18的差值与发生不良心血管事件之间做相关分析,证实术前术后12h的IL-18差值与不良心血管事件的发生呈正相关,有统计学显著性意义(r=0.86,t=361,P<0.05)。
5.全部研究者中,基因型分布与高血压病(P=0.043)和体重指数(P=0.034)有统计学显著性差异(P<0.05),但是与其他冠心病的危险因素(年龄、性别、糖尿病、血脂异常、吸烟等)比较无统计学显著性差异(P>0.05)。病例组(CAD+)G等位基因频率(频率=0.90)与对照组(频率=0.83)比较有统计学显著性差异(P=0.004)；并且病例组GG基因型频率(频率=0.81)高于与对照组(频率=0.63),两组比较有统计学显著性差异(P=0.005)。多支病变(MVD)患者G等位基因频率或GG基因型频率与单支病变(SVD)比较无统计学显著性差异(P>0.05)。病例组(CAD+)含GG纯合子基因型的患者中,其IL-18蛋白浓度水平高于CG杂合子和CC纯合子合并后患者IL-18蛋白水平,有统计学显著性差异(P=0.000)；对于对照组(CAD-)同样如此。
结论
IL-18、TNFa和IL-10可以反映动脉粥样硬化斑块的严重程度和稳定性状态,可作为监测病情的临床生化指标。合并2型糖尿病的冠心病患者血清IL-18水平高,可能是其易发生致死性心血管事件的重要原因,对这类人群需积极采取措施进行二级预防。颈动脉内膜中层厚度、斑块发生率、血清IL-18水平的检测可作为定量检测冠状动脉粥样硬化,进而判断冠心病危险度的良好指标。冠状动脉介入治疗术后存在炎性反应,IL-18是反映介入治疗后早期炎性反应的敏感指标,它的变化程度对不良心血管事件的发生可能具有预测价值,介入治疗加剧了局部炎症反应,并随着血管开通炎症反应逐渐减弱。IL-18基因启动子区-137G／C单核苷酸基因多态性可影响血浆中IL-18蛋白水平和冠心病的发生,表明IL-18可能参与动脉粥样硬化及其并发症的发生和发展。
总之,IL-18与冠心病关系密切,是冠心病诊治过程中极有前景的靶点。
Background
Atherosclerosis is clearly an inflammatory disease and does not result simply from the accumulation of lipids. The discovery and functional assessment of cytokines and cytokine networks involved in the inflammatory cascade are receiving growing emphasis.
Interleukin 18 (IL-18) is a pleiotropic proinflammatory cytokine that has immunomodulatory effects on both the innate and the adaptive immune systems. Originally identified as an interferon-gamma inducing factor, it stimulates interferon-gamma production in T lymphocytes and natural killer cells, both of which are essential for atherosclerotic plaque progression and stability. IL-18 plays a critical role for in neointimal formation, induces endothelial cell apoptosis via activating p38MAPK-NF-kappaB-PTEN signal transduction pathway and human coronary artery smooth muscle cell migration in matrix metalloproteinase-9-dependent manner, and accelerates atherosclerosis and plaque vulnerability. Plasma IL-18 concentrations are increased in patients with acute coronary syndromes and correlate with the severity of myocardial dysfunction, and plasma IL-18 levels are an independent predictor of coronary events, which suggest that IL-18 mediates later events in plaque unstability and eventual disruption. IL-18 is not an independent risk factors for atherosclerosis in asymptomatic individuals, but IL-18 mRNA is expressed at higher levels in unstable human carotid plaques compared with stable plaques.
Among the risk factors for coronary artery disease, diabetes mellitus has a privileged position. Cardiovascular complications are the leading cause of mortality in patients with diabetes mellitus. Diabetes mellitus is a strong independent predictor for both death and myocardial infarction (MI).
Increased carotid artery intima-media thickness is a marker of coronary vascular disease which can be measured non-invasively and may be used as a biological marker of coronary artery disease. In addition, an increased carotid artery intima-media thickness may have considerable importance as a screening tool for coronary atheroma.
Recently, variations within the IL-18 gene have been shown to influence circulating levels of IL-18 and clinical outcome in subjects with coronary artery disease and play an active role in age-related functional impairment, as well as to affect IL-18 production capability by monocytes. It has been identified single nucleotide polymorphisms (SNPs) in the promoter of IL-18 gene at the position-137G/C (RS187238) can influence the expression of IL-18 and also potentially of IFN-gamma. However, the relationship between the functional promoter polymorphism and coronary artery disease has not been clearly defined.
Objectives
1 To study the relations of the levels of serum interleukin-18, tumor necrosis factor-a and interleukin 10 with acute coronary syndrome and their clinical significance.
2 To investigate the expression and significance of interleukin-18 in coronary heart disease patients with type 2 diabetes mellitus.
3 To investigate the clinical relationship of carotid artery intima-media thickness, atherosclerotic plaque and serum interleukin-18 levels in patients with coronary heart diseases.
4 To investigate the changes of serum interleukin-18 before and after percutaneous coronary intervention therapy for exploring the Clinical significance.
5 To investigate the clinical significance of the single nucleotide polymorphisms (SNPs) in promoter of IL-18 gene at the position-137G/C (RS187238) in patients with coronary artery disease, using the ligase detection reaction-polymerase chain reaction (LDR-PCR) method. Subjects studied in this research are Chinese Han population in Xiangfan region.
Methods
1 Patient:Cases of coronary artery disease and Control Cases were identified by coronary angiography. Assessment of coronary stenosis requires in at least two orthogonal projections. Lesion severity was then assessed in the projection revealing the greatest extent of narrowing. The diameter of the narrowed segment and reference vessel may be measured by digital and stenosis severity calculated as: %stenosis= (lumen diameter at stenosis site/reference diameter)×100. Diameter narrowing of more than 50% was considered to be Patients Group. The degree of severity is commonly classified into one of the following categories:(1), Normal coronary arteries; (2), Irregularities; (3),< 50% stenosis; (4),50%-69% stenosis; (5),70%-89% stenosis; (6),> or= 90% stenosis; (7), Occlusion. Categories (1), (2), and (3) were belonged to the Control Cases; Category 4) defined as Patients Group 1 (50%～69%stenosis); Category (5) defined as Patients Group 2 (70%～89% stenosis); Categories (6) and (7) were defined as Patients Group 3 (> or= 90% stenosis and Occlusion). Blood was collected from the arteriae femoralis for detection of the serum levels of IL-18 before selective coronary angiography. The concentration of serum IL-18, TNFaand IL-10 was measured with ELISA in patients with acute coronary syndrome (including unstable angina pectoris and acute myocardial infarction), patients with stable angina pectoris and control cases. The relations of the levels of serum interleukin-18, tumor necrosis factor-a and interleukin 10 between groups were analyzed.
2 Patients with coronary heart disease were divided in two groups based on the presence or absence of type 2 diabetes mellitus. Diabetes mellitus was considered present if the fasting glucose level was at least 7 mmol/L, or if the patient had been informed of the diagnosis and treatment had been prescribed with a special diet, oral antidiabetic drugs or insulin. The concentration of serum IL-18 was measured with ELISA. The relations of the levels of serum interleukin-18 between groups were analyzed.
3 Ultrasonography was performed to measure the carotid artery intima-media thickness and to observe the incidence rate of carotid atheromatous plaque in patients who had been examined by selective coronary angiography. The concentration of serum IL-18 was measured.
4 The levels of serum IL-18 in patients with coronary artery disease before percutaneous coronary intervention (PCI) and 12 hours and 2 weeks after percutaneous coronary intervention therapy were measured, changes of IL-18 were analyzed. The cardiovascular events were followed up 12 months after therapy.
5 The functional-137 G/C polymorphism (rs187238) in the promoter region of IL-18 gene was genotyped using the ligase detection reaction-polymerase chain reaction. Case patients of coronary artery disease and control patients were identified by coronary angiography and the plasma IL-18 concentrations were measured. Correlation between plasma IL-18 protein levels and genotypes of IL-18 polymorphism in studied population were analyzed.
Results
1 The serum levels of IL-18 and TNF-awere higher, and level of IL-10 was lower in than patients with coronary heart disease than those in control cases (P< 0.01). The levels of IL-18 and TNF-awere higher, and level of IL-10 was lower in acute coronary syndrome (including unstable angina pectoris and acute myocardial infarction) than patients with stable angina pectoris (P< 0.01). The level of IL-18 in Patients Group 2 (70%～90%stenosis) and Patients Group 3 (> 90% stenosis and Occlusion) was higher than Patients Group 1 (50%～70% stenosis) respectively. There were no significant differences in the levels of TNF-αand IL-10 between these groups.
2 The coronary heart disease patients with type 2 diabetes mellitus were similar to the non-diabetic coronary heart disease patients with respect to age, BMI and lipid (P> 0.05). The serum level of IL-18 in patients with coronary heart disease was higher than that with control patients (P< 0.01). Concentration of IL-18 was higher in patients with diabetes mellitus than patients with non-diabetes mellitus.
3 Carotid artery intima-media thickness in coronary disease group was significantly greater than control group (0.93mm±0.26mm vs 0.65mm±0.13mm, P< 0.01). The incidence rate of an carotid atherosclerotic plaques in coronary disease group was significantly higher than control group (97.65% vs 6.9%, P< 0.01). The serum level of IL-18 was in coronary disease group was higher than control group (316.5 pg/ml±94.2 pg/ml vs 36.38 pg/ml±18.99 pg/ml, P< 0.01).
4 The concentration of IL-18 12 hours after percutaneous coronary intervention therapy in patients with coronary artery disease was significantly increased than that before therapy (423.5 pg/ml±298.7 pg/ml vs.316.5 pg/ml±274.2 pg/ml, P<0.01), but 2 weeks later it was decreased significantly than that before therapy (286.7 pg/ml±256.9 pg/ml vs.316.5 pg/ml±274.2 pg/ml, P<0.01).
5 A significant increase of G allele or GG-genotype was observed in 241 case patients compared to 145 control individuals (frequency of G allele= 0.90 vs 0.83, P=0.004; frequency of GG-genotype= 0.81 vs 0.68, P= 0.005). In case patients, G allele carriers in multi-vessel disease patients had a higher occurrence rate when compared to single-vessel disease patients, but no significant difference was detected (frequency of G allele= 0.92 vs 0.88, P=0.107; frequency of GG-genotype = 0.84 vs 0.75, P= 0.089). IL-18 protein concentration of the-137GG genotype was much higher than concentration of CG and CC genotype (case patients:229.1±131.5 vs 122.7±73.6 pg/ml, P< 0.001; control patients:65.9±31.6 vs 42.4±19.5 pg/ml, P< 0.001).
Conclusions
IL-18 and TNF-a are suggested to play a role in atherogenesis and atheromatous plaque rupture leading to the coronary artery disease. Conversely, the anti-inflammatory cytokine IL-10 seems to have an atheroprotective role. Patients of type 2 diabetes mellitus predispose to a higher serum level of IL-18, which may explain their vulnerability to fatal cardiovascular events. Carotid artery intima-media thickness, the incidence rate of carotid atheromatous plaque and the serum levels of IL-18 can be used as a satisfactory index to quantitatively detect carotid artery atherosclerosis, and further to judge the risk factors of coronary heart disease. There is inflammation after percutaneous coronary intervention therapy. IL-18 are sensitive to reflect early inflammation and the changing degree of IL-18 may be one of predictors for cardiovascular events after coronary intervention therapy. IL-18 promoter-137G/C polymorphism influences IL-18 levels and the occurrence of coronary artery disease, suggesting that IL-18 is causally involved in the development of atherosclerosis. In summary, IL-18 and Coronary Artery Disease are closely related.
引文
[1]Armstrong EJ, Morrow DA, Sabatine MS. Inflammatory biomarkers in acute coronary syndromes. Part I:introduction and cytokines. Circulation.2006;113(6):e72-75.
[2]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation.2002,106(1):24-30.
[3]Chandrasekar B, Mummidi S, Valente AJ, et al. The pro-atherogenic cytokine interleukin-18 induces CXCL16 expression in rat aortic smooth muscle cells via MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor 6, c-Src, phosphatidylinositol 3-kinase, Akt, c-Jun N-terminal kinase, and activator protein-1 signaling. J Biol Chem.2005 Jul 15;280(28):26263-77.
[4]Chandrasekar B, Valente AJ, Freeman GL, et al. Interleukin-18 induces human cardiac endothelial cell death via a novel signaling pathway involving NF-kappaB-dependent PTEN activation. Biochem Biophys Res Commun.2006 Jan 20;339(3):956-63.
[5]Chen MC, Chen CJ, Yang CH, et al. Interleukin-18:a strong predictor of the extent of coronary artery disease in patients with unstable angina. Heart Vessels.2007 Nov;22(6):371-5.
[6]Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol.2003 Feb;73(2):213-24.
[7]Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol.2007;27(1):15-26.
[8]Libby P. Inflammation in atherosclerosis. Nature.2002;420:868-874.
[9]Lusis AJ. Atherosclerosis. Nature.2000;407(6801):233-241.
[10]Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res.2001,89(7):e41-e45
[11]Nakamura K, Okamura H, Wada M, et al. Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun.1989 Feb;57(2):590-5.
[12]Nakamura K, Okamura H, Nagata K, et al. Purification of a factor which provides a costimulatory signal for gamma interferon production. Infect Immun.1993 Jan;61(1):64-70.
[13]Okamura H, Nagata K, Komatsu T, et al. A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock. Infect Immun.1995 Oct;63 (10):3966-72.
[14]Okamura H, Tsutsi H, Komatsu T, et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature.1995 Nov 2;378(6552):88-91.
[15]Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med.1999,340(2):115-126.
[16]Tenger C, Sundborger A, Jawien J, et al. IL-18 accelerate atherosclerosis accompanied by elevation of IFN-gamma and CXCL16 expression independently of T cells. Arterioscler Thromb Vasc Biol.2005,25(4):791-796
[17]Whitman SC, Ravisankar P, Daugherty A. Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res.2002 Feb 8;90(2):E34-8.
[18]Zirlik A, Abdullah SM, Gerdes N, et al. Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis:results from the Dallas Heart Study. Arterioscler Thromb Vasc Biol.2007 Sep;27(9):2043-9.
[1]Armstrong EJ, Morrow DA, Sabatine MS. Inflammatory biomarkers in acute coronary syndromes. Part I:introduction and cytokines. Circulation.2006;113(6):e72-75.
[2]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation.2002,106(1):24-30.
[3]Boekstegers P, Kainz I, Giehrl W, Peter W, Werdan K. Subchronic exposure of cardiomyocytes to low concentrations of tumor necrosis factor alpha attenuates the positive inotropic response not only to catecholamines but also to cardiac glycosides and high calcium concentrations. Mol Cell Biochem.1996 Mar 23;156(2):135-43.
