Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal
Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal
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DOI：
10.1096/fj.08-107169
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发表时间：
2008-08-01
期刊：
影响因子：
4.8
通讯作者：
Spiegel, Sarah
中科院分区：
文献类型：
--
作者：
Gude, David R.;Alvarez, Sergio E.;Spiegel, Sarah
鞘氨醇-1-磷酸（S1 P）是一种生物活性脂质，调节无数重要的细胞过程，包括生长，存活，细胞骨架重排，运动和免疫。在这里，我们报告说，治疗Jurkat和U937白血病细胞与泛鞘氨醇激酶（SphK）抑制剂N，N-二甲基鞘氨醇，以阻止S1 P的形成令人惊讶地引起了大量增加SphK 1的表达伴随着诱导细胞凋亡。另一种SphK抑制剂，D，L-苏型-二氢鞘氨醇，也诱导细胞凋亡，并产生显着增加SphK 1的表达。然而，SphK 1的上调不是其抑制的特异性效应，而是凋亡应激的结果。化疗药物多柔比星是这些细胞中细胞凋亡的有效诱导剂，也刺激SphK 1的表达和活性，并促进S1 P分泌。caspase抑制剂ZVAD不仅降低阿霉素诱导的死亡率，而且降低SphK 1表达和S1 P分泌的增加。凋亡细胞分泌趋化因子吸引吞噬细胞，我们发现，S1 P强效刺激单核细胞THP-1和U937细胞和初级单核细胞和巨噬细胞的趋化性。总的来说，我们的数据表明，凋亡细胞可能上调SphK 1产生和分泌S1 P，作为一个“来吧，让我”信号的清道夫细胞吞噬他们，以防止坏死。
Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates myriad important cellular processes, including growth, survival, cytoskeleton rearrangements, motility, and immunity. Here we report that treatment of Jurkat and U937 leukemia cells with the pan-sphingosine kinase (SphK) inhibitor N,N-dimethylsphingosine to block S1P formation surprisingly caused a large increase in expression of SphK1 concomitant with induction of apoptosis. Another SphK inhibitor, D, L-threo-dihydrosphingosine, also induced apoptosis and produced dramatic increases in SphK1 expression. However, up-regulation of SphK1 was not a specific effect of its inhibition but rather was a consequence of apoptotic stress. The chemotherapeutic drug doxorubicin, a potent inducer of apoptosis in these cells, also stimulated SphK1 expression and activity and promoted S1P secretion. The caspase inhibitor ZVAD reduced not only doxorubicin-induced lethality but also the increased expression of SphK1 and secretion of S1P. Apoptotic cells secrete chemotactic factors to attract phagocytic cells, and we found that S1P potently stimulated chemotaxis of monocytic THP-1 and U937 cells and primary monocytes and macrophages. Collectively, our data suggest that apoptotic cells may upregulate SphK1 to produce and secrete S1P that serves as a "come-and-get-me" signal for scavenger cells to engulf them in order to prevent necrosis.