TNF-α response of vascular endothelial and vascular smooth muscle cells involve differential utilization of ASK1 kinase and p73.
TNF-α response of vascular endothelial and vascular smooth muscle cells involve differential utilization of ASK1 kinase and p73.
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DOI：
10.1038/cdd.2011.93
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发表时间：
2012-02
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
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动脉粥样硬化是一个特殊的炎症过程，受细胞因子和趋化因子信号的复杂网络调节。动脉粥样硬化病变导致细胞因子的释放，这些细胞因子可以对各种血管细胞功能产生多重影响，要么促进病变扩张，要么延缓进展。TNF-α是一种可以同时激活细胞存活和死亡机制的细胞因子。本研究表明，TNFα诱导人主动脉内皮细胞凋亡，同时促进血管平滑肌细胞增殖。这两个事件都涉及Rb-E2F1转录调控通路的激活。TNF-α刺激HAECs导致p73蛋白表达增加，p53水平降低。这涉及ASK1介导的Rb失活及其与p73启动子的分离。相比之下，TNF-α刺激血管平滑肌细胞增强了E2F1与胸苷酸合成酶和cdc25A等增殖启动子的关联，而Rb被解离。ASK1激酶在凋亡过程中起关键作用，因为其从Rb中去除或分离可减少TNF-α诱导的凋亡。这些结果表明，细胞因子TNF-α可以在血管内皮细胞和血管平滑肌细胞中引起完全相反的反应，利用Rb-E2F途径。
Atherosclerosis involves a specialized inflammatory process regulated by an intricate network of cytokine and chemokine signaling. Atherosclerotic lesions lead to the release of cytokines that can have multiple affects on various vascular cell functions either promoting lesion expansion or alternatively retard progression. TNF-α is one such cytokine that can activate both cell survival and cell death mechanisms simultaneously. Here we show that TNFα induces apoptosis in human aortic endothelial cells, while it promotes the proliferation of vascular smooth muscle cells. Both events involved the activation of the Rb-E2F1 transcriptional regulatory pathway. Stimulation of HAECs with TNF-α led to an increased expression of p73 protein and a reduction in the levels of p53. This involved ASK1 mediated inactivation of Rb and its dissociation from the p73 promoter. In contrast, TNF-α stimulation of vascular smooth muscle cells enhanced the association of E2F1 with proliferative promoters like thymidylate synthase and cdc25A, while Rb was dissociated. ASK1 kinase plays a critical role in the apoptotic process, since its depletion or dissociation from Rb reduced TNF-α induced apoptosis. These results show that the cytokine TNF-α can elicit diametrically opposite responses in vascular endothelial cells and vascular smooth muscle cells, utilizing the Rb-E2F pathway.
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