[4]Caligiuri G, Rudling M, Ollivier V, et al. Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol Med.2003 Jan-Feb;9(1-2):10-7.
[5]Cesari M, Penninx BW, Newman AB, et al. Inflammatory markers and onset of cardiovascular events:results from the Health ABC study. Circulation.2003 Nov 11; 108(19):2317-22.
[6]Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol.2003 Feb;73(2):213-24.
[7]Heeschen C, Dimmeler S, Hamm CW, et al. Serum level of the antiinflammatory cytokine interleukin-10 is an important prognostic determinant in patients with acute coronary syndromes. Circulation.2003 Apr 29;107(16):2109-14.
[8]Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol.2007;27(1):15-26.
[9]Libby P. Inflammation in atherosclerosis. Nature.2002;420:868-874.
[10]Lindmark E, Diderholm E, Wallentin L, Siegbahn A. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease:effects of an early invasive or noninvasive strategy. JAMA.2001 Nov 7;286(17):2107-13.
[11]Mallat Z, Besnard S, Duriez M, et al. Protective role of interleukin-10 in atherosclerosis. Circ Res.1999 Oct 15;85(8):e17-24.
[12]Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res.2001,89(7):e41-e45.
[13]Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation.2001 Oct 2;104(14):1598-603.
[14]Marian AJ. Interleukin-18 and cardiovascular events. Curr Atheroscler Rep.2006 May;8(3):173-4.
[15]Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002 Nov 14;347(20):1557-65.
[16]Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med.1999,340(2):115-126.
[17]Scarabin PY, Arveiler D, Amouyel P, et al. Plasma fibrinogen explains much of the difference in risk of coronary heart disease between France and Northern Ireland. The PRIME study. Atherosclerosis.2003 Jan;166(1):103-9.
[18]Tenger C, Sundborger A, Jawien J,et al:IL-18 accelerate atherosclerosis accompanied by elevation of IFN-gamma and CXCL16 expression independently of T cells. Arterioscler Thromb Vasc Biol.2005,25(4):791-796.
[19]Whitman SC, Ravisankar P, Daugherty A. Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res.2002 Feb 8; 90(2): E34-8.
[20]Yang Z, Zingarelli B, Szabo C. Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. Circulation.2000 Mar 7;101(9):1019-26.
[1]Aso Y, Okumura K, Takebayashi K, et al. Relationships of plasma interleukin-18 concentrations to hyperhomocysteinemia and carotid intimal-media wall thickness in patients with type 2 diabetes. Diabetes Care 2003,26(9):2622-2627
[2]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 2002,106(1):24-30
[3]Gerdes N, Sukhova GK, Libby P, et al. Expression of interleukin(IL)-18 and functional IL-18 receptor on human vascular endothelial cells,smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med 2002,195(2):245-257
[4]Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol 2003,73(2):213-224
[5]Gu K, Cowie CC, Harris MI, et al. Diabetes and decline in heart disease mortality in US adults. JAMA 1999:1291-1297
[6]Hu FB, Meigs JB, Li TY, et al. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes.2004,53(3):693-700
[7]Kouroedov A, Eto M, Joch H, et al. Selective inhibition of protein kinase Cbeta2 prevents acute effects of high glucose on vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 2004,110(1):91-96
[8]Luc G, Bard JM, Juhan-Vaque I,et al.C-reactive protein,interleukin-6,and fibrinogen as predictors of coronary heart disease The PRIME study. Arterioscler Thromb Vasc Biol.2003, 23(7):1255-1261
[9]Marfella R, Esposito K, Siniscalchi M, et al. Effect of weight loss on cardiac synchronization and proinflammatory cytokines in premenopausal obese women. Diabetes Care.2004,27(1): 47-52
[10]Moriwaki Y, Yamamoto T, Shibutani Y, et al.Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus:relationship with diabetic nephropathy. Metabolism,2003,52(5):605-608
[11]Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin-6, and risk of developing type 2 diabetes mellitus. JAMA.2001,286(3):327-334
[12]刘永胜,沈青山,朱锐等.氟伐他汀对不稳定型心绞痛患者CRP、TNFa和cTnl的影响.国外医学／心血管疾病分册.2005,32(5)：307-308
[1]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation.2006,106(1):24-30
[2]Bots ML, Baldassarre D, Simon A, et al. Carotid intima-media thickness and coronary atherosclerosis:weak or strong relations? Eur Heart J.2007 Feb;28(4):398-406.
[3]Crouse JR. Predictive value of carotid 2-dimensional ultrasound. Am J Cardiol.2001,88(suppl): 27E-30E
[4]Geroulakos G, O'Gorman DJ, Kalodiki E, et al. The carotid intima media thickness as a marker of the presence of severe symptomatic coronary artery disease. Eur Heart J.1994,15(3): 781-785
[5]Kanwar M, Rosman HS, Fozo PK, et al. Usefulness of carotid ultrasound to improve the ability of stress testing to predict coronary artery disease. Am J Cardiol.2007 May 1; 99(9):1196-200.
[6]Lorenz MW,Markus HS,Bots ML,et al. Prediction of clinical cardiovascular events with carotid intima-media thickness:a systematic review and meta-analysis. Circulation.2007,115(4): 459-467
[7]Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res.2001,89(7):E41-E45
[8]Mallat Z, Henry P, Fressonnet R,et al. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart.2002,88(5):467-469
[9]Mallat Z, Silvestre JS, Le Ricousse-Roussanne S, et al, Interleukin-18/interleukin-18 binding protein signaling modulates ischemia-induced neovascularization in mice hindlimb. Circ Res. 2002,91(5):441-448
[10]Nagai Y, Metter EJ, Earley CJ, et al.Increased carotid artery intimal-medial thickness in asymptomatic older subjects with exercise-induced myocardial ischemia. Circulation.1998 Oct 13;98(15):1504-9.
[11]Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol 2001,19(2):423-74.
[12]Yamagami H, Kitagawa K, Hoshi T, et al. Associations of serum IL-18 levels with carotid intima-media thickness. Arterioscler Thromb Vase Biol.2005 Jul;25(7):1458-62.
[13]Zielins ki T, Dzielinska Z, Januszewicz A, et al. Carotid intima-media thickness as a marker of cardiovascular risk in hypertensive patients with coronary artery disease. Am J Hypertens.2007 Oct;20(10):1058-64.
[1]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina.Circulation,2002,106:24-30
[2]Gach O, Louis O, Chapelle JP, et al. Baseline inflammation is not predictive of periprocedural troponin elevation after elective percutaneous coronary intervention. Heart and Vessels.2009, 24(4):267-270.
[3]Glaser R, Selzer F, Jacobs AK, et al. Effect of gender on prognosis following percutaneous coronary intervention for stable angina pectoris and acute coronary syndromes. Amercian Journal Cardiology.2006,98(11):1446-1450.
[4]Kalra S, Duggal S, Valdez G, Smalligan RD. Review of acute coronary syndrome diagnosis and management. Postgrad Med.2008 Apr;120(1):18-27. Review.
[5]Koening RW, Sund M, Frohlich M, et al.C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronery heart disease in initially healthy middle aged men:msuh from the MONICA Augshurg cohort study (1984-1992). Circulation.1999,19(1):237-242
[6]Libby P. Inflammation in atherosclerosis.Nature.2002;420:868-874.
[7]Mallat Z, Henry P, Alouani S, et al. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart 2002; 88:467-9.
[8]Sambola A, Ferreira-Gonzalez I, Angel J, et al. Therapeutic strategies after coronary stenting in chronically anticoagulated patients:the MUSICA study. Heart.2009,95(18):1483-1488.
[9]Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J.2005 Apr;26(8):804-47.
[10]Stone GW, Bordie BR, Griffin JJ, et al. A prospective multicenter study of the safety and feasibility of primary stenting in acute coronary infarction:in-hospital and 30 day results of the PAMI Stent Pilot T rial. J AM Coll Cardiol.1998,31:23-30.
[11]Youssef AA, Chang LT, Hang CL, et al. Level and value of interleukin-18 in patients with acute myocardial infarction undergoing primary coronary angioplasty. Circulation Journal. 2007,71(5):703-708.
[12]Zurakowski A, Wojakowski W, Dzielski T, et al. Plasma levels of C-reactive protein and interleukin-10 predict late coronary in-stent restenosis 6 months after elective stenting. Kardiologia Polska.2009,67(6):623-630.
[1]Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med.1999;340(2):115-126.
[2]Lusis AJ. Atherosclerosis. Nature.2000;407(6801):233-241.
[3]Libby P. Inflammation in atherosclerosis. Nature.2002; 420:868-874
[4]Armstrong EJ, Morrow DA, Sabatine MS. Inflammatory biomarkers in acute coronary syndromes:part I:introduction and cytokines. Circulation.2006;113(6):e72-75.
[5]Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol.2007;27(1):15-26.
[6]Anderson JL, Carlquist JF. Cytokines, interleukin-18, and the genetic determinants of vascular inflammation. Circulation.2005 Aug 2;112(5):620-623.
[7]Dinarello CA. Interleukin-18. Methods 1999;19:121-132.
[8]Okamura H, Tsutsi H, Komatsu T, et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 1995;378:88-91.
[9]Gupta S, Pablo AM, Jiang X, et al. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest 1997;99:2752-61.
[10]Maffia P, Grassia G, Di Meglio P, et al. Neutralization of interleukin-18 inhibits neointimal formation in a rat model of vascular injury. Circulation.2006;114(5):430-437.
[11]Chandrasekar B, Vemula K, Surabhi RM, et al. Activation of intrinsic and extrinsic proapoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death. J Biol Chem.2004;279(19):20221-20233.
[12]Chandrasekar B, Valente AJ, et al. Interleukin-18 induces human cardiac endothelial cell death via a novel signaling pathway involving NF-kappaB-dependent PTEN activation. Biochem Biophys Res Commun.2006;339(3):956-963.
[13]Chandrasekar B, Mummidi S, Mahimainathan L, et al. Interleukin-18-induced human coronary artery smooth muscle cell migration is dependent on NF-kappaB-and AP-1-mediated matrix metalloproteinase-9 expression and is inhibited by atorvastatin. J Biol Chem.2006;281(22): 15099-15109.
[14]Whitman SC, Ravisankar P, Daugherty A. Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res.2002;90(2):E34-38.
[15]de Nooijer R, von der Thusen J, Verkleij C, et al. Overexpression of IL-18 decreases intimal collagen content and promotes a vulnerable plaque phenotype in apolipoprotein-E-deficient mice. Arterioscler Thromb Vasc Biol.2004; 24:2313-2319.
[16]Mallat Z, Henry P, Fressonnet R, et al. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart.2002;88(5):467-469.
[17]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation.2002;106(1):24-30.
[18]Blankenberg S, Luc G, Ducimetiere P, et al. Interleukin-18 and the risk of coronary heart disease in European men:the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation.2003;108(20):2453-2459.
[19]Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation.2001; 104:1598-1603.
[20]Gerdes N, Sukhova GK, Libby P, et al. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med 2002; 195:245-257.
[21]Zirlik A, Abdullah SM, Gerdes N, et al. Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis:results from the Dallas Heart Study. Arterioscler Thromb Vasc Biol. 2007;27(9):2043-2049.
[22]Tiret L, Godefroy T, Lubos E, et al. Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease. Circulation.2005;112(5):643-650.
[23]Frayling TM, Rafiq S, Murray A, et al. An interleukin-18 polymorphism is associated with reduced serum concentrations and better physical functioning in older people. J Gerontol A Biol Sci Med Sci.2007;62(1):73-78.
[24]Arimitsu J, Hirano T, Higa S, et al. IL-18 gene polymorphisms affect IL-18 production capability by monocytes. Biochem Biophys Res Commun.2006;342(4):1413-1416.
[25]Giedraitis V, He B, Huang WX, Hillert J. Cloning and mutation analysis of the human IL-18 promoter:a possible role of polymorphisms in expression regulation. J Neuroimmunol.2001; 112(1-2):146-152.
[26]Scanlon PJ, Faxon DP, Audet AM, et al. ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol.1999;33(6):1756-1824.
[27]Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res.1988;16(3):1215.
[28]Espinola-Klein C, Rupprecht HJ, Bickel C, et al. Inflammation, atherosclerotic burden and cardiovascular prognosis. Atherosclerosis 2007;1:1.
[29]Rosso R, Roth A, Herz I, Miller H, Keren G, George J. Serum levels of interleukin-18 in patients with stable and unstable angina pectoris. Int J Cardiol 2005;98:45-48
[30]Koenig W, Khuseyinova N, Baumert J, Thorand B, Loewel H, Chambless L, Meisinger C, Schneider A, Martin S, Kolb H, Herder C.Increased concentrations of C-reactive protein and IL-6 but not IL-18 are independently associated with incident coronary events in middle-aged men and women:results from the MONICA/KORA Augsburg case-cohort study, 1984-2002.Arterioscler Thromb Vasc Biol.2006;26(12):2745-2751.
[31]Hulthe J, McPheat W, Samnegard A, et al. Plasma interleukin (IL)-18 concentrations is elevated in patients with previous myocardial infarction and related to severity of coronary atherosclerosis independently of C-reactive protein and IL-6. Atherosclerosis 2006;4:4.
[32]Liang XH, Cheung W, Heng CK, Wang de Y. Reduced transcriptional activity in individuals with IL-18 gene variants detected from functional but not association study. Biochem Biophys Res Commun 2005;338:736-41.
[33]Hernesniemi JA, Karhunen PJ, Rontu R, et al. Interleukin-18 promoter polymorphism associates with the occurrence of sudden cardiac death among Caucasian males:the Helsinki Sudden Death Study. Atherosclerosis.2008;196(2):643-649.
[1]Adachi O, Kawai T, Takeda K, et al. Targeted disruption of the MyD88 gene results in loss of IL-1-and IL-18-mediated function. Immunity.1998 Jul;9(1):143-50.
[2]Amin MA, Mansfield PJ, Pakozdi A, et al. Interleukin-18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways. Arthritis Rheum. 2007 Jun;56(6):1787-97.
[3]An P, Thio CL, Kirk GD, et al.. Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance. J Infect Dis.2008 Oct 15; 198(8):1159-65.
[4]Armstrong EJ, Morrow DA, Sabatine MS. Inflammatory biomarkers in acute coronary syndromes. Part Ⅰ:introduction and cytokines. Circulation.2006;1 13(6):e72-75.
[5]Balligand JL, Ungureanu-Longrois D, Simmons WW, et al. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem. 1994 Nov 4;269(44):27580-8.
[6]Balligand JL, Ungureanu-Longrois D, Simmons WW, et al. Induction of NO synthase in rat cardiac microvascular endothelial cells by IL-1 beta and IFN-gamma.Am J Physiol.1995 Mar;268(3 Pt 2):H1293-303.
