Sphingosine 1‐phosphate induces the production of glial cell line‐derived neurotrophic factor and cellular proliferation in astrocytes

Abstract

Sphingosine 1-phosphate (S1P) is a platelet-derived bioactive sphingolipid that evokes a variety of biological responses. To understand the role of S1P in the central nervous system, we have examined the effect of S1P on the production of glial cell line-derived neurotrophic factor (GDNF) and growth regulation of cortical astrocytes from rat embryo. Moreover, we examined the possibility that the expression of GDNF is regulated differently in cultured astrocytes from the stroke-prone spontaneously hypertensive rat (SHRSP) than in those from Wistar kyoto rats (WKY). The mRNA expression was quantitated by RT-PCR based on the fluorescent TaqMan methodology. A new instrument capable of measuring fluorescence in real time was used to quantify gene amplification in astrocytes. GDNF protein was investigated by enzyme-linked immunosorbent assay. S1P induced the expression of GDNF mRNA and the production of GDNF protein in a dose-dependent manner in WKY astrocytes. Moreover, S1P increased cell numbers and induced the proliferation of astrocytes. In addition, the level of mRNA expression and protein production of GDNF was significantly lower in SHRSP than WKY astrocytes following exposure to S1P. These findings revealed that S1P augments GDNF protein production and cellular growth in astrocytes. Also, our results indicate that production in SHRSP astrocytes was attenuated in response to S1P compared with that observed in WKY. We conclude that S1P specifically triggers a cascade of events that regulate the production of GDNF and cell growth in astrocytes. Our results also suggest that the reduced expression of GDNF caused by S1P is a factor in the stroke proneness of SHRSP.

Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells

“…Whether treatment with S1P receptor modulators in MS would enhance or attenuate OLG regeneration and remyelination may depend not only on the concentrations reached in brain tissues, but also on the summation of their effects on all CNS cell types. S1P has been reported to induce proliferation of astrocytes and neural progenitor cells, though the S1P receptor subtype involved was not determined in these studies (Bassi et al, 2006;Harada et al, 2004;Pebay et al, 2001;Yamagata et al, 2003). S1P also stimulates the production of glial cell line-derived neurotrophic factor in astrocytes Yamagata et al, 2003), which can enhance PNS myelination, as observed in our Schwann cell-neuron coculture studies (Iwase et al, 2005).…”

“…S1P has been reported to induce proliferation of astrocytes and neural progenitor cells, though the S1P receptor subtype involved was not determined in these studies (Bassi et al, 2006;Harada et al, 2004;Pebay et al, 2001;Yamagata et al, 2003). S1P also stimulates the production of glial cell line-derived neurotrophic factor in astrocytes Yamagata et al, 2003), which can enhance PNS myelination, as observed in our Schwann cell-neuron coculture studies (Iwase et al, 2005). Furthermore, S1P signaling in OLG lineage cells is likely to be regulated by growth factors, and vice versa, as demonstrated with PDGF in this study.…”

Common Signaling Pathways Link Activation of Murine PAR-1, LPA, and S1P Receptors to Proliferation of Astrocytes

“…In addition, studies with pharmacological inhibitors suggest that activation of Rho pathways also plays a role in regulating proliferative responses for all three receptor classes that is independent of MAPK signaling cascades. Whereas previous reports have described varying aspects of PAR-or LPL-receptor mediated effects on astrocyte proliferation in vitro (Keller et al, 1997;Ramakers and Moolenaar, 1998;Tabuchi et al, 2000;Pebay et al, 2001;Steiner et al, 2002;Wang et al, 2002a;Yamagata et al, 2003), in this study we have sought to link in vivo effects of PAR-1, LPA, and S1P on reactive astrogliosis with shared signaling pathways for these receptors that mediate proliferative responses in vitro.…”

“…LPA is abundant in rat brain (Das and Hajra, 1989), and physiologically active concentrations of LPA have been detected in cerebrospinal fluid in an experimental model of hemorrhagic injury (Tigyi et al, 1995). LPA and S1P have been shown to induce proliferation of astrocytes in culture (Keller et al, 1997;Ramakers and Moolenaar, 1998;Tabuchi et al, 2000;Pebay et al, 2001;Steiner et al, 2002;Yamagata et al, 2003), although some reports indicate that LPA is not a mitogen for astrocytes (Tigyi et al, 1994;Fuentes et al, 1999;Pebay et al, 1999).…”

Cellular Localization of Sphingosine-1-phosphate Receptor 1 Expression in the Human Central Nervous System

“…S1PRs are widely expressed in the central nervous system (CNS), with region-specific distributions (Toman and Spiegel 2002;Jaillard et al 2005;Ohuchi et al 2008;Chun and Hartung 2010). The S1P/S1PR signal has been shown to play an important role in neural development, regulation of neural stem cells and glial migration, astrocyte proliferation, protection against apoptosis, and, more recently, modulation of neuronal excitability and glutamatergic neurotransmission (Chun et al 2000;Toman and Spiegel 2002;Yamagata et al 2003;Harada et al 2004;Kajimoto et al 2007;Kimura et al 2007;Milstien et al 2007;Ohuchi et al 2008). However, in situ localization of S1PRs in the human CNS remains unclear because of the lack of specific antibodies against S1PRs; most findings have been obtained from experiments at the mRNA level (Brinkmann 2009).…”