Atorvastatin inhibits T cell activation through 3-hydroxy-3-methylglutaryl coenzyme a reductase without decreasing cholesterol synthesis
Atorvastatin inhibits T cell activation through 3-hydroxy-3-methylglutaryl coenzyme a reductase without decreasing cholesterol synthesis
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DOI：
10.4049/jimmunol.179.6.3613
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发表时间：
2007-09-15
影响因子：
4.4
通讯作者：
Lorenz, Hanns-Martin
中科院分区：
文献类型：
--
作者：
Blank, Norbert;Schiller, Martin;Lorenz, Hanns-Martin
TCR和其他信号分子在膜筏(MR)中的定位对于T淋巴细胞的激活是至关重要的。神经鞘脂脂和胆固醇可以稳定MR。T淋巴细胞的激活导致小MR的汇合和免疫突触的形成，这是持续激活和增殖所必需的。在这项研究中，我们研究了他汀类药物对超抗原刺激的人PBMC中MR和T细胞活化的影响。阿托伐他汀显著抑制细胞活化和增殖。低剂量的他汀类药物可抑制霍乱毒素B亚单位与分离的MR和整个细胞的结合。他汀类药物减少T细胞中关键信号蛋白如Lck和激活连接物与刺激T细胞中MR的关联。活化标志物CD69和CD25的表达受到抑制。他汀类药物介导的几种机制，如对MHC-II的较低刺激，通过他汀类药物与LFA-1的直接结合而抑制共刺激作用，减少细胞因子的分泌，或耗尽细胞胆固醇池，被排除在外。抑制蛋白质预烯基化对T细胞的增殖也有类似的影响，提示蛋白质预烯基化的降低可能是他汀类药物抑制T细胞活化的原因之一。他汀类药物可降低低密度脂蛋白胆固醇水平并抑制T细胞活化，这可能有助于抑制动脉粥样硬化。
The localization of the TCR and other signaling molecules in membrane rafts (MR) is essential for the activation of T lymphocytes. MR are stabilized by sphingolipids and cholesterol. Activation of T lymphocytes leads to the confluence of small MR and the formation of an immunological synapse that is essential for sustained activation and proliferation. In this study, we investigated the effect of statins on MR and T cell activation in superantigen-stimulated human PBMC. Atorvastatin significantly inhibited cellular activation and proliferation. The binding of cholera toxin B subunit to isolated MR and to whole cells was inhibited by low doses of statins. Statins reduce the association of critical signaling proteins such as Lck and linker of activation in T cells with MR in stimulated T cells. The expression of activation markers CD69 and CD25 was inhibited. Several statin-mediated mechanisms, such as a lower stimulation with MHC-II, an inhibition of costimulation by direct binding of statins to LFA-1, a reduced secretion of cytokines, or a depletion of cellular cholesterol pools, were excluded. Inhibition of protein prenylation had a similar effect on T cell proliferation, suggesting that a reduced protein prenylation might contribute to the statin-mediated inhibition of T cell activation. Statins induce both lower levels of low-density lipoprotein cholesterol and inhibition of T cell activation, which might contribute to an inhibition of atherosclerosis.