Involvement of sphingosine in mitochondria-dependent Fas-induced apoptosis of type II Jurkat T cells
Involvement of sphingosine in mitochondria-dependent Fas-induced apoptosis of type II Jurkat T cells
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DOI：
10.1074/jbc.m000280200
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发表时间：
2000-05-26
影响因子：
4.8
通讯作者：
Spiegel, S
中科院分区：
文献类型：
--
作者：
Cuvillier, O;Edsall, L;Spiegel, S
Jurkat细胞（II型细胞）的特点是死亡诱导信号复合体（DISC）的caspase-8激活较弱，暴露于抗fas抗体可诱导神经酰胺水平双期升高。神经酰胺的早期生成在酸性神经酰胺酶的短暂激活和随后鞘氨醇的产生之前，随后是细胞色素c的释放，caspase -2、-3、-6、-7、-8和-9的激活，Bid裂解，以及后来持续的神经酰胺积累。caspase抑制剂benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl酮抑制神经酰胺和鞘氨醇的早期增加，而Bcl-x(L)的过表达则没有影响，两者都阻止了后期持续的神经酰胺积累。外源性鞘氨醇以及细胞可渗透的c -2神经酰胺，以一种不依赖于caspase的方式诱导线粒体释放细胞色素c，导致caspase-9和刽子手caspase的激活，令人惊讶的是，启动物caspase-8的激活及其底物Bid的加工。Bcl-x(L)过表达也完全消除了这些影响。我们的研究结果表明，鞘氨醇也可能参与fas诱导II型细胞死亡的线粒体介导途径。
Exposure to anti-Fas antibody in Jurkat cells (type II cells), which are characterized by a weak caspase-8 activation at the death-inducing signaling complex (DISC), induced a biphasic increase in ceramide levels. The early generation of ceramide preceded transient activation of acidic ceramidase and subsequent production of sphingosine, followed by cytochrome c release, activation of caspases-2, -3, -6, -7, -8, and -9, Bid cleavage, and a later sustained ceramide accumulation. The caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone inhibited early increases of ceramide and sphingosine, whereas overexpression of Bcl-x(L), had no effect, and both prevented the later sustained ceramide accumulation. Exogenous sphingosine, as well as cell-permeable C-2-ceramide, induced cytochrome c release from mitochondria in a caspase-independent fashion leading to activation of caspase-9 and executioner caspases and, surprisingly, activation of the initiator caspase-8 and processing of its substrate Bid. These effects were also completely abolished by Bcl-x(L) overexpression. Our results suggest that sphingosine might also be involved in the mitochondria-mediated pathway of Fas-induced cell death in type II cells.