TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation
TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation
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DOI：
10.1194/jlr.m800484-jlr200
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发表时间：
2009-06-01
影响因子：
6.5
通讯作者：
Li, Bo-Liang
中科院分区：
文献类型：
--
作者：
Lei, Lei;Xiong, Ying;Li, Bo-Liang
动脉粥样硬化病变中存在高水平的炎性细胞因子肿瘤坏死因子-α（TNF-α）。TNF-α调节参与动脉粥样硬化不同阶段的多个基因的表达，并且它表现出促动脉粥样硬化和抗动脉粥样硬化特性。ACAT催化单核/巨噬细胞胆固醇酯（CE）的形成，促进动脉粥样硬化早期泡沫细胞的形成。我们推测TNF-α可能参与调节单核细胞/巨噬细胞中ACAT基因的表达。在这篇文章中，我们表明，在培养的，分化的人单核细胞，TNF-α增强ACAT 1，但不是ACAT 2基因的表达，增加胆固醇酯的积累，并促进脂质负载细胞的形成。测试的几种其他促炎细胞因子不影响ACAT 1基因表达。刺激作用与受体依赖性过程一致，并且通过使用核因子-κ B（NF-κ B）抑制剂来阻断。需要位于人ACAT 1基因近端启动子内的功能性和独特的NF-κ B元件来介导TNF-α的作用。我们的数据表明，TNF-α，通过NF-κ B途径，特异性地增强人ACAT 1基因的表达，以促进分化中的单核细胞形成CE负载细胞，并且我们的数据支持TNF-α在病变发展的早期阶段是促动脉粥样硬化的假设。Lei，L.，Y. Xiong，J. Chen，J-B. Yang，Y. Wang，X-Y.杨角，澳-地C. Y. Chang，B-L.宋，T-Y。Chang和B-L.李TNF-α刺激分化中的单核细胞中的ACAT 1表达以促进载有CE的细胞形成。J. Lipid Res. 2009. 50：1057-1067。
High levels of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are present in atherosclerotic lesions. TNF-alpha regulates expression of multiple genes involved in various stages of atherosclerosis, and it exhibits proatherosclerotic and antiatherosclerotic properties. ACAT catalyzes the formation of cholesteryl esters (CE) in monocytes/macrophages, and it promotes the foam cell formation at the early stage of atherosclerosis. We hypothesize that TNF-alpha may be involved in regulating the ACAT gene expression in monocytes/macrophages. In this article, we show that in cultured, differentiating human monocytes, TNF-alpha enhances the expression of the ACAT1 but not ACAT2 gene, increases the cholesteryl ester accumulation, and promotes the lipid-laden cell formation. Several other proinflammatory cytokines tested do not affect the ACAT1 gene expression. The stimulation effect is consistent with a receptor-dependent process, and is blocked by using nuclear factor-kappa B (NF-kappa B) inhibitors. A functional and unique NF-kappa B element located within the human ACAT1 gene proximal promoter is required to mediate the action of TNF-alpha. Our data demonstrate that TNF-alpha, through the NF-kappa B pathway, specifically enhances the expression of human ACAT1 gene to promote the CE-laden cell formation from the differentiating monocytes, and our data support the hypothesis that TNF-alpha is proatherosclerotic during early phase of lesion development.-Lei, L., Y. Xiong, J. Chen, J-B. Yang, Y. Wang, X-Y. Yang, C. C. Y. Chang, B-L. Song, T-Y. Chang, and B-L. Li. TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation. J. Lipid Res. 2009. 50: 1057-1067.