Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720
Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720
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DOI：
10.1074/jbc.m406512200
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发表时间：
2004-12-10
影响因子：
4.8
通讯作者：
Proia, RL
中科院分区：
文献类型：
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作者：
Allende, ML;Sasaki, T;Proia, RL
鞘氨醇-1-磷酸（S1P）是一种调节多种细胞功能的脂质信号分子，由鞘氨醇和ATP在鞘氨醇激酶的作用下合成。已经鉴定出两种这样的激酶，SPHK1和SPHK2。为了开始研究鞘氨酸激酶和S1P信号的生理功能，我们制造了SPHK1缺失的小鼠。Sphk1缺失小鼠存活，可生育，无明显异常。在大多数Sphk1-/-组织中，SPHK总活性显著降低，但不完全降低，表明存在多种鞘氨酸激酶。Sphk1 -/-小鼠大部分组织中S1P水平未明显降低。血清中S1P水平明显降低。虽然S1P信号调节淋巴细胞运输，但Sphk1 -/-小鼠淋巴器官中的淋巴细胞分布不受影响。免疫抑制剂FTY720在Sphk1缺失的小鼠中被磷酸化并引起淋巴细胞减少，这表明Sphk1不是这种鞘氨醇类似物前药功能激活所必需的。这些Sphk1缺失小鼠的研究结果表明，一些需要S1P受体信号传导的关键生理过程，如血管发育和适当的淋巴细胞分布，可以在Sphk1缺失的情况下发生。
Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1. Sphk1 null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in most Sphk1-/- tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from the Sphk1 -/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs of Sphk1 -/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in the Sphk1 null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with these Sphk1 null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.