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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Canonical pathway of nuclear factor κB activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis
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Canonical pathway of nuclear factor κB activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis

机译：核因子κB激活的典型途径选择性调节人动脉粥样硬化的促炎和血栓形成反应

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摘要

Nuclear factor κB (NF-κB) activation has been observed in human atherosclerotic plaques and is enhanced in unstable coronary plaques, but whether such activation has a protective or patho-physiological role remains to be determined. We addressed this question by developing a short-term culture system of cells isolated from human atherosclerotic tissue, allowing efficient gene transfer to directly investigate signaling pathways in human atherosclerosis. We found that NF-κB is activated in these cells and that this activity involves p65, p50, and c-Rel but not p52 or RelB. This NF-κB activation can be blocked by overexpression of IκBα or dominant-negative IκB kinase (IKK)-2 but not dominant-negative IKK-1 or NF-κB-inducing kinase, resulting in selective inhibition of inflammatory cytokines (tumor necrosis factor α, IL-6, and IL-8), tissue factor, and matrix metalloproteinases without affecting the antiinflammatory cytokine IL-10 or tissue inhibitor of matrix metalloproteinases. Our results demonstrate that the canonical pathway of NF-κB activation that involves p65, p50, c-Rel, and IKK-2 is activated in human atherosclerosis and results in selective up-regulation of major proinflammatory and prothrombotic mediators of the disease.
机译：在人的动脉粥样硬化斑块中已经观察到核因子κB（NF-κB）的活化，在不稳定的冠状动脉斑块中核转录因子κB（NF-κB）的活化得到增强，但是这种活化是否具有保护作用或病理生理作用尚待确定。我们通过开发从人动脉粥样硬化组织分离的细胞的短期培养系统解决了这个问题，允许有效的基因转移直接研究人动脉粥样硬化中的信号传导途径。我们发现NF-κB在这些细胞中被激活，并且该活性涉及p65，p50和c-Rel，但不涉及p52或RelB。这种NF-κB激活可以被IκBα或显性负IκB激酶（IKK）-2的过表达所阻断，而不是显性负IKK-1或NF-κB诱导激酶的过表达，从而导致炎性细胞因子（肿瘤坏死因子）的选择性抑制。 α，IL-6和IL-8），组织因子和基质金属蛋白酶，而不会影响抗炎细胞因子IL-10或基质金属蛋白酶的组织抑制剂。我们的结果表明，涉及p65，p50，c-Rel和IKK-2的NF-κB激活的经典途径在人的动脉粥样硬化中被激活，并导致该疾病的主要促炎和血栓形成介质选择性上调。

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