Alvarez SE, Milstien S, Spiegel S.. Autocrine and paracrine roles of sphingosine-1-phosphate. Trends Endocrinol Metab 18: 300-307

Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Trends in Endocrinology and Metabolism (Impact Factor: 9.39). 11/2007; 18(8):300-7. DOI: 10.1016/j.tem.2007.07.005
Source: PubMed


Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that has been implicated in many biological processes, including cell migration, survival, proliferation, angiogenesis and immune and allergic responses. S1P levels inside cells are regulated tightly by the balance between its synthesis by sphingosine kinases and degradation by S1P lyases and S1P phosphatases. Activation of sphingosine kinase by any of a variety of agonists increases S1P levels, which in turn can function intracellularly as a second messenger or in an autocrine and/or paracrine fashion to activate and signal through S1P receptors present on the surface of the cell. This review summarizes recent findings on the roles of S1P as a mediator of the actions of cytokines, growth factors and hormones.

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    • "These receptors belong to the superfamily of G protein-coupled receptors (GPCR) which are ubiquitously expressed and couple to diverse sets of signaling cascades (Brinkmann, 2007; Chun et al., 2010). This diversity of S1P receptors implicates a multitude of physiological and pathophysiological functions of extracellular S1P including the promotion of cell growth and survival, cell migration and the modulation of inflammatory reactions (Alvarez et al., 2007; Schuchardt et al., 2011; Maceyka et al., 2012). Consequently, the targeting of S1P signaling and the development of pharmacological S1P receptor agonists or antagonists has become a key interest for scientists involved in drug research (Huwiler and Zangemeister-Wittke, 2007; Huwiler and Pfeilschifter, 2008, 2009). "
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    ABSTRACT: The immunomodulatory FTY720 (fingolimod) is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that acts by modulating sphingosine 1-phosphate (S1P) receptor signaling. In this study, we have developed and characterized two novel oxazolo-oxazole derivatives of FTY720, ST-968 and the oxy analog ST-1071, which require no preceding activating phosphorylation, and proved to be active in intact cells and triggered S1P(1) and S1P(3), but not S1P(2), receptor internalization as a result of receptor activation. Functionally, ST-968 and ST-1071 acted similar to FTY720 to abrogate S1P-triggered chemotaxis of mouse splenocytes, mouse T cells and human U937 cells, and reduced TNFa- and LPS-stimulated endothelial cell permeability. The compounds also reduced TNF alpha-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNF alpha-mediated downregulation of PECAM-1 mRNA expression. In an in vivo setting, the application of ST-968 or ST-1071 to mice resulted in a reduction of blood lymphocytes and significantly reduced the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice comparable to FTY720 either by prophylactic or therapeutic treatment. In parallel to the reduced clinical symptoms, infiltration of immune cells in the brain was strongly reduced, and in isolated tissues of brain and spinal cord, the mRNA and protein expressions of ICAM-1 and VCAM-1, as well as of matrix metalloproteinase-9 were reduced by all compounds, whereas PECAM-1 and tissue inhibitor of metalloproteinase TIMP-1 were upregulated. In summary, the data suggest that these novel butterfly derivatives of FTY720 could have considerable implication for future therapies of multiple sclerosis and other autoimmune diseases.
    Neuropharmacology 05/2014; 85. DOI:10.1016/j.neuropharm.2014.05.012 · 5.11 Impact Factor
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    • "SphK1 activation is modulated by many agonists including IGF-1 which induces the translocation of SphK1 to the plasma membrane [52]. In a previous study, we showed that the deleterious effect of Aβ exposition on SphK1 activity could be reversed by adjunction of IGF-1 to the culture medium [33]. "
