Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels
Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels
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DOI：
10.1124/jpet.115.225862
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发表时间：
2015-10-01
影响因子：
3.5
通讯作者：
Lynch, Kevin R.
中科院分区：
文献类型：
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作者：
Kharel, Yugesh;Morris, Emily A.;Lynch, Kevin R.
血液和淋巴中的1-磷酸鞘氨醇(S1P)水平明显高于组织中的水平。这种S1P浓度差异对于次级淋巴组织中适当的淋巴细胞出口和维持内皮屏障的完整性是必要的。对缺乏SphK 1型和2型的小鼠的研究表明，这两种酶是S1P的唯一生物合成来源，但它们在设定S1P血液水平方面扮演着不同的角色。我们已经开发了一组类药物SphK抑制剂，对这种酶的两种异构体具有不同的选择性。尽管所有被测试的SphK抑制剂在应用于培养的U937细胞时都会降低S1P，但只有那些偏爱SphK2的抑制剂能显著提高小鼠的血液S1P，而且这种升高在给药几分钟内就能检测到。SphK2抑制剂对大鼠的血S1P也有促进作用。将大量标记的S1P静脉注射到SphK2抑制剂治疗的小鼠或缺乏SphK2功能基因的小鼠体内后，清除速度较慢；因此，S1P在血液中积累的增加似乎是由于S1P从血液中清除减少的结果。因此，SphK2似乎具有独立于在细胞中产生S1P的功能。我们的结果表明，药物对SphK的不同抑制可能提供了一种在降低组织S1P水平的同时，在两个方向上控制血液S1P水平的方法。
Sphingosine 1-phosphate (S1P) levels are significantly higher in blood and lymph than in tissues. This S1P concentration difference is necessary for proper lymphocyte egress from secondary lymphoid tissue and to maintain endothelial barrier integrity. Studies with mice lacking either sphingosine kinase (SphK) type 1 and 2 indicate that these enzymes are the sole biosynthetic source of S1P, but they play different roles in setting S1P blood levels. We have developed a set of drug-like SphK inhibitors, with differing selectivity for the two isoforms of this enzyme. Although all SphK inhibitors tested decrease S1P when applied to cultured U937 cells, only those inhibitors with a bias for SphK2 drove a substantial increase in blood S1P in mice and this rise was detectable within minutes of administration of the inhibitor. Blood S1P also increased in response to SphK2 inhibitors in rats. Mass-labeled S1P was cleared more slowly after intravenous injection into SphK2 inhibitor-treated mice or mice lacking a functional SphK2 gene; thus, the increased accumulation of S1P in the blood appears to result from the decreased clearance of S1P from the blood. Therefore, SphK2 appears to have a function independent of generating S1P in cells. Our results suggest that differential SphK inhibition with a drug might afford a method to manipulate blood S1P levels in either direction while lowering tissue S1P levels.