[7]Barbaux S, Poirier O, Godefroy T, et al. Differential haplotypic expression of the interleukin-18 gene. Eur J Hum Genet.2007 Aug;15(8):856-63.
[8]Bazan JF, Timans JC, Kastelein RA. A newly defined interleukin-1? Nature.1996 Feb 15;379(6566):591
[9]Bis JC, Heckbert SR, Smith NL, et al. Variation in inflammation-related genes and risk of incident nonfatal myocardial infarction or ischemic stroke. Atherosclerosis.2008 May; 198(1):166-73.
[10]Blankenberg S, Luc G, Ducimetiere P, et al. Interleukin-18 and the risk of coronary heart disease in European men:the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation.2003 Nov 18;108(20):2453-9.
[11]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation.2002,106(1):24-30
[12]Brenner C, Kroemer G. Apoptosis. Mitochondria-the death signal integrators. Science.2000 Aug 18;289(5482):1150-1.
[13]Buhlin K, Hultin M, Norderyd O, et al. Risk factors for atherosclerosis in cases with severe periodontitis. J Clin Periodontol.2009 Jul;36(7):541-9.
[14]Cain BS, Meldrum DR, Dinarello CA, et al. Tumor necrosis factor-alpha and interleukin-lbeta synergistically depress human myocardial function. Crit Care Med.1999 Jul;27(7):1309-18.
[15]Chandrasekar B, Mummidi S, Claycomb WC, et al. Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-l-Akt-GATA4 signaling pathway in cardiomyocytes. J Biol Chem.2005 Feb 11;280(6): 4553-67.
[16]Chandrasekar B, Mummidi S, Mahimainathan L, et al. Interleukin-18-induced human coronary artery smooth muscle cell migration is dependent on NF-kappaB-and AP-1-mediated matrix metalloproteinase-9 expression and is inhibited by atorvastatin. J Biol Chem.2006 Jun 2;281(22):15099-109.
[17]Chandrasekar B, Mummidi S, Valente AJ, et al. The pro-atherogenic cytokine interleukin-18 induces CXCL16 expression in rat aortic smooth muscle cells via MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor 6, c-Src, phosphatidylinositol 3-kinase, Akt, c-Jun N-terminal kinase, and activator protein-1 signaling. J Biol Chem.2005 Jul 15;280(28):26263-77.
[18]Chandrasekar B, Valente AJ, Freeman GL, et al. Interleukin-18 induces human cardiac endothelial cell death via a novel signaling pathway involving NF-kappaB-dependent PTEN activation. Biochem Biophys Res Commun.2006 Jan 20;339(3):956-63.
[19]Chandrasekar B, Vemula K, Surabhi RM, et al. Activation of intrinsic and extrinsic proapoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death. J Biol Chem.2004 May 7;279(19):20221-33.
[20]Chen MC, Chen CJ, Yang CH, et al. Interleukin-18:a strong predictor of the extent of coronary artery disease in patients with unstable angina. Heart Vessels.2007 Nov;22(6):371-5.
[21]Chen SY, Wan L, Huang YC, et al. Interleukin-18 gene 105A/C genetic polymorphism is associated with the susceptibility of Kawasaki disease. J Clin Lab Anal.2009;23(2):71-6.
[22]Cho ML, Jung YO, Moon YM, et al. Interleukin-18 induces the production of vascular endothelial growth factor (VEGF) in rheumatoid arthritis synovial fibroblasts via AP-1-dependent pathways. Immunol Lett.2006 Mar 15;103(2):159-66.
[23]Chien KL, Su TC, Jeng JS, et al.Carotid artery intima-media thickness, carotid plaque and coronary heart disease and stroke in Chinese. PLoS One.2008;3(10):e3435. Epub 2008 Oct 17.PMID:18927612
[24]Colston JT, Boylston WH, Feldman MD, et al. Interleukin-18 knockout mice display maladaptive cardiac hypertrophy in response to pressure overload. Biochem Biophys Res Commun.2007 Mar 9;354(2):552-8.
[25]Coughlin CM, Salhany KE, Wysocka M, et al. Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis. J Clin Invest.1998 Mar 15;101(6):1441-52.
[26]Dao T, Ohashi K, Kayano T, et al. Interferon-gamma-inducing factor, a novel cytokine, enhances Fas ligand-mediated cytotoxicity of murine T helper 1 cells. Cell Immunol.1996 Nov 1;173(2):230-5.
[27]Dao T, Mehal WZ, Crispe IN. IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells. J Immunol.1998 Sep 1;161(5):2217-22.
[28]Daugherty A, Cassis L. Angiotensin Ⅱ-mediated development of vascular diseases. Trends Cardiovasc Med.2004; 14:117-120.
[29]Daugherty A, Manning MW, Cassis LA. Angiotensin Ⅱ promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest.2000; 105:1605-1612.
[30]de Saint-Vis B, Fugier-Vivier I, Massacrier C, et al. The cytokine profile expressed by human dendritic cells is dependent on cell subtype and mode of activation. J Immunol.1998 Feb 15; 160(4):1666-76.
[31]Dinarello CA. Targeting interleukin 18 with interleukin 18 binding protein. Ann Rheum Dis. 2000Nov;59 Suppl 1:i17-20. Review.
[32]Dinarello CA. IL-18:a TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol.1999Jan;103(1 Pt 1):11-24. Review.
[33]Dinarello CA. Interleukin-18, a proinflammatory cytokine. Eur Cytokine Netw.2000 Sep;11(3):483-6. Review.
[34]Dinarello CA. Interleukin-18. Methods.1999 Sep;19(1):121-32. Review.
[35]Dinarello CA. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr.2006 Feb;83(2):447S-455S. Review.
[36]Dinarello CA:Interleukin-18 and the pathogenesis of inflammatory diseases. Semin Nephrol. 2007 Jan;27(1):98-114. Review.
[37]Dinarello CA, Novick D, Puren AJ, et al. Overview of interleukin-18:more than an interferon-gamma inducing factor. J Leukoc Biol.1998 Jun;63(6):658-64. Review.
[38]Emmanuilidis K, Weighardt H, Matevossian E, et al. Differential regulation of systemic IL-18 and IL-12 release during postoperative sepsis:high serum IL-18 as an early predictive indicator of lethal outcome. Shock.2002 Oct;18(4):301-5.
[39]Endo S, Inada K, Yamada Y, et al. Interleukin 18 (IL-18) levels in patients with sepsis. J Med. 2000;31(1-2):15-20.
[40]Ensley RD, Ives M, Zhao L, et al. Effects of alloimmune injury on contraction and relaxation in cultured myocytes and intact cardiac allografts. J Am Coll Cardiol.1994 Dec;24(7):1769-78.
[41]Espinola-Klein C, Rupprecht HJ, Bickel C, et al. Inflammation, atherosclerotic burden and cardiovascular prognosis. Atherosclerosis.2007 Dec; 195(2):e 126-34.
[42]Everett BM, Bansal S, Rifai N, et al. Interleukin-18 and the risk of future cardiovascular disease among initially healthy women. Atherosclerosis.2009 Jan;202(1):282-8.
[43]Fairweather D, Yusung S, Frisancho S, et al. IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta-and IL-18-associated myocarditis and coxsackievirus replication. J Immunol. 2003 May 1;170(9):4731-7.
[44]Faggioni R, Cattley RC, Guo J, et al. IL-18-binding protein protects against lipopolysaccharide-induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice. J munol.2001 Nov 15;167(10):5913-20.
[45]Frantz S, Ducharme A, Sawyer D, et al. Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction. J Mol Cell Cardiol.2003 Jun;35(6):685-94
[46]Gerdes N, Sukhova GK, Libby P, et al. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med.2002 Jan 21;195(2):245-57.
[47]Ghayur T, Banerjee S, Hugunin M, et al. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature.1997 Apr 10;386(6625):619-23.
[48]Gracie JA, Forsey RJ, Chan WL, et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest.1999 Nov;104(10):1393-401.
[49]Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol.2003 Feb;73(2):213-24.
[50]Graebe M, Pedersen SF, Borgwardt L, et al. Molecular pathology in vulnerable carotid plaques: correlation with [18]-fluorodeoxyglucose positron emission tomography (FDG-PET). Eur J Vasc Endovasc Surg.2009 Jun;37(6):714-21.
[51]Grisoni ML, Proust C, Alanne M, et al. Haplotypic analysis of tag SNPs of the interleukin-18 gene in relation to cardiovascular disease events:the MORGAM Project. Eur J Hum Genet. 2008Dec;16(12):1512-20.
[52]Grisoni ML, Proust C, Alanne M, et al. Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk:the MORGAM Project. BMC Med Genet. 2009 May 27;10:44.
[53]Grobmyer SR, Lin E, Lowry SF, et al. Elevation of IL-18 in human sepsis. J Clin Immunol. 2000 May;20(3):212-5
[54]Gu Y, Kuida K, Tsutsui H, et al. Activation of interferon-gamma inducing factor mediated by interleukin-1 beta converting enzyme. Science.1997 Jan 10;275(5297):206-9.
[55]Gupta S, Pablo AM, Jiang X, et al. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice[J]. J Clin Invest.1997,99(11):2752-2761
[56]Hayashida K, Kume N, Murase T, et al. Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are elevated in acute coronary syndrome:a novel marker for early diagnosis. Circulation.2005 Aug 9;112(6):812-8.
[57]Hernesniemi JA, Karhunen PJ, Rontu R, et al. Interleukin-18 promoter polymorphism associates with the occurrence of sudden cardiac death among Caucasian males:the Helsinki Sudden Death Study. Atherosclerosis.2008 Feb;196(2):643-9.
[58]Hernesniemi JA, Karhunen PJ, Oksala N, et al. Interleukin 18 gene promoter polymorphism:a link between hypertension and pre-hospital sudden cardiac death:the Helsinki Sudden Death Study. Eur Heart J.2009 Aug 17. [Epub ahead of print]
[59]Home BD, Anderson JL, John JM, et al.Which white blood cell subtypes predict increased cardiovascular risk? J Am Coll Cardiol.2005,45(10):1638-1643.
[60]Hoshino K, Tsutsui H, Kawai T, et al. Cutting edge:generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding receptor. J Immunol. 1999 May 1;162(9):5041-4.
[61]John T, Kohl B, Mobasheri A, et al. Interleukin-18 induces apoptosis in human articular chondrocytes. Histol Histopathol.2007 May;22(5):469-82.
[62]Jung MK, Song HK, Kim KE, et al. IL-18 enhances the migration ability of murine melanoma cells through the generation of ROI and the MAPK pathway. Immunol Lett.2006 Nov 15;107(2):125-30.
[63]Kanakaraj P, Ngo K, Wu Y, et al. Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. J Exp Med.1999 Apr 5;189(7):1129-38.
[64]Kanda T, Tanaka T, Sekiguchi K, et al. Effect of interleukin-18 on viral myocarditis: enhancement of interferon-gamma and natural killer cell activity. J Mol Cell Cardiol.2000 Dec;32(12):2163-71.
[65]Kawamura A, Baitsch D, Telgmann R, et al. Apolipoprotein E interrupts interleukin-1beta signaling in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol.2007 Jul;27(7):1610-7.
[66]Kawasaki D, Tsujino T, Morimoto S, et al. Plasma interleukin-18 concentration:a novel marker of myocardial ischemia rather than necrosis in humans. Coron Artery Dis.2005 Nov;16(7):437-41.
[67]Keira N, Tatsumi T, Matoba S, et al. Lethal effect of cytokine-induced nitric oxide and peroxynitrite on cultured rat cardiac myocytes. J Mol Cell Cardiol.2002 May;34(5):583-96.
[68]Kelly RA, Smith TW. Cytokines and cardiac contractile function. Circulation.1997 Feb 18;95(4):778-81. Review.
[69]Kim SH, Azam T, Novick D, et al. Identification of amino acid residues critical for biological activity in human interleukin-18. J Biol Chem.2002 Mar 29;277(13):10998-1003.
[70]Kim SH, Eisenstein M, Reznikov L, et al. Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci USA.2000 Feb 1;97(3):1190-5.
[71]Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol.2007;27(1):15-26.
[72]Kohka H, Yoshino T, Iwagaki H, et al. Interleukin-18/interferon-gamma-inducing factor, a novel cytokine, up-regulates ICAM-1 (CD54) expression in KG-1 cells. J Leukoc Biol.1998 Oct;64(4):519-27.
[73]Kohno K, Kataoka, Ohtsuki T, et al. IFN-gamma-inducing factor(IGIF) is a costimulatory factor on the activiation of Thl but not Th2 cells and exerts its effect independently of IL-12. J Immunol.1997,158(4):1541-1550
[74]Kojima H, Takeuchi M, Ohta T, et al. Interleukin-18 activates the IRAK-TRAF6 pathway in mouse EL-4 cells. Biochem Biophys Res Commun.1998 Mar 6;244(1):183-6.
[75]Konopleva M, Zhao S, Xie Z, et al. Apoptosis. Molecules and mechanisms. Adv Exp Med Biol. 1999;457:217-36.
[76]Leite-de-Moraes MC, Herbelin A, Gouarin C, et al. Fas/Fas ligand interactions promote activation-induced cell death of NK T lymphocytes. J Immunol.2000 Oct 15;165(8):4367-71.
[77]Li C, Zhang XL, Liu H, et al. Association among plasma interleukin-18 levels, carotid intima-media thickness and severity of obstructive sleep apnea. Chin Med J (Engl).2009 Jan 5;122(1): 24-9.
[78]Li DY, Chen HJ, Staples ED, et al. Oxidized low-density lipoprotein receptor LOX-1 and apoptosis in human atherosclerotic lesions. J Cardiovasc Pharmacol Ther. 2002 Jul;7(3):147-53.
[79]Li S, Jiao X, Tao L, et al. Tumor necrosis factor-alpha in mechanic trauma plasma mediates cardiomyocyte apoptosis. Am J Physiol Heart Circ Physiol.2007 Sep;293(3):H1847-52.
[80]Li JM, Eslami MH, Rohrer MJ, et al. Interleukin 18 binding protein (IL18-BP) inhibits neointimal hyperplasia after balloon injury in an atherosclerotic rabbit model. J Vasc Surg.2008 May;47(5):1048-57.
[81]Liao B, McCall E, Cox K, et al. Circulating Markers Reflect Both Anti-and Pro-Atherogenic Drug Effects in ApoE-Deficient Mice. Biomark Insights.2008 Mar 12;3:147-157.
[82]Libby P. Inflammation in atherosclerosis. Nature.2002;420:868-874.
[83]Liao X, Liu JM, Du L, Tang A, et bal. Nitric oxide signaling in stretch-induced apoptosis of neonatal rat cardiomyocytes. FASEB J.2006 Sep;20(11):1883-5.