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    ABSTRACT: The accumulation of beta amyloid (Abeta) peptides, a hallmark of Alzheimer's disease (AD) is related to mechanisms leading to neurodegeneration. Among its pleiotropic cellular effects, Abeta accumulation has been associated with a deregulation of sphingolipid metabolism. Sphingosine 1-phosphate (S1P) derived from sphingosine is emerging as a critical lipid mediator regulating various biological activities including cell proliferation, survival, migration, inflammation, or angiogenesis. S1P tissue level is low and kept under control through equilibrium between its synthesis mostly governed by sphingosine kinase-1 (SphK1) and its degradation by sphingosine 1-phosphate lyase (SPL). We have previously reported that Abeta peptides were able to decrease the activity of SphK1 in cell culture models, an effect that could be blocked by the prosurvival IGF-1/IGF-1R signaling. Herein, we report for the first time the expression of both SphK1 and SPL by immunohistochemistry in frontal and entorhinal cortices from 56 human AD brains. Immunohistochemical analysis revealed a decreased expression of SphK1 and an increased expression of SPL both correlated to amyloid deposits in the entorhinal cortex. Otherwise, analysis of brain tissue extracts showed a decrease of SphK1 expression in AD brains whereas SPL expression was increased. The content of IGF-1R, an activator of SphK1, was found decreased in AD brains as well as S1P1, the major receptor for S1P. Collectively, these results highlight the importance of S1P in AD suggesting the existence of a global deregulation of S1P signaling in this disease from its synthesis by SphK1 and degradation by SPL to its signaling by the S1P1 receptor.
    01/2014; 2(1):12. DOI:10.1186/2051-5960-2-12
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    • "Depending on the concentration and intracellular localisation, S1P plays an important role in the regulation of cell proliferation, differentiation, and motility, and is also involved in a wide array of stress signals, which leads to growth arrest and apoptosis [4–6]. Extracellular S1P is an agonist of 5 surface G-protein-coupled receptors (GPCR), termed S1P1-5, but it may also act intracellularly as a second messenger and directly influence different cellular targets [7, 8]. In addition to mobilising intracellular Ca2+ [9], S1P can regulate histone deacetylases and the ubiquitin ligase activity of tumour necrosis factor receptor-associated factor 2 [10–12]. "
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    ABSTRACT: It has been postulated that disturbances in the sphingolipid metabolism play a key role in the pathogenesis of Alzheimer's disease (AD). An alteration in sphingosine kinases 1, 2 (SphK1/2) and sphingosine-1-phosphate (S1P) was recently reported in AD. However, the effect of AD-related amyloid beta (Aβ) peptides on SphK1/2 and the role of S1P in Aβ toxicity have not been fully elucidated. In this study the relationship between the Aβ concentration and SphK1/2 expression/activity was analysed in PC12 cells transfected with the Aβ precursor protein, wild-type (APPwt) or bearing a double Swedish mutation (APPsw). The role of SphK(s)/S1P in cell survival and death was also investigated. Our results indicated that endogenously liberated Aβ significantly decreases expression and activity of SphK1/2. The SphK(s) inhibitor (SKI II, 10 μM) decreased the viability of APPwt, APPsw as well as empty vector-transfected PC12 control cells. Our data demonstrated that expression of S1P receptor-1 (S1P1) was significantly reduced in APP-transfected cells. The effect of S1P applied exogenously was cell type-dependent. In control and APPwt cells S1P reduced the effect of the SphK1 inhibitor on death signalling. Conversely, it decreased the survival of APPsw cells and had no protective effect on cells treated with SKI II. Using the S1P1 agonist (SEW2871, 5 μM) and antagonist (W123, 20 μM), we demonstrated that the cytoprotective effect of S1P was receptor-independent. Summarising, we showed that Aβ peptides evoke down-regulation of gene expression and activity for SphK(s) and S1P1. Inhibition of SphK(s) significantly decreased cell survival. The effect of exogenous S1P depended on the concentration of Aβ peptides.
    Neurochemical Research 01/2014; 39(4). DOI:10.1007/s11064-014-1240-3 · 2.59 Impact Factor
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