Inflammatory responses associated with acute coronary syndrome up-regulate IRAK-M and induce endotoxin tolerance in circulating monocytes
Inflammatory responses associated with acute coronary syndrome up-regulate IRAK-M and induce endotoxin tolerance in circulating monocytes
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DOI：
10.1177/0968051907078623
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Lopez-Collazo, Eduardo
中科院分区：
文献类型：
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作者：
del Fresno, Carlos;Soler-Rangel, Llanos;Lopez-Collazo, Eduardo
急性冠状动脉综合征（ACS）是一组不同的心脏疾病，其发展与炎症有关。在这里，我们分析了炎症细胞因子和TLR/IRAK通路成员（包括IRAK-M）在ACS患者单核细胞中的水平，ACS患者分为UA（不稳定型心绞痛）、STEMI（ST段抬高型心肌梗死）或NSTEMI（非ST段抬高型心肌梗死）。来自所有患者但不是来自健康个体的循环单核细胞显示出高水平的促炎细胞因子TNF-α和IL-6以及IRAK-M和IL-10。TLR 4也上调，但IRAK-1，IRAK-4和MyD 88水平在患者和对照组中相似。此外，我们研究了细胞因子/IRAK-M表达对内毒素先天免疫应答的影响。与对照组相比，患者单核细胞对LPS的体外反应明显减弱。在补充培养基（10%来自ACS患者的血清）中培养6小时的对照单核细胞表达IRAK-M，并且LPS刺激未能在这些培养物中诱导TNF-α和IL-6。血清与阻断性抗TNF-α抗体的预孵育降低了这种内毒素耐受作用，表明TNF-α至少部分地控制了这种现象。我们第一次表明，与ACS相关的炎症反应诱导循环单核细胞对内毒素攻击的无反应状态，这与IRAK-M，TLR 4和IL-10的表达相关。这种反应的幅度根据临床状况（UA，STEMI或NSTEMI）而变化，并受TNF-α调节。
Acute coronary syndrome (ACS) groups different cardiac diseases whose development is associated with inflammation. Here we have analyzed the levels of inflammatory cytokines and of members of the TLR/IRAK pathway including IRAK-M in monocytes from ACS patients classified as either UA (unstable angina), STEMI (ST elevation myocardial infarction) or NSTEMI (non-ST-elevation myocardial infarction). Circulating monocytes from all patients, but not from healthy individuals, showed high levels of pro-inflammatory cytokines, TNF-a and IL-6, as well as of IRAK-M and IL10. TLR4 was also up-regulated, but IRAK-1, IRAK-4 and MyD88 levels were similar in patients and controls. Further, we investigated the consequences of cytokines/IRAK-M expression on the innate immune response to endotoxin. Ex vivo responses to LPS were markedly attenuated in patient monocytes compared to controls. Control monocytes cultured for 6 h in supplemented medium (10% serum from ACS patients) expressed IRAK-M, and LPS stimulation failed to induce TNF-a and IL-6 in these cultures. Pre-incubation of the serum with a blocking anti-TNF-a antibody reduced this endotoxin tolerance effect, suggesting that TNF-alpha controls this phenomenon, at least partially. We show for the first time that inflammatory responses associated with ACS induce an unresponsiveness state to endotoxin challenge in circulating monocytes, which correlates with expression of IRAK-M, TLR4 and IL-10. The magnitude of this response varies according to the clinical condition (UA, STEMI or NSTEMI), and is regulated by TNF-alpha.