[84]Liu W, Tang Q, Jiang H, et al. Promoter polymorphism of interleukin-18 in angiographically proven coronary artery disease. Angiology.2009 Apr-May;60(2):180-5.
[85]Luft FC. Angiotensin, inflammation, hypertension, and cardiovascular disease. Curr Hypertens Rep.2001; 3:61-67.
[86]Lusis AJ. Atherosclerosis. Nature.2000;407(6801):233-241.
[87]Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation.2001 Oct 2;104(14):1598-603.
[88]Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res.2001 Sep 28;89(7):E41-5.
[89]Mallat Z, Henry P, Fressonnet R, et al. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart.2002 Nov;88(5):467-9.
[90]Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res.2001,89(7):e41-e45
[91]Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation.2001 Oct 2;104(14):1598-603.
[92]Mallat Z, Heymes C, Corbaz A, et al. Evidence for altered interleukin 18 (IL)-18 pathway in human heart failure. FASEB J.2004 Nov; 18(14):1752-4.
[93]Mallat Z, Silvestre JS, Le Ricousse-Roussanne S, et al. Interleukin-18/interleukin-18 binding protein signaling modulates ischemia-induced neovascularization in mice hindlimb. Circ Res. 2002 Sep6;91(5):441-8.
[94]Manigold T, Bocker U, Traber P, et al. Lipopolysaccharide/endotoxin induces IL-18 via CD14 in human peripheral blood mononuclear cells in vitro. Cytokine.2000 Dec;12(12):1788-92.
[95]Marino E, Cardier JE. Differential effect of IL-18 on endothelial cell apoptosis mediated by TNF-alpha and Fas (CD95). Cytokine.2003 Jun 7;22(5):142-8.
[96]Martin TJ, Romas E, Gillespie MT. Interleukins in the control of osteoclast differentiation. Crit Rev Eukaryot Gene Expr.1998;8(2):107-23. Review.
[97]Matsui Y, Jia N, Okamoto H, et al. Role of osteopontin in cardiac fibrosis and remodeling in angiotensin Ⅱ-induced cardiac hypertrophy. Hypertension.2004 Jun;43(6):1195-201.
[98]Meldrum DR:Tumor necrosis factor in the heart. Am J Physiol.1998 Mar;274(3 Pt 2):R577-95; Review.
[99]Melnikov VY, Ecder T, Fantuzzi G, et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest.2001 May; 107(9):1145-52.
[100]Mitsuoka H, Kume N, Hayashida K, et al. Interleukin 18 stimulates release of soluble lectin-like oxidized LDL receptor-1 (sLOX-1). Atherosclerosis.2009 Jan;202(1):176-82.
[101]Morel JC, Park CC, Woods JM, Koch AE. A novel role for interleukin-18 in adhesion molecule induction through NF kappa B and phosphatidylinositol (PI) 3-kinase-dependent signal transduction pathways. J Biol Chem.2001 Oct 5;276(40):37069-75.
[102]Morel JC, Park CC, Zhu K, et al. Signal transduction pathways involved in rheumatoid arthritis synovial fibroblast interleukin-18-induced vascular cell adhesion molecule-1 expression. J Biol Chem.2002 Sep 20;277(38):34679-91.
[103]Morito N,Inoue Y, Urata M, et al. Increased carotid artery plaque score is an independent predictor of the presence and severity of coronary artery disease. J Cardiol.2008 Feb;51(1):25-32.
[104]Mousa A, Al-Zaki A, Taha S, Bakhiet M. Induction of interleukin-18 in atherosclerotic patients: a role for Chlamydia pneumoniae. Med Princ Pract.2009;18(2):105-10.
[105]Naito Y, Tsujino T, Fujioka Y, et al. Increased circulating interleukin-18 in patients with congestive heart failure. Heart.2002 Sep;88(3):296-7.
[106]Nakamura K, Okamura H, Wada M, et al. Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun.1989 Feb;57(2):590-5.
[107]Nakamura K, Okamura H, Nagata K, et al. Purification of a factor which provides a costimulatory signal for gamma interferon production. Infect Immun.1993 Jan;61(1):64-70.
[108]Netea MG, Fantuzzi G, Kullberg BJ, et al. Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia. J Immunol.2000 Mar 1;164(5):2644-9.
[109]Netea MG, Kullberg BJ, Verschueren I, et al. Interleukin-18 induces production of proinflammatory cytokines in mice:no intermediate role for the cytokines of the tumor necrosis factor family and interleukin-lbeta. Eur J Immunol.2000 Oct;30(10):3057-60.
[110]Novick D, Schwartsburd B, Pinkus R, et al. A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. Cytokine.2001 Jun 21;14(6):334-42.
[111]Oberholzer A, Steckholzer U, Kurimoto M, et al. Interleukin-18 plasma levels are increased in patients with sepsis compared to severely injured patients. Shock.2001 Dec;16(6):411-4.
[112]Okamura H, Nagata K, Komatsu T, et al. A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock. Infect Immun.1995 Oct;63(10):3966-72.
[113]Okamura H, Tsutsi H, Komatsu T, et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature.1995 Nov 2;378(6552):88-91.
[114]Okamura H, Tsutsui H, Kashiwamura S, et al. Interleukin-18:a novel cytokine that augments both innate and acquired immunity. Adv Immunol.1998;70:281-312.
[115]Olee T, Hashimoto S, Quach J, Lotz M. IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. J Immunol.1999 Jan 15; 162(2):1096-100.
[116]O'Neill PJ, Ayala A, Wang P, et al. Role of Kupffer cells in interleukin-6 release following trauma-hemorrhage and resuscitation. Shock.1994 Jan;1(1):43-7.
[117]Panafidina TA, Popkova TV, Alekberova ZS, et al. [Interleukin-18 in systemic lupus erythematosus:link with clinical symptoms and vascular atherosclerosis]. Ter Arkh. 2008;80(5):41-6. [Article in Russian]
[118]Park CC, Morel JC, Amin MA, et al. Evidence of IL-18 as a novel angiogenic mediator. J Immunol.2001 Aug 1;167(3):1644-53.
[119]Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease:application to clinical and public health practice:a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation,2003,107(3):499-511.
[120]Pei F, Han Y, Zhang X, Yan C, et al. Association of interleukin-18 gene promoter polymorphisms with risk of acute myocardial infarction in northern Chinese Han population. Clin Chem Lab Med.2009;47(5):523-9.
[121]Pomerantz BJ, Reznikov LL, Harken AH, Dinarello CA. Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-lbeta. Proc Natl Acad Sci USA.2001 Feb 27;98(5):2871-6.
[122]Puren AJ, Fantuzzi G, Dinarello CA. Gene expression, synthesis, and secretion of interleukin 18 and interleukin lbeta are differentially regulated in human blood mononuclear cells and mouse spleen cells. Proc Natl Acad Sci USA.1999 Mar 2;96(5):2256-61.
[123]Puren AJ, Fantuzzi G, Gu Y, Su MS, Dinarello CA. Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-lbeta via TNFalpha production from non-CD 14+human blood mononuclear cells. J Clin Invest.1998 Feb 1;101(3):711-21.
[124]Puren AJ, Razeghi P, Fantuzzi G, Dinarello CA. Interleukin-18 enhances lipopolysaccharide-induced interferon-gamma production in human whole blood cultures. J Infect Dis.1998 Dec; 178(6):1830-4.
[125]Rabkin SW. The role of interleukin 18 in the pathogenesis of hypertension-induced vascular disease. Nat Clin Pract Cardiovasc Med.2009 Mar;6(3):192-9.
[126]Raeburn CD, Dinarello CA, Zimmerman MA, et al. Neutralization of IL-18 attenuates lipopolysaccharide-induced myocardial dysfunction. Am J Physiol Heart Circ Physiol.2002 Aug;283(2):H650-7.
[127]Reddy P. Interleukin-18:recent advances. Curr Opin Hematol.2004 Nov;11(6):405-10.
[128]Reddy VS, Harskamp RE, van Ginkel MW, et al. Interleukin-18 stimulates fibronectin expression in primary human cardiac fibroblasts via PI3K-Akt-dependent NF-kappaB activation. J Cell Physiol.2008 Jun;215(3):697-707.
[129]Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med.1999,340(2):1 15-126.
[130]Ruotsalainen E, Vauhkonen I, Salmenniemi U, et al. Markers of endothelial dysfunction and low-grade inflammation are associated in the offspring of type 2 diabetic subjects. Atherosclerosis.2008 Mar;197(1):271-7.
[131]Sahar S, Dwarakanath RS, Reddy MA, et al. Angiotensin II enhances interleukin-18 mediated inflammatory gene expression in vascular smooth muscle cells:a novel cross-talk in the pathogenesis of atherosclerosis. Circ Res.2005 May 27;96(10):1064-71.
[132]Saito Y, Berk BC. Angiotensin II-mediated signal transduction pathways. Curr Hypertens Rep. 2002;4:167-171.
[133]Samnegard A, Hulthe J, Silveira A, et al. Gender specific associations between matrix metalloproteinases and inflammatory markers in post myocardial infarction patients. Atherosclerosis.2009 Feb;202(2):550-6.
[134]Seki E, Tsutsui H, Nakano H, et al. Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta. J Immunol.2001 Feb 15;166(4):2651-7.
[135]Seta Y, Kanda T, Tanaka T, et al. Interleukin-18 in patients with congestive heart failure: induction of atrial natriuretic peptide gene expression. Res Commun Mol Pathol Pharmacol. 2000Jul-Aug;108(1-2):87-95.
[136]Seta Y, Kanda T, Tanaka T, et al. Interleukin 18 in acute myocardial infarction. Heart.2000 Dec;84(6):668.
[137]Simms MG, Walley KR. Activated macrophages decrease rat cardiac myocyte contractility: importance of ICAM-1-dependent adhesion. Am J Physiol.1999 Jul;277(1 Pt 2):H253-60.
[138]Song H, Hur DY, Kim KE, et al. IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. Cell Immunol.2006 JuI;242(1):39-45.
[139]Souza JR, Oliveira RT, Blotta MH, Coelho OR. Serum levels of interleukin-6 (11-6), interleukin-18 (I1-18) and C-reactive protein (CRP) in patients with type-2 diabetes and acute coronary syndrome without ST-segment elevation. Arq Bras Cardiol.2008 Feb;90(2):86-90.
[140]Steinbrugger I, Haas A, Maier R, et al. Analysis of inflammation-and atherosclerosis-related gene polymorphisms in branch retinal vein occlusion. Mol Vis.2009;15:609-18.
[141]Stoll S, Muller G, Kurimoto M, et al. Production of IL-18 (IFN-gamma-inducing factor) messenger RNA and functional protein by murine keratinocytes. J Immunol.1997 Jul 1;159(1):298-302.
[142]Stoll S, Jonuleit H, Schmitt E, et al. Production of functional IL-18 by different subtypes of murine and human dendritic cells (DC):DC-derived IL-18 enhances IL-12-dependent Th1 development. Eur J Immunol.1998 Oct;28(10):3231-9.
[143]Suchanek H, Mysliwska J, Siebert J, et al. High serum interleukin-18 concentrations in patients with coronary artery disease and type 2 diabetes mellitus. Eur Cytokine Netw.2005 Sep;16(3):177-85.
[144]Takeuchi M, Nishizaki Y, Sano O, et al. Immunohistochemical and immuno-electron-microscopic detection of interferon-gamma-inducing factor ("interleukin-18") in mouse intestinal epithelial cells. Cell Tissue Res.1997 Sep;289(3):499-503.
[145]Takeuchi D, Yoshidome H, Kato A, et al. Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice. Hepatology.2004 Mar; 39(3):699-710.
[146]Tao L, Gao E, Jiao X, et al. Adiponectin cardioprotection after myocardial ischemia/ reperfusion involves the reduction of oxidative/nitrative stress. Circulation.2007 Mar 20; 115(11):1408-16.
[147]Tan HW, Liu X, Bi XP, et al. IL-18 overexpression promotes vascular inflammation and remodeling in a rat model of metabolic syndrome. Atherosclerosis.2009 Aug 7. [Epub ahead of print] PMID:19717152
[148]Tenger C, Sundborger A, Jawien J, et al. IL-18 accelerate atherosclerosis accompanied by elevation of IFN-gamma and CXCL16 expression independently of T cells. Arterioscler Thromb Vase Biol.2005,25(4):791-796
[149]Thompson SR, McCaskie PA, Beilby JP, et al. IL18 haplotypes are associated with serum IL-18 concentrations in a population-based study and a cohort of individuals with premature coronary heart disease. Clin Chem.2007 Dec;53(12):2078-85.
[150]Thompson SR, Novick D, Stock CJ, et al. Free Interleukin (IL)-18 levels, and the impact of IL18 and IL18BP genetic variation, in CHD patients and healthy men. Arterioscler Thromb Vasc Biol.2007 Dec;27(12):2743-9.
[151]Thompson SR, Sanders J, Stephens JW, et al. A common interleukin 18 haplotype is associated with higher body mass index in subjects with diabetes and coronary heart disease. Metabolism. 2007 May;56(5):662-9.
[152]Tone M, Thompson SA, Tone Y, et al. Regulation of IL-18 (IFN-gamma-inducing factor) gene expression. J Immunol.1997 Dec 15;159(12):6156-63.
[153]Torigoe K, Ushio S, Okura T, et al. Purification and characterization of the human interleukin-18 receptor. J Biol Chem.1997 Oct 10;272(41):25737-42.
[154]Tr(?)seid M, Arnesen H, Hjerkinn EM, Seljeflot I. Serum levels of interleukin-18 are reduced by diet and n-3 fatty acid intervention in elderly high-risk men. Metabolism.2009 Jul 10. [Epub ahead of print] PMID:19595382
[155]Tschoeke SK, Oberholzer A, Moldawer LL. Interleukin-18:a novel prognostic cytokine in bacteria-induced sepsis. Crit Care Med.2006 Apr;34(4):1225-33. Review.
[156]Tsutsui H, Nakanishi K, Matsui K, et al. IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones. J Immunol.1996 Nov 1;157(9):3967-73.
[157]Tziakas DN, Chalikias GK, Kaski JC, et al. Inflammatory and anti-inflammatory variable clusters and risk prediction in acute coronary syndrome patients:a factor analysis approach. Atherosclerosis.2007 Jul;193(1):196-203.
[158]Ueno N, Kashiwamura S, Ueda H, et al. Role of interleukin 18 in nitric oxide production and pancreatic damage during acute pancreatitis. Shock.2005 Dec;24(6):564-70.
[159]Ushio S, Namba M, Okura T, et al. Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J Immunol.1996 Jun 1;156(11):4274-9.J Immunol.1996 Jun 1;156(11):4274-9.
