Excess TNF-α in the blood activates monocytes with the potential to directly form cholesteryl ester-laden cells.
Excess TNF-α in the blood activates monocytes with the potential to directly form cholesteryl ester-laden cells.
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DOI：
10.1093/abbs/gmv092
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发表时间：
2015-11
影响因子：
3.7
通讯作者：
M. Zhu;L. Lei;Zhenhua Zhu;Qin Li;Dongqing Guo;Jiajia Xu;Jia Chen;H. Sha;Xiaowei Zhang;Xinying Yang;B. Song;Bo-Liang Li;Yan Yan-Yan;Ying Xiong
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文献类型：
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作者：
M. Zhu;L. Lei;Zhenhua Zhu;Qin Li;Dongqing Guo;Jiajia Xu;Jia Chen;H. Sha;Xiaowei Zhang;Xinying Yang;B. Song;Bo-Liang Li;Yan Yan-Yan;Ying Xiong
肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）和单核细胞在动脉粥样硬化（atherosclerosis，AS）的发生、发展中起重要作用，是冠心病（coronary heart disease，CHD）的主要病因。在这项工作中，我们研究了过量的TNF-α对血液中单核细胞的影响，并发现来自CHD患者的血液单核细胞在体外与oxLDL孵育下具有直接形成胆固醇酯（CE）负载细胞的潜力。CHD患者血浆TNF-α、IL-6、CRP水平均显著高于健康对照组。然而，只有TNF-α的血浆水平，而不是IL-6或CRP，与血液单核细胞直接形成CE负载细胞的潜力呈正相关。用人血单核细胞和单核细胞THP-1细胞证实了TNF-α对载CE细胞形成的激活作用，这种激活作用可被抗TNF-α抗体特异性阻断。TNF-α可通过增强单核细胞功能性粘附分子和清道夫受体的表达，促进单核细胞粘附和oxLDL摄取。最后，小鼠模型的体内和体外实验结果证实，血液中过量的TNF-α可激活单核细胞，并有可能直接形成载有CE的细胞。这些数据表明，血液中过量的TNF-α是动脉粥样硬化和CHD发展的主要触发因素。
The tumor necrosis factor-α (TNF-α) and monocytic cells play a critical role in the development of atherosclerosis, which is the major cause of coronary heart disease (CHD). In this work, we investigated the effect of excess TNF-α on monocytes in the blood and found that blood monocytes from the CHD patients had the potential to directly form cholesteryl ester (CE)-laden cells under the in vitro incubation with oxLDL. The plasma levels of proinflammatory cytokines, such as TNF-α, interleukin 6 (IL-6), and C reactive protein (CRP), in the CHD patients were significantly higher than those in the control healthy volunteers. However, only the plasma level of TNF-α, but not of IL-6 or CRP, is positively correlated with the potential of blood monocytes to directly form CE-laden cells. By using human blood monocytes and monocytic THP-1 cells, the activating effect of TNF-α on the formation of the CE-laden cells was demonstrated, which could be specifically blocked by the anti-TNF-α antibody. Furthermore, it was also revealed that TNF-α could boost adhesion and oxLDL uptake of the monocytes by enhancing the expression of the functional adhesion molecules and scavenger receptors, respectively. Finally, the results of in vivo and in vitro experiments with a mouse model confirmed that excess TNF-α in the blood activates monocytes with the potential to directly form CE-laden cells. These data demonstrate that excess TNF-α in the blood is the primary trigger for the development of atherosclerosis and CHD.