Jung C G, Kim H J, Miron V E, Cook S, Kennedy T E, Foster C A, Antel J P, Soliven B
Department of Neurology, University of Chicago, Chicago, Illinois 60637, USA.
Glia. 2007 Dec;55(16):1656-67. doi: 10.1002/glia.20576.
Fingolimod (FTY720) and its phosphorylated form FTY720P are modulators of sphingosine-1-phosphate (S1P) receptors, which are G-protein coupled receptors linked to cell migration and vascular maturation. The efficacy of FTY720 in autoimmune diseases such as multiple sclerosis and its animal models has been attributed to its inhibition of lymphocyte trafficking to target organs. In this study, we examined the role of S1P receptors in cultured rat oligodendrocytes (OLGs) and OLG progenitor cells (OPCs) using the active phosphorylated form of FTY720. We found that (1) FTY720P improves the survival of neonatal rat OLGs during serum withdrawal, which is associated with the phosphorylation of extracellular signal regulated kinases (ERK1/2) and Akt; (2) FTY720P regulates OPC differentiation into OLGs in a concentration-dependent manner; and (3) S1P receptors are differentially modulated by platelet-derived growth factor (PDGF) resulting in downregulation of S1P5 and upregulation of S1P1 in OPCs. In addition, siRNA studies revealed that S1P1 participates in PDGF-induced OPC mitogenesis. We conclude that S1P1 and S1P5 serve different functions during oligodendroglial development, and possibly during remyelination.
芬戈莫德（FTY720）及其磷酸化形式FTY720P是1-磷酸鞘氨醇（S1P）受体的调节剂，这些受体是与细胞迁移和血管成熟相关的G蛋白偶联受体。FTY720在自身免疫性疾病如多发性硬化症及其动物模型中的疗效归因于其对淋巴细胞向靶器官迁移的抑制作用。在本研究中，我们使用FTY720的活性磷酸化形式研究了S1P受体在培养的大鼠少突胶质细胞（OLGs）和少突胶质前体细胞（OPCs）中的作用。我们发现：（1）FTY720P在血清撤出期间提高新生大鼠OLGs的存活率，这与细胞外信号调节激酶（ERK1/2）和Akt的磷酸化有关；（2）FTY720P以浓度依赖的方式调节OPCs向OLGs的分化；（3）血小板衍生生长因子（PDGF）对S1P受体有不同的调节作用，导致OPCs中S1P5下调和S1P1上调。此外，小干扰RNA研究表明S1P1参与PDGF诱导的OPC有丝分裂。我们得出结论，S1P1和S1P5在少突胶质细胞发育过程中以及可能在髓鞘再生过程中发挥不同的功能。