[160]Venkatesan B, Valente AJ, Reddy VS, et al. Resveratrol blocks interleukin-18-EMMPRIN cross-regulation and smooth muscle cell migration. Am J Physiol Heart Circ Physiol.2009 Aug;297(2):H874-86.
[161]Vidal-Vanaclocha F, Fantuzzi G, Mendoza L, et al. IL-18 regulates IL-1 beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1. Proc Natl Acad Sci USA.2000 Jan 18;97(2):734-9.
[162]Wald D, Qin J, Zhao Z, et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol.2003 Sep;4(9):920-7.
[163]Wang M, Markel T, Crisostomo P, et al. Deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1 beta. Am J Physiol Heart Circ Physiol.2007 Apr;292(4):H1694-9.
[164]Wang M, Markel TA, Meldrum DR. Interleukin 18 in the heart. Shock.2008 Jul;30(1):3-10. Review.
[165]Welsh P, Woodward M, Rumley A, Lowe G Associations of circulating TNFalpha and IL-18 with myocardial infarction and cardiovascular risk markers:the Glasgow Myocardial Infarction Study. Cytokine.2009 Aug;47(2):143-7.
[166]Whitman SC, Ravisankar P, Daugherty A. Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res.2002 Feb 8;90(2):E34-8.
[167]Wigginton JM, Lee JK, Wiltrout TA, et al. Synergistic engagement of an ineffective endogenous anti-tumor immune response and induction of IFN-gamma and Fas-ligand-dependent tumor eradication by combined administration of IL-18 and IL-2. J Immunol.2002 Oct 15;169(8):4467-74.
[168]Woldbaek PR, Sande JB, Stromme TA, et al. Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice. Am J Physiol Heart Circ Physiol.2005 Aug;289(2): H708-14.
[169]Woldbaek PR, Tonnessen T, Henriksen UL, et al. Increased cardiac IL-18 mRNA, pro-IL-18 and plasma IL-18 after myocardial infarction in the mouse; a potential role in cardiac dysfunction. Cardiovasc Res.2003 Jul 1;59(1):122-31.
[170]Wyman TH, Dinarello CA, Banerjee A, et al. Physiological levels of interleukin-18 stimulate multiple neutrophil functions through p38 MAP kinase activation. J Leukoc Biol.2002 Aug;72(2):401-9.
[171]Xia Y, Roman LJ, Masters BS, Zweier JL. Inducible nitric-oxide synthase generates superoxide from the reductase domain. J Biol Chem.1998 Aug 28;273(35):22635-9.
[172]Xia Y, Zweier JL. Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci USA.1997 Jun 24;94(13):6954-8.
[173]Xu D, Trajkovic V, Hunter D, et al. IL-18 induces the differentiation of Thl or Th2 cells depending upon cytokine milieu and genetic background. Eur J Immunol.2000 Nov;30(11):3147-56.
[174]Yamaoka-Tojo M, Tojo T, Inomata T, et al. Circulating levels of interleukin 18 reflect etiologies of heart failure:Thl/Th2 cytokine imbalance exaggerates the pathophysiology of advanced heart failure. J Card Fail.2002 Feb;8(1):21-7.
[175]Yang S, Hu S, Hsieh YC, et al. Mechanism of IL-6-mediated cardiac dysfunction following trauma-hemorrhage. J Mol Cell Cardiol.2006 Apr;40(4):570-9.
[176]Yang S, Zheng R, Hu S, et al. Mechanism of cardiac depression after trauma-hemorrhage: increased cardiomyocyte IL-6 and effect of sex steroids on IL-6 regulation and cardiac function. Am J Physiol Heart Circ Physiol.2004 Nov;287(5):H2183-91.
[177]Yang S, Hu S, Choudhry MA, et al. Anti-rat soluble IL-6 receptor antibody down-regulates cardiac IL-6 and improves cardiac function following trauma-hemorrhage. J Mol Cell Cardiol. 2007 Mar;42(3):620-30.
[178]Ye XJ, Tang B, Ma Z, et al. The effects of interleukin-18 on rat articular chondrocytes:a study of mRNA expression and protein synthesis of proinflammatory substances. Clin Exp Immunol. 2007Sep;149(3):553-60.
[179]Yearley JH, Xia D, Pearson CB, Carville A, et al. Interleukin-18 predicts atherosclerosis progression in SIV-infected and uninfected rhesus monkeys (Macaca mulatta) on a high-fat/high-cholesterol diet. Lab Invest.2009 Jun;89(6):657-67.
[180]Yoshida A, Kand T, Tanaka T, et al. Interleukin-18 reduces expression of cardiac tumor necrosis factor-alpha and atrial natriuretic peptide in a murine model of viral myocarditis. Life Sci.2002 Feb 1;70(11):1225-34.
[181]Yoo JK, Kwon H, Khil LY, et al. IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways. J Immunol.2005 Dec 15;175(12):8280-6.
[182]Yoshimoto T, Min B, Sugimoto T, et al. Nonredundant roles for CD1d-restricted natural killer T cells and conventional CD4+T cells in the induction of immunoglobulin E antibodies in response to interleukin 18 treatment of mice. J Exp Med.2003 Apr 21;197(8):997-1005.
[183]Yoshimoto T, Mizutani H, Tsutsui H, et al. IL-18 induction of IgE:dependence on CD4+T cells, IL-4 and STAT6. Nat Immunol.2000 Aug; 1(2):132-7.
[184]Yoshimoto T, Okamura H, Tagawa YI, et al. Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-gamma production from activated B cells. Proc Natl Acad Sci USA.1997 Apr 15;94(8):3948-53.
[185]Yoshimoto T, Tsutsui H, Tominaga K, et al. IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils. Proc Natl Acad Sci USA. 1999 Nov 23;96(24):13962-6.
[186]Yu Q, Vazquez R, Khojeini EV, et al. IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice. Am J Physiol Heart Circ Physiol.2009 Jul;297(1):H76-85.
[187]Zirlik A, Abdullah SM, Gerdes N, et al. Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis:results from the Dallas Heart Study. Arterioscler Thromb Vasc Biol. 2007 Sep;27(9):2043-9.
[2]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation.2002,106(1):24-30.
[3]Chandrasekar B, Mummidi S, Valente AJ, et al. The pro-atherogenic cytokine interleukin-18 induces CXCL16 expression in rat aortic smooth muscle cells via MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor 6, c-Src, phosphatidylinositol 3-kinase, Akt, c-Jun N-terminal kinase, and activator protein-1 signaling. J Biol Chem.2005 Jul 15;280(28):26263-77.
[4]Chandrasekar B, Valente AJ, Freeman GL, et al. Interleukin-18 induces human cardiac endothelial cell death via a novel signaling pathway involving NF-kappaB-dependent PTEN activation. Biochem Biophys Res Commun.2006 Jan 20;339(3):956-63.
[5]Chen MC, Chen CJ, Yang CH, et al. Interleukin-18:a strong predictor of the extent of coronary artery disease in patients with unstable angina. Heart Vessels.2007 Nov;22(6):371-5.
[6]Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol.2003 Feb;73(2):213-24.
[7]Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol.2007;27(1):15-26.
[8]Libby P. Inflammation in atherosclerosis. Nature.2002;420:868-874.
[9]Lusis AJ. Atherosclerosis. Nature.2000;407(6801):233-241.
[10]Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res.2001,89(7):e41-e45
[11]Nakamura K, Okamura H, Wada M, et al. Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun.1989 Feb;57(2):590-5.
[12]Nakamura K, Okamura H, Nagata K, et al. Purification of a factor which provides a costimulatory signal for gamma interferon production. Infect Immun.1993 Jan;61(1):64-70.
[13]Okamura H, Nagata K, Komatsu T, et al. A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock. Infect Immun.1995 Oct;63 (10):3966-72.
[14]Okamura H, Tsutsi H, Komatsu T, et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature.1995 Nov 2;378(6552):88-91.
[15]Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med.1999,340(2):115-126.
[16]Tenger C, Sundborger A, Jawien J, et al. IL-18 accelerate atherosclerosis accompanied by elevation of IFN-gamma and CXCL16 expression independently of T cells. Arterioscler Thromb Vasc Biol.2005,25(4):791-796
[17]Whitman SC, Ravisankar P, Daugherty A. Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res.2002 Feb 8;90(2):E34-8.
[18]Zirlik A, Abdullah SM, Gerdes N, et al. Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis:results from the Dallas Heart Study. Arterioscler Thromb Vasc Biol.2007 Sep;27(9):2043-9.
[1]Armstrong EJ, Morrow DA, Sabatine MS. Inflammatory biomarkers in acute coronary syndromes. Part I:introduction and cytokines. Circulation.2006;113(6):e72-75.
[2]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation.2002,106(1):24-30.
[3]Boekstegers P, Kainz I, Giehrl W, Peter W, Werdan K. Subchronic exposure of cardiomyocytes to low concentrations of tumor necrosis factor alpha attenuates the positive inotropic response not only to catecholamines but also to cardiac glycosides and high calcium concentrations. Mol Cell Biochem.1996 Mar 23;156(2):135-43.
[4]Caligiuri G, Rudling M, Ollivier V, et al. Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol Med.2003 Jan-Feb;9(1-2):10-7.
[5]Cesari M, Penninx BW, Newman AB, et al. Inflammatory markers and onset of cardiovascular events:results from the Health ABC study. Circulation.2003 Nov 11; 108(19):2317-22.
[6]Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol.2003 Feb;73(2):213-24.
[7]Heeschen C, Dimmeler S, Hamm CW, et al. Serum level of the antiinflammatory cytokine interleukin-10 is an important prognostic determinant in patients with acute coronary syndromes. Circulation.2003 Apr 29;107(16):2109-14.
[8]Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol.2007;27(1):15-26.
[9]Libby P. Inflammation in atherosclerosis. Nature.2002;420:868-874.
[10]Lindmark E, Diderholm E, Wallentin L, Siegbahn A. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease:effects of an early invasive or noninvasive strategy. JAMA.2001 Nov 7;286(17):2107-13.
[11]Mallat Z, Besnard S, Duriez M, et al. Protective role of interleukin-10 in atherosclerosis. Circ Res.1999 Oct 15;85(8):e17-24.
[12]Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res.2001,89(7):e41-e45.
[13]Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation.2001 Oct 2;104(14):1598-603.
[14]Marian AJ. Interleukin-18 and cardiovascular events. Curr Atheroscler Rep.2006 May;8(3):173-4.
[15]Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002 Nov 14;347(20):1557-65.
[16]Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med.1999,340(2):115-126.
[17]Scarabin PY, Arveiler D, Amouyel P, et al. Plasma fibrinogen explains much of the difference in risk of coronary heart disease between France and Northern Ireland. The PRIME study. Atherosclerosis.2003 Jan;166(1):103-9.
[18]Tenger C, Sundborger A, Jawien J,et al:IL-18 accelerate atherosclerosis accompanied by elevation of IFN-gamma and CXCL16 expression independently of T cells. Arterioscler Thromb Vasc Biol.2005,25(4):791-796.
[19]Whitman SC, Ravisankar P, Daugherty A. Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res.2002 Feb 8; 90(2): E34-8.
[20]Yang Z, Zingarelli B, Szabo C. Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. Circulation.2000 Mar 7;101(9):1019-26.
[1]Aso Y, Okumura K, Takebayashi K, et al. Relationships of plasma interleukin-18 concentrations to hyperhomocysteinemia and carotid intimal-media wall thickness in patients with type 2 diabetes. Diabetes Care 2003,26(9):2622-2627
[2]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 2002,106(1):24-30
[3]Gerdes N, Sukhova GK, Libby P, et al. Expression of interleukin(IL)-18 and functional IL-18 receptor on human vascular endothelial cells,smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med 2002,195(2):245-257
[4]Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol 2003,73(2):213-224
[5]Gu K, Cowie CC, Harris MI, et al. Diabetes and decline in heart disease mortality in US adults. JAMA 1999:1291-1297
[6]Hu FB, Meigs JB, Li TY, et al. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes.2004,53(3):693-700
[7]Kouroedov A, Eto M, Joch H, et al. Selective inhibition of protein kinase Cbeta2 prevents acute effects of high glucose on vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 2004,110(1):91-96
[8]Luc G, Bard JM, Juhan-Vaque I,et al.C-reactive protein,interleukin-6,and fibrinogen as predictors of coronary heart disease The PRIME study. Arterioscler Thromb Vasc Biol.2003, 23(7):1255-1261
[9]Marfella R, Esposito K, Siniscalchi M, et al. Effect of weight loss on cardiac synchronization and proinflammatory cytokines in premenopausal obese women. Diabetes Care.2004,27(1): 47-52
[10]Moriwaki Y, Yamamoto T, Shibutani Y, et al.Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus:relationship with diabetic nephropathy. Metabolism,2003,52(5):605-608
[11]Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin-6, and risk of developing type 2 diabetes mellitus. JAMA.2001,286(3):327-334
[12]刘永胜,沈青山,朱锐等.氟伐他汀对不稳定型心绞痛患者CRP、TNFa和cTnl的影响.国外医学／心血管疾病分册.2005,32(5)：307-308
[1]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation.2006,106(1):24-30
[2]Bots ML, Baldassarre D, Simon A, et al. Carotid intima-media thickness and coronary atherosclerosis:weak or strong relations? Eur Heart J.2007 Feb;28(4):398-406.
[3]Crouse JR. Predictive value of carotid 2-dimensional ultrasound. Am J Cardiol.2001,88(suppl): 27E-30E
[4]Geroulakos G, O'Gorman DJ, Kalodiki E, et al. The carotid intima media thickness as a marker of the presence of severe symptomatic coronary artery disease. Eur Heart J.1994,15(3): 781-785
[5]Kanwar M, Rosman HS, Fozo PK, et al. Usefulness of carotid ultrasound to improve the ability of stress testing to predict coronary artery disease. Am J Cardiol.2007 May 1; 99(9):1196-200.
[6]Lorenz MW,Markus HS,Bots ML,et al. Prediction of clinical cardiovascular events with carotid intima-media thickness:a systematic review and meta-analysis. Circulation.2007,115(4): 459-467
[7]Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res.2001,89(7):E41-E45
[8]Mallat Z, Henry P, Fressonnet R,et al. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart.2002,88(5):467-469
[9]Mallat Z, Silvestre JS, Le Ricousse-Roussanne S, et al, Interleukin-18/interleukin-18 binding protein signaling modulates ischemia-induced neovascularization in mice hindlimb. Circ Res. 2002,91(5):441-448
[10]Nagai Y, Metter EJ, Earley CJ, et al.Increased carotid artery intimal-medial thickness in asymptomatic older subjects with exercise-induced myocardial ischemia. Circulation.1998 Oct 13;98(15):1504-9.
[11]Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol 2001,19(2):423-74.
[12]Yamagami H, Kitagawa K, Hoshi T, et al. Associations of serum IL-18 levels with carotid intima-media thickness. Arterioscler Thromb Vase Biol.2005 Jul;25(7):1458-62.
