Sphingosine-1-phosphate is released by cerebellar astrocytes in response to bFGF and induces astrocyte proliferation through Gi-protein-coupled receptors
Sphingosine-1-phosphate is released by cerebellar astrocytes in response to bFGF and induces astrocyte proliferation through Gi-protein-coupled receptors
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作者：
Bassi, R;Anelli, V;Riboni, L
在原代培养的小脑星形胶质细胞中，研究了鞘氨醇-1-磷酸（S1 P）的促有丝分裂作用及其参与碱性成纤维细胞生长因子（bFGF）诱导的增殖。暴露于bFGF导致细胞外S1 P形成的快速增加，bFGF诱导星形胶质细胞在细胞外环境中释放S1 P，但不释放鞘氨醇激酶。SK抑制剂N，N-二甲基鞘氨醇抑制S1 P释放以及bFGF诱导的生长刺激。静止星形胶质细胞中的S1 P应用引起DNA合成的剂量依赖性增加。这种神经胶质营养作用是由短暂暴露于低纳摩尔S1 P诱导的，由S1 P受体激动剂二氢S1 P模拟，并由G（i）/G（o）-蛋白的灭活剂百日咳毒素（PTX）抑制。S1 P还诱导细胞外信号调节激酶的激活，该激活被PTX再次抑制。此外，S1 P裂解酶抑制剂4-脱氧吡哆醇诱导细胞积累的S1 P，但不影响DNA的合成。这些结果支持的观点，S1 P产生的有丝分裂的影响小脑星形胶质细胞的细胞外，最有可能通过细胞表面S1 P受体。一致地，mRNA或S1 P1、S1 P2和S1 P3受体在小脑星形胶质细胞中表达（Anelli et al.，2005. J Neurochem 92：1204-1215）。神经酰胺是星形胶质细胞增殖的负调节剂，并被bFGF下调（Riboni等人，2002. Cerebellum 1：129-135），有效抑制S1 P诱导的增殖。S1 P作用似乎是bFGF刺激的自分泌/旁分泌级联反应的一部分，并且与神经酰胺下调一起，对于星形胶质细胞对bFGF的反应至关重要。结果提示，S1 P和bFGF/S1 P可能在脑发育、反应性胶质增生和脑肿瘤形成等病理生理性胶质细胞增生中起重要作用。(c)2006 Wiley-Liss，Inc.
The mitogenic role of sphingosine-1-phosphate (S1P) and its involvement in basic fibroblast growth factor (bFGF)-induced proliferation were examined in primary cultures of cerebellar astrocytes. Exposure to bFGF resulted in a rapid increase of extracellular S1P formation, bFGF inducing astrocytes to release S1P, but not sphingosine kinase, in the extracellular milieu. The SK inhibitor N,N-dimethylsphingosine inhibited S1P release as well as bFGF-induced growth stimulation. S1P application in quiescent astrocytes caused a dose-dependent increase in DNA synthesis. This gliotrophic effect was induced by a brief exposure to low nanomolar S1P, mimicked by the S1P receptor agonist dihydro-S1P, and inhibited by pertussis toxin (PTX), an inactivator of G(i)/G(o)-proteins. S1P also induced activation of extracellular signal-regulated kinase that was inhibited again by PTX. Moreover, the S1P lyase inhibitor 4-deoxypyridoxine induced the cellular accumulation of S1P but did not affect DNA synthesis. These results support the view that S1P exerted a mitogenic effect on cerebellar astrocytes extracellularly, most likely through cell surface S1P receptors. In agreement, mRNAs or S1P1, S1P2, and S1P3 receptors are expressed in cerebellar astrocytes (Anelli et al., 2005. J Neurochem 92:1204-1215). Ceramide, a negative regulator of astrocyte proliferation and down-regulated by bFGF (Riboni et al., 2002. Cerebellum 1:129-135), efficiently inhibited S1P-induced proliferation. The S1P action appears to be part of an autocrine/paracrine cascade stimulated by bFGF and, together with ceramide down-regulation, essential for astrocytes to respond to bFGF. The results suggest that S1P and bFGF/S1P may play an important role in physiopathological glial proliferation, such as brain development, reactive gliosis and brain tumor formation. (c) 2006 Wiley-Liss, Inc.