Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
FASEB J. 2010 Jul;24(7):2507-15. doi: 10.1096/fj.09-153635. Epub 2010 Mar 5.
Plasma sphingosine-1-phosphate (S1P) has been suggested to mainly originate from erythrocytes; however, within the erythrocyte, how sphingosine (SPH) generation--the precursor to S1P--is controlled is unknown. SPH is only generated from the hydrolysis of ceramides via ceramidases. Five human ceramidases have been identified: 1 acid, 1 neutral, and 3 alkaline ceramidases (ACER1, ACER2, and ACER3). Here, we demonstrate that only alkaline ceramidase activity is expressed in erythrocytes and that it is instrumental for SPH generation. Erythrocytes have alkaline but not acid or neutral ceramidase activity on D-e-C(18:1)-ceramide, a common substrate of ceramidases. Not only alkaline ceramidase activity but also the generation of SPH and S1P are increased during erythroid differentiation in K562 erythroleukemic cells. Such SPH and S1P increases were inhibited by the alkaline ceramidase inhibitor D-e-MAPP, suggesting that alkaline ceramidases have a role in the generation of SPH and S1P in erythroid cells. Alkaline ceramidase activity is highly expressed in mouse erythrocytes, and intravenous administration of D-e-MAPP decreased both SPH and S1P in erythrocytes and plasma. Collectively, these results suggest that alkaline ceramidase activity is important for the generation of SPH, the S1P precursor in erythrocytes.
血浆鞘氨醇-1-磷酸（S1P）主要来源于红细胞；然而，在红细胞内，鞘氨醇（SPH）的生成——S1P 的前体——是如何被控制的还不清楚。SPH 只能通过鞘脂酶从神经酰胺的水解中产生。已经鉴定出 5 种人类鞘脂酶：1 种酸性、1 种中性和 3 种碱性鞘脂酶（ACER1、ACER2 和 ACER3）。在这里，我们证明只有碱性鞘脂酶活性在红细胞中表达，并且它是 SPH 生成所必需的。红细胞在 D-e-C（18：1）-神经酰胺上具有碱性但没有酸性或中性鞘脂酶活性，D-e-C（18：1）-神经酰胺是鞘脂酶的常见底物。不仅碱性鞘脂酶活性，而且在 K562 红白血病细胞的红细胞分化过程中 SPH 和 S1P 的生成也增加。这种 SPH 和 S1P 的增加被碱性鞘脂酶抑制剂 D-e-MAPP 抑制，表明碱性鞘脂酶在红细胞中 SPH 和 S1P 的生成中起作用。碱性鞘脂酶活性在小鼠红细胞中高度表达，静脉内给予 D-e-MAPP 可降低红细胞和血浆中的 SPH 和 S1P。总之，这些结果表明碱性鞘脂酶活性对于 SPH 的生成，即红细胞中 S1P 的前体，很重要。