[13]Zielins ki T, Dzielinska Z, Januszewicz A, et al. Carotid intima-media thickness as a marker of cardiovascular risk in hypertensive patients with coronary artery disease. Am J Hypertens.2007 Oct;20(10):1058-64.
[1]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina.Circulation,2002,106:24-30
[2]Gach O, Louis O, Chapelle JP, et al. Baseline inflammation is not predictive of periprocedural troponin elevation after elective percutaneous coronary intervention. Heart and Vessels.2009, 24(4):267-270.
[3]Glaser R, Selzer F, Jacobs AK, et al. Effect of gender on prognosis following percutaneous coronary intervention for stable angina pectoris and acute coronary syndromes. Amercian Journal Cardiology.2006,98(11):1446-1450.
[4]Kalra S, Duggal S, Valdez G, Smalligan RD. Review of acute coronary syndrome diagnosis and management. Postgrad Med.2008 Apr;120(1):18-27. Review.
[5]Koening RW, Sund M, Frohlich M, et al.C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronery heart disease in initially healthy middle aged men:msuh from the MONICA Augshurg cohort study (1984-1992). Circulation.1999,19(1):237-242
[6]Libby P. Inflammation in atherosclerosis.Nature.2002;420:868-874.
[7]Mallat Z, Henry P, Alouani S, et al. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart 2002; 88:467-9.
[8]Sambola A, Ferreira-Gonzalez I, Angel J, et al. Therapeutic strategies after coronary stenting in chronically anticoagulated patients:the MUSICA study. Heart.2009,95(18):1483-1488.
[9]Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J.2005 Apr;26(8):804-47.
[10]Stone GW, Bordie BR, Griffin JJ, et al. A prospective multicenter study of the safety and feasibility of primary stenting in acute coronary infarction:in-hospital and 30 day results of the PAMI Stent Pilot T rial. J AM Coll Cardiol.1998,31:23-30.
[11]Youssef AA, Chang LT, Hang CL, et al. Level and value of interleukin-18 in patients with acute myocardial infarction undergoing primary coronary angioplasty. Circulation Journal. 2007,71(5):703-708.
[12]Zurakowski A, Wojakowski W, Dzielski T, et al. Plasma levels of C-reactive protein and interleukin-10 predict late coronary in-stent restenosis 6 months after elective stenting. Kardiologia Polska.2009,67(6):623-630.
[1]Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med.1999;340(2):115-126.
[2]Lusis AJ. Atherosclerosis. Nature.2000;407(6801):233-241.
[3]Libby P. Inflammation in atherosclerosis. Nature.2002; 420:868-874
[4]Armstrong EJ, Morrow DA, Sabatine MS. Inflammatory biomarkers in acute coronary syndromes:part I:introduction and cytokines. Circulation.2006;113(6):e72-75.
[5]Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol.2007;27(1):15-26.
[6]Anderson JL, Carlquist JF. Cytokines, interleukin-18, and the genetic determinants of vascular inflammation. Circulation.2005 Aug 2;112(5):620-623.
[7]Dinarello CA. Interleukin-18. Methods 1999;19:121-132.
[8]Okamura H, Tsutsi H, Komatsu T, et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 1995;378:88-91.
[9]Gupta S, Pablo AM, Jiang X, et al. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest 1997;99:2752-61.
[10]Maffia P, Grassia G, Di Meglio P, et al. Neutralization of interleukin-18 inhibits neointimal formation in a rat model of vascular injury. Circulation.2006;114(5):430-437.
[11]Chandrasekar B, Vemula K, Surabhi RM, et al. Activation of intrinsic and extrinsic proapoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death. J Biol Chem.2004;279(19):20221-20233.
[12]Chandrasekar B, Valente AJ, et al. Interleukin-18 induces human cardiac endothelial cell death via a novel signaling pathway involving NF-kappaB-dependent PTEN activation. Biochem Biophys Res Commun.2006;339(3):956-963.
[13]Chandrasekar B, Mummidi S, Mahimainathan L, et al. Interleukin-18-induced human coronary artery smooth muscle cell migration is dependent on NF-kappaB-and AP-1-mediated matrix metalloproteinase-9 expression and is inhibited by atorvastatin. J Biol Chem.2006;281(22): 15099-15109.
[14]Whitman SC, Ravisankar P, Daugherty A. Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res.2002;90(2):E34-38.
[15]de Nooijer R, von der Thusen J, Verkleij C, et al. Overexpression of IL-18 decreases intimal collagen content and promotes a vulnerable plaque phenotype in apolipoprotein-E-deficient mice. Arterioscler Thromb Vasc Biol.2004; 24:2313-2319.
[16]Mallat Z, Henry P, Fressonnet R, et al. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart.2002;88(5):467-469.
[17]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation.2002;106(1):24-30.
[18]Blankenberg S, Luc G, Ducimetiere P, et al. Interleukin-18 and the risk of coronary heart disease in European men:the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation.2003;108(20):2453-2459.
[19]Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation.2001; 104:1598-1603.
[20]Gerdes N, Sukhova GK, Libby P, et al. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med 2002; 195:245-257.
[21]Zirlik A, Abdullah SM, Gerdes N, et al. Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis:results from the Dallas Heart Study. Arterioscler Thromb Vasc Biol. 2007;27(9):2043-2049.
[22]Tiret L, Godefroy T, Lubos E, et al. Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease. Circulation.2005;112(5):643-650.
[23]Frayling TM, Rafiq S, Murray A, et al. An interleukin-18 polymorphism is associated with reduced serum concentrations and better physical functioning in older people. J Gerontol A Biol Sci Med Sci.2007;62(1):73-78.
[24]Arimitsu J, Hirano T, Higa S, et al. IL-18 gene polymorphisms affect IL-18 production capability by monocytes. Biochem Biophys Res Commun.2006;342(4):1413-1416.
[25]Giedraitis V, He B, Huang WX, Hillert J. Cloning and mutation analysis of the human IL-18 promoter:a possible role of polymorphisms in expression regulation. J Neuroimmunol.2001; 112(1-2):146-152.
[26]Scanlon PJ, Faxon DP, Audet AM, et al. ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol.1999;33(6):1756-1824.
[27]Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res.1988;16(3):1215.
[28]Espinola-Klein C, Rupprecht HJ, Bickel C, et al. Inflammation, atherosclerotic burden and cardiovascular prognosis. Atherosclerosis 2007;1:1.
[29]Rosso R, Roth A, Herz I, Miller H, Keren G, George J. Serum levels of interleukin-18 in patients with stable and unstable angina pectoris. Int J Cardiol 2005;98:45-48
[30]Koenig W, Khuseyinova N, Baumert J, Thorand B, Loewel H, Chambless L, Meisinger C, Schneider A, Martin S, Kolb H, Herder C.Increased concentrations of C-reactive protein and IL-6 but not IL-18 are independently associated with incident coronary events in middle-aged men and women:results from the MONICA/KORA Augsburg case-cohort study, 1984-2002.Arterioscler Thromb Vasc Biol.2006;26(12):2745-2751.
[31]Hulthe J, McPheat W, Samnegard A, et al. Plasma interleukin (IL)-18 concentrations is elevated in patients with previous myocardial infarction and related to severity of coronary atherosclerosis independently of C-reactive protein and IL-6. Atherosclerosis 2006;4:4.
[32]Liang XH, Cheung W, Heng CK, Wang de Y. Reduced transcriptional activity in individuals with IL-18 gene variants detected from functional but not association study. Biochem Biophys Res Commun 2005;338:736-41.
[33]Hernesniemi JA, Karhunen PJ, Rontu R, et al. Interleukin-18 promoter polymorphism associates with the occurrence of sudden cardiac death among Caucasian males:the Helsinki Sudden Death Study. Atherosclerosis.2008;196(2):643-649.
[1]Adachi O, Kawai T, Takeda K, et al. Targeted disruption of the MyD88 gene results in loss of IL-1-and IL-18-mediated function. Immunity.1998 Jul;9(1):143-50.
[2]Amin MA, Mansfield PJ, Pakozdi A, et al. Interleukin-18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways. Arthritis Rheum. 2007 Jun;56(6):1787-97.
[3]An P, Thio CL, Kirk GD, et al.. Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance. J Infect Dis.2008 Oct 15; 198(8):1159-65.
[4]Armstrong EJ, Morrow DA, Sabatine MS. Inflammatory biomarkers in acute coronary syndromes. Part Ⅰ:introduction and cytokines. Circulation.2006;1 13(6):e72-75.
[5]Balligand JL, Ungureanu-Longrois D, Simmons WW, et al. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem. 1994 Nov 4;269(44):27580-8.
[6]Balligand JL, Ungureanu-Longrois D, Simmons WW, et al. Induction of NO synthase in rat cardiac microvascular endothelial cells by IL-1 beta and IFN-gamma.Am J Physiol.1995 Mar;268(3 Pt 2):H1293-303.
[7]Barbaux S, Poirier O, Godefroy T, et al. Differential haplotypic expression of the interleukin-18 gene. Eur J Hum Genet.2007 Aug;15(8):856-63.
[8]Bazan JF, Timans JC, Kastelein RA. A newly defined interleukin-1? Nature.1996 Feb 15;379(6566):591
[9]Bis JC, Heckbert SR, Smith NL, et al. Variation in inflammation-related genes and risk of incident nonfatal myocardial infarction or ischemic stroke. Atherosclerosis.2008 May; 198(1):166-73.
[10]Blankenberg S, Luc G, Ducimetiere P, et al. Interleukin-18 and the risk of coronary heart disease in European men:the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation.2003 Nov 18;108(20):2453-9.
[11]Blankenberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation.2002,106(1):24-30
[12]Brenner C, Kroemer G. Apoptosis. Mitochondria-the death signal integrators. Science.2000 Aug 18;289(5482):1150-1.
[13]Buhlin K, Hultin M, Norderyd O, et al. Risk factors for atherosclerosis in cases with severe periodontitis. J Clin Periodontol.2009 Jul;36(7):541-9.
[14]Cain BS, Meldrum DR, Dinarello CA, et al. Tumor necrosis factor-alpha and interleukin-lbeta synergistically depress human myocardial function. Crit Care Med.1999 Jul;27(7):1309-18.
[15]Chandrasekar B, Mummidi S, Claycomb WC, et al. Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-l-Akt-GATA4 signaling pathway in cardiomyocytes. J Biol Chem.2005 Feb 11;280(6): 4553-67.
[16]Chandrasekar B, Mummidi S, Mahimainathan L, et al. Interleukin-18-induced human coronary artery smooth muscle cell migration is dependent on NF-kappaB-and AP-1-mediated matrix metalloproteinase-9 expression and is inhibited by atorvastatin. J Biol Chem.2006 Jun 2;281(22):15099-109.
[17]Chandrasekar B, Mummidi S, Valente AJ, et al. The pro-atherogenic cytokine interleukin-18 induces CXCL16 expression in rat aortic smooth muscle cells via MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor 6, c-Src, phosphatidylinositol 3-kinase, Akt, c-Jun N-terminal kinase, and activator protein-1 signaling. J Biol Chem.2005 Jul 15;280(28):26263-77.
[18]Chandrasekar B, Valente AJ, Freeman GL, et al. Interleukin-18 induces human cardiac endothelial cell death via a novel signaling pathway involving NF-kappaB-dependent PTEN activation. Biochem Biophys Res Commun.2006 Jan 20;339(3):956-63.
[19]Chandrasekar B, Vemula K, Surabhi RM, et al. Activation of intrinsic and extrinsic proapoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death. J Biol Chem.2004 May 7;279(19):20221-33.
[20]Chen MC, Chen CJ, Yang CH, et al. Interleukin-18:a strong predictor of the extent of coronary artery disease in patients with unstable angina. Heart Vessels.2007 Nov;22(6):371-5.
[21]Chen SY, Wan L, Huang YC, et al. Interleukin-18 gene 105A/C genetic polymorphism is associated with the susceptibility of Kawasaki disease. J Clin Lab Anal.2009;23(2):71-6.
[22]Cho ML, Jung YO, Moon YM, et al. Interleukin-18 induces the production of vascular endothelial growth factor (VEGF) in rheumatoid arthritis synovial fibroblasts via AP-1-dependent pathways. Immunol Lett.2006 Mar 15;103(2):159-66.
[23]Chien KL, Su TC, Jeng JS, et al.Carotid artery intima-media thickness, carotid plaque and coronary heart disease and stroke in Chinese. PLoS One.2008;3(10):e3435. Epub 2008 Oct 17.PMID:18927612
[24]Colston JT, Boylston WH, Feldman MD, et al. Interleukin-18 knockout mice display maladaptive cardiac hypertrophy in response to pressure overload. Biochem Biophys Res Commun.2007 Mar 9;354(2):552-8.
[25]Coughlin CM, Salhany KE, Wysocka M, et al. Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis. J Clin Invest.1998 Mar 15;101(6):1441-52.
[26]Dao T, Ohashi K, Kayano T, et al. Interferon-gamma-inducing factor, a novel cytokine, enhances Fas ligand-mediated cytotoxicity of murine T helper 1 cells. Cell Immunol.1996 Nov 1;173(2):230-5.
[27]Dao T, Mehal WZ, Crispe IN. IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells. J Immunol.1998 Sep 1;161(5):2217-22.
[28]Daugherty A, Cassis L. Angiotensin Ⅱ-mediated development of vascular diseases. Trends Cardiovasc Med.2004; 14:117-120.
[29]Daugherty A, Manning MW, Cassis LA. Angiotensin Ⅱ promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest.2000; 105:1605-1612.
[30]de Saint-Vis B, Fugier-Vivier I, Massacrier C, et al. The cytokine profile expressed by human dendritic cells is dependent on cell subtype and mode of activation. J Immunol.1998 Feb 15; 160(4):1666-76.
[31]Dinarello CA. Targeting interleukin 18 with interleukin 18 binding protein. Ann Rheum Dis. 2000Nov;59 Suppl 1:i17-20. Review.
[32]Dinarello CA. IL-18:a TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol.1999Jan;103(1 Pt 1):11-24. Review.
[33]Dinarello CA. Interleukin-18, a proinflammatory cytokine. Eur Cytokine Netw.2000 Sep;11(3):483-6. Review.
[34]Dinarello CA. Interleukin-18. Methods.1999 Sep;19(1):121-32. Review.
[35]Dinarello CA. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr.2006 Feb;83(2):447S-455S. Review.
[36]Dinarello CA:Interleukin-18 and the pathogenesis of inflammatory diseases. Semin Nephrol. 2007 Jan;27(1):98-114. Review.
[37]Dinarello CA, Novick D, Puren AJ, et al. Overview of interleukin-18:more than an interferon-gamma inducing factor. J Leukoc Biol.1998 Jun;63(6):658-64. Review.
