Low doses of lipopolysaccharide and minimally oxidized low-density lipoprotein cooperatively activate macrophages via nuclear factor kappa B and activator protein-1: possible mechanism for acceleration of atherosclerosis by subclinical endotoxemia.
Low doses of lipopolysaccharide and minimally oxidized low-density lipoprotein cooperatively activate macrophages via nuclear factor kappa B and activator protein-1: possible mechanism for acceleration of atherosclerosis by subclinical endotoxemia.
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DOI：
10.1161/circresaha.110.218420
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发表时间：
2010-07-09
影响因子：
20.1
通讯作者：
Miller YI
中科院分区：
文献类型：
--
作者：
Wiesner P;Choi SH;Almazan F;Benner C;Huang W;Diehl CJ;Gonen A;Butler S;Witztum JL;Glass CK;Miller YI
氧化低密度脂蛋白（LDL）是动脉粥样硬化病变中炎症的重要决定因素。也有文献表明，某些慢性传染病，如牙周炎和衣原体感染，会加剧动脉粥样硬化的临床表现。此外，低水平但持续的代谢性内毒素血症常见于糖尿病和肥胖受试者，并在喂食高脂肪饮食的小鼠中引起。在这项研究中，我们通过低水平的细菌LPS和最低氧化LDL （mmLDL）检测巨噬细胞的协同活化，作为亚临床内毒素血症并发动脉粥样硬化的模型。我们发现，在体外和体内，mmLDL和LPS （Kdo2-LipidA）协同激活巨噬细胞表达促炎细胞因子Cxcl2 （MIP-2）、Ccl3 （mip -1 α）和Ccl4 （mip -1 β）。重要的是，在阈值LPS浓度（1 ng/ml）下，mmLDL和LPS的协同效应是明显的，LPS仅诱导有限的巨噬细胞反应。使用从头基序发现算法分析微阵列数据，我们发现含有AP-1结合位点的启动子转录的基因在mmLDL和LPS的共同刺激下显着上调。在核因子-DNA结合实验中，mmLDL和LPS共同刺激对c-Jun和c-Fos DNA结合的协同作用，而不是对p65或p50的协同作用，依赖于mmLDL诱导的ERK1/2激活。此外，mmLDL通过去除趋化因子启动子中的共抑制因子NCoR，诱导jnk依赖性AP-1的下调。mmLDL和LPS对AP-1和NF-kappaB的协同作用可能构成了动脉粥样硬化病变中炎症细胞因子转录增加的机制。
Oxidized low-density lipoprotein (LDL) is an important determinant of inflammation in atherosclerotic lesions. It has also been documented that certain chronic infectious diseases, such as periodontitis and chlamydial infection, exacerbate clinical manifestations of atherosclerosis. In addition, low-level but persistent metabolic endotoxemia is often found in diabetic and obese subjects and is induced in mice fed a high-fat diet. In this study, we examined cooperative macrophage activation by low levels of bacterial LPS and by minimally oxidized LDL (mmLDL), as a model for subclinical endotoxemia-complicated atherosclerosis. We found that both in vitro and in vivo, mmLDL and LPS (Kdo2-LipidA) cooperatively activated macrophages to express pro-inflammatory cytokines Cxcl2 (MIP-2), Ccl3 (MIP-1alpha), and Ccl4 (MIP-1beta). Importantly, the mmLDL and LPS cooperative effects were evident at a threshold LPS concentration (1 ng/ml) at which LPS alone induced only a limited macrophage response. Analyzing microarray data with a de novo motif discovery algorithm, we found that genes transcribed by promoters containing an AP-1 binding site were significantly upregulated by co-stimulation with mmLDL and LPS. In a nuclear factor-DNA binding assay, the cooperative effect of mmLDL and LPS co-stimulation on c-Jun and c-Fos DNA binding, but not on p65 or p50, was dependent on mmLDL-induced activation of ERK1/2. In addition, mmLDL induced JNK-dependent derepression of AP-1 by removing the corepressor NCoR from the chemokine promoters. The cooperative engagement of AP-1 and NF-kappaB by mmLDL and LPS may constitute a mechanism of increased transcription of inflammatory cytokines within atherosclerotic lesions.