Inhibition of sphingolipid synthesis impairs cellular activation, cytokine production and proliferation in human lymphocytes
Inhibition of sphingolipid synthesis impairs cellular activation, cytokine production and proliferation in human lymphocytes
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DOI：
10.1016/j.bcp.2005.10.004
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发表时间：
2005-12-19
影响因子：
5.8
通讯作者：
Lorenz, HM
中科院分区：
文献类型：
--
作者：
Blank, N;Schiller, M;Lorenz, HM
T细胞受体和其他信号分子在膜微区（MM）中的定位对于T淋巴细胞的活化至关重要。这些MM由鞘脂和胆固醇稳定。最近表明，T淋巴细胞的活化导致小MM的汇合和免疫突触的形成，这被认为是持续活化和增殖所必需的。我们研究了鞘脂合成抑制对T淋巴细胞功能的影响。两种鞘脂抑制剂PDMP和多球菌素都能抑制全细胞脂质提取物和MM中的葡萄糖鞘脂。这两种化合物都能抑制超抗原刺激的PBMC的增殖，而不会诱导细胞死亡。然而，只有神经酰胺样化合物PdR抑制活化标志物的表达和IFN-γ的分泌，这在多球壳菌素治疗中没有观察到。MM本地化的LCK和LAT没有显着减少在PDMP处理cells.In结论，我们的研究结果表明，鞘糖脂是必要的人类T淋巴细胞的细胞生长。然而，葡萄糖鞘脂合成的抑制本身并不抑制细胞活化。我们的数据表明，与胆固醇相反，鞘糖脂对MM的稳定性不是必不可少的。（c）2005 Elsevier Inc. All rights reserved.
The localisation of the T cell receptor and other signalling molecules in membrane microdomains (MM) is essential for the activation of T lymphocytes. These MM are stabilized by sphingolipids and cholesterol. It was recently shown that the activation of T lymphocytes leads to the confluence of small MM and the formation of an immunological synapse which is thought to be essential for a persistent activation and proliferation. We studied the effects of an inhibition of sphingolipid synthesis on T lymphocyte function. Both sphingolipid inhibitors, PDMP and myriocin, inhibited glucosphingolipids in whole cell lipid extracts and in MM. Both compounds inhibited the proliferation of superantigen-stimulated PBMC without inducing cell death. However, only the ceramide-like compound PDMP inhibited the expression of activation markers and the secretion of IFN-gamma which was not seen with myriocin treatment. The MM localisation of Lck and LAT was not significantly reduced in PDMP-treated cells.In conclusion, our results show that glucosphingolipids are necessary for cell growth of human T lymphocytes. However, inhibition of glucosphingolipid synthesis itself did not inhibit cellular activation. Our data show that glucosphingolipids - in contrast to cholesterol - are not essential for the stabilisation of MM. (c) 2005 Elsevier Inc. All rights reserved.