[38]Emmanuilidis K, Weighardt H, Matevossian E, et al. Differential regulation of systemic IL-18 and IL-12 release during postoperative sepsis:high serum IL-18 as an early predictive indicator of lethal outcome. Shock.2002 Oct;18(4):301-5.
[39]Endo S, Inada K, Yamada Y, et al. Interleukin 18 (IL-18) levels in patients with sepsis. J Med. 2000;31(1-2):15-20.
[40]Ensley RD, Ives M, Zhao L, et al. Effects of alloimmune injury on contraction and relaxation in cultured myocytes and intact cardiac allografts. J Am Coll Cardiol.1994 Dec;24(7):1769-78.
[41]Espinola-Klein C, Rupprecht HJ, Bickel C, et al. Inflammation, atherosclerotic burden and cardiovascular prognosis. Atherosclerosis.2007 Dec; 195(2):e 126-34.
[42]Everett BM, Bansal S, Rifai N, et al. Interleukin-18 and the risk of future cardiovascular disease among initially healthy women. Atherosclerosis.2009 Jan;202(1):282-8.
[43]Fairweather D, Yusung S, Frisancho S, et al. IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta-and IL-18-associated myocarditis and coxsackievirus replication. J Immunol. 2003 May 1;170(9):4731-7.
[44]Faggioni R, Cattley RC, Guo J, et al. IL-18-binding protein protects against lipopolysaccharide-induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice. J munol.2001 Nov 15;167(10):5913-20.
[45]Frantz S, Ducharme A, Sawyer D, et al. Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction. J Mol Cell Cardiol.2003 Jun;35(6):685-94
[46]Gerdes N, Sukhova GK, Libby P, et al. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med.2002 Jan 21;195(2):245-57.
[47]Ghayur T, Banerjee S, Hugunin M, et al. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature.1997 Apr 10;386(6625):619-23.
[48]Gracie JA, Forsey RJ, Chan WL, et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest.1999 Nov;104(10):1393-401.
[49]Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol.2003 Feb;73(2):213-24.
[50]Graebe M, Pedersen SF, Borgwardt L, et al. Molecular pathology in vulnerable carotid plaques: correlation with [18]-fluorodeoxyglucose positron emission tomography (FDG-PET). Eur J Vasc Endovasc Surg.2009 Jun;37(6):714-21.
[51]Grisoni ML, Proust C, Alanne M, et al. Haplotypic analysis of tag SNPs of the interleukin-18 gene in relation to cardiovascular disease events:the MORGAM Project. Eur J Hum Genet. 2008Dec;16(12):1512-20.
[52]Grisoni ML, Proust C, Alanne M, et al. Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk:the MORGAM Project. BMC Med Genet. 2009 May 27;10:44.
[53]Grobmyer SR, Lin E, Lowry SF, et al. Elevation of IL-18 in human sepsis. J Clin Immunol. 2000 May;20(3):212-5
[54]Gu Y, Kuida K, Tsutsui H, et al. Activation of interferon-gamma inducing factor mediated by interleukin-1 beta converting enzyme. Science.1997 Jan 10;275(5297):206-9.
[55]Gupta S, Pablo AM, Jiang X, et al. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice[J]. J Clin Invest.1997,99(11):2752-2761
[56]Hayashida K, Kume N, Murase T, et al. Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are elevated in acute coronary syndrome:a novel marker for early diagnosis. Circulation.2005 Aug 9;112(6):812-8.
[57]Hernesniemi JA, Karhunen PJ, Rontu R, et al. Interleukin-18 promoter polymorphism associates with the occurrence of sudden cardiac death among Caucasian males:the Helsinki Sudden Death Study. Atherosclerosis.2008 Feb;196(2):643-9.
[58]Hernesniemi JA, Karhunen PJ, Oksala N, et al. Interleukin 18 gene promoter polymorphism:a link between hypertension and pre-hospital sudden cardiac death:the Helsinki Sudden Death Study. Eur Heart J.2009 Aug 17. [Epub ahead of print]
[59]Home BD, Anderson JL, John JM, et al.Which white blood cell subtypes predict increased cardiovascular risk? J Am Coll Cardiol.2005,45(10):1638-1643.
[60]Hoshino K, Tsutsui H, Kawai T, et al. Cutting edge:generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding receptor. J Immunol. 1999 May 1;162(9):5041-4.
[61]John T, Kohl B, Mobasheri A, et al. Interleukin-18 induces apoptosis in human articular chondrocytes. Histol Histopathol.2007 May;22(5):469-82.
[62]Jung MK, Song HK, Kim KE, et al. IL-18 enhances the migration ability of murine melanoma cells through the generation of ROI and the MAPK pathway. Immunol Lett.2006 Nov 15;107(2):125-30.
[63]Kanakaraj P, Ngo K, Wu Y, et al. Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. J Exp Med.1999 Apr 5;189(7):1129-38.
[64]Kanda T, Tanaka T, Sekiguchi K, et al. Effect of interleukin-18 on viral myocarditis: enhancement of interferon-gamma and natural killer cell activity. J Mol Cell Cardiol.2000 Dec;32(12):2163-71.
[65]Kawamura A, Baitsch D, Telgmann R, et al. Apolipoprotein E interrupts interleukin-1beta signaling in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol.2007 Jul;27(7):1610-7.
[66]Kawasaki D, Tsujino T, Morimoto S, et al. Plasma interleukin-18 concentration:a novel marker of myocardial ischemia rather than necrosis in humans. Coron Artery Dis.2005 Nov;16(7):437-41.
[67]Keira N, Tatsumi T, Matoba S, et al. Lethal effect of cytokine-induced nitric oxide and peroxynitrite on cultured rat cardiac myocytes. J Mol Cell Cardiol.2002 May;34(5):583-96.
[68]Kelly RA, Smith TW. Cytokines and cardiac contractile function. Circulation.1997 Feb 18;95(4):778-81. Review.
[69]Kim SH, Azam T, Novick D, et al. Identification of amino acid residues critical for biological activity in human interleukin-18. J Biol Chem.2002 Mar 29;277(13):10998-1003.
[70]Kim SH, Eisenstein M, Reznikov L, et al. Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci USA.2000 Feb 1;97(3):1190-5.
[71]Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol.2007;27(1):15-26.
[72]Kohka H, Yoshino T, Iwagaki H, et al. Interleukin-18/interferon-gamma-inducing factor, a novel cytokine, up-regulates ICAM-1 (CD54) expression in KG-1 cells. J Leukoc Biol.1998 Oct;64(4):519-27.
[73]Kohno K, Kataoka, Ohtsuki T, et al. IFN-gamma-inducing factor(IGIF) is a costimulatory factor on the activiation of Thl but not Th2 cells and exerts its effect independently of IL-12. J Immunol.1997,158(4):1541-1550
[74]Kojima H, Takeuchi M, Ohta T, et al. Interleukin-18 activates the IRAK-TRAF6 pathway in mouse EL-4 cells. Biochem Biophys Res Commun.1998 Mar 6;244(1):183-6.
[75]Konopleva M, Zhao S, Xie Z, et al. Apoptosis. Molecules and mechanisms. Adv Exp Med Biol. 1999;457:217-36.
[76]Leite-de-Moraes MC, Herbelin A, Gouarin C, et al. Fas/Fas ligand interactions promote activation-induced cell death of NK T lymphocytes. J Immunol.2000 Oct 15;165(8):4367-71.
[77]Li C, Zhang XL, Liu H, et al. Association among plasma interleukin-18 levels, carotid intima-media thickness and severity of obstructive sleep apnea. Chin Med J (Engl).2009 Jan 5;122(1): 24-9.
[78]Li DY, Chen HJ, Staples ED, et al. Oxidized low-density lipoprotein receptor LOX-1 and apoptosis in human atherosclerotic lesions. J Cardiovasc Pharmacol Ther. 2002 Jul;7(3):147-53.
[79]Li S, Jiao X, Tao L, et al. Tumor necrosis factor-alpha in mechanic trauma plasma mediates cardiomyocyte apoptosis. Am J Physiol Heart Circ Physiol.2007 Sep;293(3):H1847-52.
[80]Li JM, Eslami MH, Rohrer MJ, et al. Interleukin 18 binding protein (IL18-BP) inhibits neointimal hyperplasia after balloon injury in an atherosclerotic rabbit model. J Vasc Surg.2008 May;47(5):1048-57.
[81]Liao B, McCall E, Cox K, et al. Circulating Markers Reflect Both Anti-and Pro-Atherogenic Drug Effects in ApoE-Deficient Mice. Biomark Insights.2008 Mar 12;3:147-157.
[82]Libby P. Inflammation in atherosclerosis. Nature.2002;420:868-874.
[83]Liao X, Liu JM, Du L, Tang A, et bal. Nitric oxide signaling in stretch-induced apoptosis of neonatal rat cardiomyocytes. FASEB J.2006 Sep;20(11):1883-5.
[84]Liu W, Tang Q, Jiang H, et al. Promoter polymorphism of interleukin-18 in angiographically proven coronary artery disease. Angiology.2009 Apr-May;60(2):180-5.
[85]Luft FC. Angiotensin, inflammation, hypertension, and cardiovascular disease. Curr Hypertens Rep.2001; 3:61-67.
[86]Lusis AJ. Atherosclerosis. Nature.2000;407(6801):233-241.
[87]Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation.2001 Oct 2;104(14):1598-603.
[88]Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res.2001 Sep 28;89(7):E41-5.
[89]Mallat Z, Henry P, Fressonnet R, et al. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart.2002 Nov;88(5):467-9.
[90]Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res.2001,89(7):e41-e45
[91]Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation.2001 Oct 2;104(14):1598-603.
[92]Mallat Z, Heymes C, Corbaz A, et al. Evidence for altered interleukin 18 (IL)-18 pathway in human heart failure. FASEB J.2004 Nov; 18(14):1752-4.
[93]Mallat Z, Silvestre JS, Le Ricousse-Roussanne S, et al. Interleukin-18/interleukin-18 binding protein signaling modulates ischemia-induced neovascularization in mice hindlimb. Circ Res. 2002 Sep6;91(5):441-8.
[94]Manigold T, Bocker U, Traber P, et al. Lipopolysaccharide/endotoxin induces IL-18 via CD14 in human peripheral blood mononuclear cells in vitro. Cytokine.2000 Dec;12(12):1788-92.
[95]Marino E, Cardier JE. Differential effect of IL-18 on endothelial cell apoptosis mediated by TNF-alpha and Fas (CD95). Cytokine.2003 Jun 7;22(5):142-8.
[96]Martin TJ, Romas E, Gillespie MT. Interleukins in the control of osteoclast differentiation. Crit Rev Eukaryot Gene Expr.1998;8(2):107-23. Review.
[97]Matsui Y, Jia N, Okamoto H, et al. Role of osteopontin in cardiac fibrosis and remodeling in angiotensin Ⅱ-induced cardiac hypertrophy. Hypertension.2004 Jun;43(6):1195-201.
[98]Meldrum DR:Tumor necrosis factor in the heart. Am J Physiol.1998 Mar;274(3 Pt 2):R577-95; Review.
[99]Melnikov VY, Ecder T, Fantuzzi G, et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest.2001 May; 107(9):1145-52.
[100]Mitsuoka H, Kume N, Hayashida K, et al. Interleukin 18 stimulates release of soluble lectin-like oxidized LDL receptor-1 (sLOX-1). Atherosclerosis.2009 Jan;202(1):176-82.
[101]Morel JC, Park CC, Woods JM, Koch AE. A novel role for interleukin-18 in adhesion molecule induction through NF kappa B and phosphatidylinositol (PI) 3-kinase-dependent signal transduction pathways. J Biol Chem.2001 Oct 5;276(40):37069-75.
[102]Morel JC, Park CC, Zhu K, et al. Signal transduction pathways involved in rheumatoid arthritis synovial fibroblast interleukin-18-induced vascular cell adhesion molecule-1 expression. J Biol Chem.2002 Sep 20;277(38):34679-91.
[103]Morito N,Inoue Y, Urata M, et al. Increased carotid artery plaque score is an independent predictor of the presence and severity of coronary artery disease. J Cardiol.2008 Feb;51(1):25-32.
[104]Mousa A, Al-Zaki A, Taha S, Bakhiet M. Induction of interleukin-18 in atherosclerotic patients: a role for Chlamydia pneumoniae. Med Princ Pract.2009;18(2):105-10.
[105]Naito Y, Tsujino T, Fujioka Y, et al. Increased circulating interleukin-18 in patients with congestive heart failure. Heart.2002 Sep;88(3):296-7.
[106]Nakamura K, Okamura H, Wada M, et al. Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun.1989 Feb;57(2):590-5.
[107]Nakamura K, Okamura H, Nagata K, et al. Purification of a factor which provides a costimulatory signal for gamma interferon production. Infect Immun.1993 Jan;61(1):64-70.
[108]Netea MG, Fantuzzi G, Kullberg BJ, et al. Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia. J Immunol.2000 Mar 1;164(5):2644-9.
[109]Netea MG, Kullberg BJ, Verschueren I, et al. Interleukin-18 induces production of proinflammatory cytokines in mice:no intermediate role for the cytokines of the tumor necrosis factor family and interleukin-lbeta. Eur J Immunol.2000 Oct;30(10):3057-60.
[110]Novick D, Schwartsburd B, Pinkus R, et al. A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. Cytokine.2001 Jun 21;14(6):334-42.
[111]Oberholzer A, Steckholzer U, Kurimoto M, et al. Interleukin-18 plasma levels are increased in patients with sepsis compared to severely injured patients. Shock.2001 Dec;16(6):411-4.
[112]Okamura H, Nagata K, Komatsu T, et al. A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock. Infect Immun.1995 Oct;63(10):3966-72.
[113]Okamura H, Tsutsi H, Komatsu T, et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature.1995 Nov 2;378(6552):88-91.
[114]Okamura H, Tsutsui H, Kashiwamura S, et al. Interleukin-18:a novel cytokine that augments both innate and acquired immunity. Adv Immunol.1998;70:281-312.
[115]Olee T, Hashimoto S, Quach J, Lotz M. IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. J Immunol.1999 Jan 15; 162(2):1096-100.
[116]O'Neill PJ, Ayala A, Wang P, et al. Role of Kupffer cells in interleukin-6 release following trauma-hemorrhage and resuscitation. Shock.1994 Jan;1(1):43-7.
[117]Panafidina TA, Popkova TV, Alekberova ZS, et al. [Interleukin-18 in systemic lupus erythematosus:link with clinical symptoms and vascular atherosclerosis]. Ter Arkh. 2008;80(5):41-6. [Article in Russian]
[118]Park CC, Morel JC, Amin MA, et al. Evidence of IL-18 as a novel angiogenic mediator. J Immunol.2001 Aug 1;167(3):1644-53.
[119]Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease:application to clinical and public health practice:a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation,2003,107(3):499-511.
[120]Pei F, Han Y, Zhang X, Yan C, et al. Association of interleukin-18 gene promoter polymorphisms with risk of acute myocardial infarction in northern Chinese Han population. Clin Chem Lab Med.2009;47(5):523-9.
[121]Pomerantz BJ, Reznikov LL, Harken AH, Dinarello CA. Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-lbeta. Proc Natl Acad Sci USA.2001 Feb 27;98(5):2871-6.
[122]Puren AJ, Fantuzzi G, Dinarello CA. Gene expression, synthesis, and secretion of interleukin 18 and interleukin lbeta are differentially regulated in human blood mononuclear cells and mouse spleen cells. Proc Natl Acad Sci USA.1999 Mar 2;96(5):2256-61.
[123]Puren AJ, Fantuzzi G, Gu Y, Su MS, Dinarello CA. Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-lbeta via TNFalpha production from non-CD 14+human blood mononuclear cells. J Clin Invest.1998 Feb 1;101(3):711-21.
[124]Puren AJ, Razeghi P, Fantuzzi G, Dinarello CA. Interleukin-18 enhances lipopolysaccharide-induced interferon-gamma production in human whole blood cultures. J Infect Dis.1998 Dec; 178(6):1830-4.
[125]Rabkin SW. The role of interleukin 18 in the pathogenesis of hypertension-induced vascular disease. Nat Clin Pract Cardiovasc Med.2009 Mar;6(3):192-9.
[126]Raeburn CD, Dinarello CA, Zimmerman MA, et al. Neutralization of IL-18 attenuates lipopolysaccharide-induced myocardial dysfunction. Am J Physiol Heart Circ Physiol.2002 Aug;283(2):H650-7.
[127]Reddy P. Interleukin-18:recent advances. Curr Opin Hematol.2004 Nov;11(6):405-10.
[128]Reddy VS, Harskamp RE, van Ginkel MW, et al. Interleukin-18 stimulates fibronectin expression in primary human cardiac fibroblasts via PI3K-Akt-dependent NF-kappaB activation. J Cell Physiol.2008 Jun;215(3):697-707.
[129]Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med.1999,340(2):1 15-126.
[130]Ruotsalainen E, Vauhkonen I, Salmenniemi U, et al. Markers of endothelial dysfunction and low-grade inflammation are associated in the offspring of type 2 diabetic subjects. Atherosclerosis.2008 Mar;197(1):271-7.
[131]Sahar S, Dwarakanath RS, Reddy MA, et al. Angiotensin II enhances interleukin-18 mediated inflammatory gene expression in vascular smooth muscle cells:a novel cross-talk in the pathogenesis of atherosclerosis. Circ Res.2005 May 27;96(10):1064-71.
[132]Saito Y, Berk BC. Angiotensin II-mediated signal transduction pathways. Curr Hypertens Rep. 2002;4:167-171.
[133]Samnegard A, Hulthe J, Silveira A, et al. Gender specific associations between matrix metalloproteinases and inflammatory markers in post myocardial infarction patients. Atherosclerosis.2009 Feb;202(2):550-6.
[134]Seki E, Tsutsui H, Nakano H, et al. Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta. J Immunol.2001 Feb 15;166(4):2651-7.
[135]Seta Y, Kanda T, Tanaka T, et al. Interleukin-18 in patients with congestive heart failure: induction of atrial natriuretic peptide gene expression. Res Commun Mol Pathol Pharmacol. 2000Jul-Aug;108(1-2):87-95.
[136]Seta Y, Kanda T, Tanaka T, et al. Interleukin 18 in acute myocardial infarction. Heart.2000 Dec;84(6):668.
[137]Simms MG, Walley KR. Activated macrophages decrease rat cardiac myocyte contractility: importance of ICAM-1-dependent adhesion. Am J Physiol.1999 Jul;277(1 Pt 2):H253-60.
[138]Song H, Hur DY, Kim KE, et al. IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. Cell Immunol.2006 JuI;242(1):39-45.
[139]Souza JR, Oliveira RT, Blotta MH, Coelho OR. Serum levels of interleukin-6 (11-6), interleukin-18 (I1-18) and C-reactive protein (CRP) in patients with type-2 diabetes and acute coronary syndrome without ST-segment elevation. Arq Bras Cardiol.2008 Feb;90(2):86-90.
[140]Steinbrugger I, Haas A, Maier R, et al. Analysis of inflammation-and atherosclerosis-related gene polymorphisms in branch retinal vein occlusion. Mol Vis.2009;15:609-18.
[141]Stoll S, Muller G, Kurimoto M, et al. Production of IL-18 (IFN-gamma-inducing factor) messenger RNA and functional protein by murine keratinocytes. J Immunol.1997 Jul 1;159(1):298-302.
[142]Stoll S, Jonuleit H, Schmitt E, et al. Production of functional IL-18 by different subtypes of murine and human dendritic cells (DC):DC-derived IL-18 enhances IL-12-dependent Th1 development. Eur J Immunol.1998 Oct;28(10):3231-9.
[143]Suchanek H, Mysliwska J, Siebert J, et al. High serum interleukin-18 concentrations in patients with coronary artery disease and type 2 diabetes mellitus. Eur Cytokine Netw.2005 Sep;16(3):177-85.
[144]Takeuchi M, Nishizaki Y, Sano O, et al. Immunohistochemical and immuno-electron-microscopic detection of interferon-gamma-inducing factor ("interleukin-18") in mouse intestinal epithelial cells. Cell Tissue Res.1997 Sep;289(3):499-503.
[145]Takeuchi D, Yoshidome H, Kato A, et al. Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice. Hepatology.2004 Mar; 39(3):699-710.
[146]Tao L, Gao E, Jiao X, et al. Adiponectin cardioprotection after myocardial ischemia/ reperfusion involves the reduction of oxidative/nitrative stress. Circulation.2007 Mar 20; 115(11):1408-16.
[147]Tan HW, Liu X, Bi XP, et al. IL-18 overexpression promotes vascular inflammation and remodeling in a rat model of metabolic syndrome. Atherosclerosis.2009 Aug 7. [Epub ahead of print] PMID:19717152
[148]Tenger C, Sundborger A, Jawien J, et al. IL-18 accelerate atherosclerosis accompanied by elevation of IFN-gamma and CXCL16 expression independently of T cells. Arterioscler Thromb Vase Biol.2005,25(4):791-796
[149]Thompson SR, McCaskie PA, Beilby JP, et al. IL18 haplotypes are associated with serum IL-18 concentrations in a population-based study and a cohort of individuals with premature coronary heart disease. Clin Chem.2007 Dec;53(12):2078-85.
[150]Thompson SR, Novick D, Stock CJ, et al. Free Interleukin (IL)-18 levels, and the impact of IL18 and IL18BP genetic variation, in CHD patients and healthy men. Arterioscler Thromb Vasc Biol.2007 Dec;27(12):2743-9.
[151]Thompson SR, Sanders J, Stephens JW, et al. A common interleukin 18 haplotype is associated with higher body mass index in subjects with diabetes and coronary heart disease. Metabolism. 2007 May;56(5):662-9.
[152]Tone M, Thompson SA, Tone Y, et al. Regulation of IL-18 (IFN-gamma-inducing factor) gene expression. J Immunol.1997 Dec 15;159(12):6156-63.
[153]Torigoe K, Ushio S, Okura T, et al. Purification and characterization of the human interleukin-18 receptor. J Biol Chem.1997 Oct 10;272(41):25737-42.
[154]Tr(?)seid M, Arnesen H, Hjerkinn EM, Seljeflot I. Serum levels of interleukin-18 are reduced by diet and n-3 fatty acid intervention in elderly high-risk men. Metabolism.2009 Jul 10. [Epub ahead of print] PMID:19595382
[155]Tschoeke SK, Oberholzer A, Moldawer LL. Interleukin-18:a novel prognostic cytokine in bacteria-induced sepsis. Crit Care Med.2006 Apr;34(4):1225-33. Review.
[156]Tsutsui H, Nakanishi K, Matsui K, et al. IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones. J Immunol.1996 Nov 1;157(9):3967-73.
[157]Tziakas DN, Chalikias GK, Kaski JC, et al. Inflammatory and anti-inflammatory variable clusters and risk prediction in acute coronary syndrome patients:a factor analysis approach. Atherosclerosis.2007 Jul;193(1):196-203.
[158]Ueno N, Kashiwamura S, Ueda H, et al. Role of interleukin 18 in nitric oxide production and pancreatic damage during acute pancreatitis. Shock.2005 Dec;24(6):564-70.
[159]Ushio S, Namba M, Okura T, et al. Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J Immunol.1996 Jun 1;156(11):4274-9.J Immunol.1996 Jun 1;156(11):4274-9.
[160]Venkatesan B, Valente AJ, Reddy VS, et al. Resveratrol blocks interleukin-18-EMMPRIN cross-regulation and smooth muscle cell migration. Am J Physiol Heart Circ Physiol.2009 Aug;297(2):H874-86.
[161]Vidal-Vanaclocha F, Fantuzzi G, Mendoza L, et al. IL-18 regulates IL-1 beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1. Proc Natl Acad Sci USA.2000 Jan 18;97(2):734-9.
[162]Wald D, Qin J, Zhao Z, et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol.2003 Sep;4(9):920-7.
[163]Wang M, Markel T, Crisostomo P, et al. Deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1 beta. Am J Physiol Heart Circ Physiol.2007 Apr;292(4):H1694-9.
[164]Wang M, Markel TA, Meldrum DR. Interleukin 18 in the heart. Shock.2008 Jul;30(1):3-10. Review.
[165]Welsh P, Woodward M, Rumley A, Lowe G Associations of circulating TNFalpha and IL-18 with myocardial infarction and cardiovascular risk markers:the Glasgow Myocardial Infarction Study. Cytokine.2009 Aug;47(2):143-7.
[166]Whitman SC, Ravisankar P, Daugherty A. Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res.2002 Feb 8;90(2):E34-8.
[167]Wigginton JM, Lee JK, Wiltrout TA, et al. Synergistic engagement of an ineffective endogenous anti-tumor immune response and induction of IFN-gamma and Fas-ligand-dependent tumor eradication by combined administration of IL-18 and IL-2. J Immunol.2002 Oct 15;169(8):4467-74.
[168]Woldbaek PR, Sande JB, Stromme TA, et al. Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice. Am J Physiol Heart Circ Physiol.2005 Aug;289(2): H708-14.
[169]Woldbaek PR, Tonnessen T, Henriksen UL, et al. Increased cardiac IL-18 mRNA, pro-IL-18 and plasma IL-18 after myocardial infarction in the mouse; a potential role in cardiac dysfunction. Cardiovasc Res.2003 Jul 1;59(1):122-31.
[170]Wyman TH, Dinarello CA, Banerjee A, et al. Physiological levels of interleukin-18 stimulate multiple neutrophil functions through p38 MAP kinase activation. J Leukoc Biol.2002 Aug;72(2):401-9.
[171]Xia Y, Roman LJ, Masters BS, Zweier JL. Inducible nitric-oxide synthase generates superoxide from the reductase domain. J Biol Chem.1998 Aug 28;273(35):22635-9.
[172]Xia Y, Zweier JL. Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci USA.1997 Jun 24;94(13):6954-8.
[173]Xu D, Trajkovic V, Hunter D, et al. IL-18 induces the differentiation of Thl or Th2 cells depending upon cytokine milieu and genetic background. Eur J Immunol.2000 Nov;30(11):3147-56.
[174]Yamaoka-Tojo M, Tojo T, Inomata T, et al. Circulating levels of interleukin 18 reflect etiologies of heart failure:Thl/Th2 cytokine imbalance exaggerates the pathophysiology of advanced heart failure. J Card Fail.2002 Feb;8(1):21-7.
[175]Yang S, Hu S, Hsieh YC, et al. Mechanism of IL-6-mediated cardiac dysfunction following trauma-hemorrhage. J Mol Cell Cardiol.2006 Apr;40(4):570-9.
[176]Yang S, Zheng R, Hu S, et al. Mechanism of cardiac depression after trauma-hemorrhage: increased cardiomyocyte IL-6 and effect of sex steroids on IL-6 regulation and cardiac function. Am J Physiol Heart Circ Physiol.2004 Nov;287(5):H2183-91.
[177]Yang S, Hu S, Choudhry MA, et al. Anti-rat soluble IL-6 receptor antibody down-regulates cardiac IL-6 and improves cardiac function following trauma-hemorrhage. J Mol Cell Cardiol. 2007 Mar;42(3):620-30.
[178]Ye XJ, Tang B, Ma Z, et al. The effects of interleukin-18 on rat articular chondrocytes:a study of mRNA expression and protein synthesis of proinflammatory substances. Clin Exp Immunol. 2007Sep;149(3):553-60.
[179]Yearley JH, Xia D, Pearson CB, Carville A, et al. Interleukin-18 predicts atherosclerosis progression in SIV-infected and uninfected rhesus monkeys (Macaca mulatta) on a high-fat/high-cholesterol diet. Lab Invest.2009 Jun;89(6):657-67.
[180]Yoshida A, Kand T, Tanaka T, et al. Interleukin-18 reduces expression of cardiac tumor necrosis factor-alpha and atrial natriuretic peptide in a murine model of viral myocarditis. Life Sci.2002 Feb 1;70(11):1225-34.
[181]Yoo JK, Kwon H, Khil LY, et al. IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways. J Immunol.2005 Dec 15;175(12):8280-6.
[182]Yoshimoto T, Min B, Sugimoto T, et al. Nonredundant roles for CD1d-restricted natural killer T cells and conventional CD4+T cells in the induction of immunoglobulin E antibodies in response to interleukin 18 treatment of mice. J Exp Med.2003 Apr 21;197(8):997-1005.
[183]Yoshimoto T, Mizutani H, Tsutsui H, et al. IL-18 induction of IgE:dependence on CD4+T cells, IL-4 and STAT6. Nat Immunol.2000 Aug; 1(2):132-7.
[184]Yoshimoto T, Okamura H, Tagawa YI, et al. Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-gamma production from activated B cells. Proc Natl Acad Sci USA.1997 Apr 15;94(8):3948-53.
[185]Yoshimoto T, Tsutsui H, Tominaga K, et al. IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils. Proc Natl Acad Sci USA. 1999 Nov 23;96(24):13962-6.
[186]Yu Q, Vazquez R, Khojeini EV, et al. IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice. Am J Physiol Heart Circ Physiol.2009 Jul;297(1):H76-85.
[187]Zirlik A, Abdullah SM, Gerdes N, et al. Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis:results from the Dallas Heart Study. Arterioscler Thromb Vasc Biol. 2007 Sep;27(9):2043-9.