Sphingosine-1-phosphate receptors: Biology and therapeutic potential in kidney disease
2008; Elsevier BV; Volume: 73; Issue: 11 Linguagem: Inglês
10.1038/ki.2008.34
ISSN1523-1755
AutoresSung-Yoon Jo, Amandeep Bajwa, Alaa S. Awad, Kevin R. Lynch, Mark D. Okusa,
Tópico(s)Lipid Membrane Structure and Behavior
ResumoThe major sphingolipid metabolite, sphingosine-1-phosphate (S1P), has important biological functions. S1P is the ligand for a family of five G-protein-coupled receptors with distinct signaling pathways that regulate angiogenesis, vascular maturation, immunity, chemotaxis, and other important biological pathways. Recently, clinical trials have targeted S1P receptors (S1PRs) for autoimmune diseases and transplantation and have generated considerable interest in developing additional, more selective compounds. This review summarizes current knowledge on the biology of S1P and S1PRs that forms the basis for future drug development and the treatment of kidney disease. The major sphingolipid metabolite, sphingosine-1-phosphate (S1P), has important biological functions. S1P is the ligand for a family of five G-protein-coupled receptors with distinct signaling pathways that regulate angiogenesis, vascular maturation, immunity, chemotaxis, and other important biological pathways. Recently, clinical trials have targeted S1P receptors (S1PRs) for autoimmune diseases and transplantation and have generated considerable interest in developing additional, more selective compounds. This review summarizes current knowledge on the biology of S1P and S1PRs that forms the basis for future drug development and the treatment of kidney disease. Sphingolipid metabolites are emerging as important lipid signaling molecules in health and disease.1.Hla T. Signaling and biological actions of sphingosine 1-phosphate.Pharmacol Res. 2003; 47: 401-407Crossref PubMed Scopus (202) Google Scholar, 2.Siess W. Tigyi G. Thrombogenic and atherogenic activities of lysophosphatidic acid.J Cell Biochem. 2004; 92: 1086-1094Crossref PubMed Scopus (75) Google Scholar, 3.Goetzl E.J. Rosen H. 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A high level of S1P produced by SPHK elicits a variety of functional responses in immune systems in a paracrine or autocrine manner, depending on the expression pattern of S1PR subtypes in immune cells (Table 1). Until recently, S1P–S1PR signaling in immune cells has been examined mainly in lymphocytes, mast cells, and dendritic cells (DCs).Table 1S1P receptors in immune cellsImmune cellS1PRFunctionsT cellS1P1Decreased chemotaxis at low concentration (0.1–100 nM) of S1P, increased chemotaxis at high concentration (0.3–3 μM) of S1P, decreased proliferation, decreased IFN-γ and IL-4 secretionS1P4Decreased proliferation, decreased IFN-γ and IL-2 secretion, enhanced IL-10 secretionB cellS1P1Decreased chemotaxis at low concentration (0.1–100 nM), increased chemotaxis at high concentration (0.3–3 μM)S1P4Decreased proliferationMast cellS1P1Increased chemotaxis, no effect on degranulationS1P2Increased degranulationDendritic cellS1P1Increased chemotaxisS1P2Decreased chemotaxisS1P3Migration to S1PMacrophageS1P1Increased chemotaxisIFN-γ, interferon-γ; IL, interleukin; S1P, sphingosine-1-phosphate; S1PR, S1P receptor. Open table in a new tab IFN-γ, interferon-γ; IL, interleukin; S1P, sphingosine-1-phosphate; S1PR, S1P receptor. In human and mouse CD4 and CD8 T cells, S1P1 and S1P4 are the predominant S1PRs mediating the functional responses to S1P.64.Graeler M. Goetzl E.J. Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells.FASEB J. 2002; 16: 1874-1878Crossref PubMed Scopus (154) Google Scholar The effect of S1P on T-cell function is concentration dependent. At low concentrations (0.1–100 nM), S1P inhibits apoptosis and enhances chemotaxis to a variety of chemokines; at higher concentrations (0.3–3 μM), S1P inhibits T-cell chemotaxis,65.Graeler M. Shankar G. Goetzl E.J. Cutting edge: suppression of T cell chemotaxis by sphingosine 1-phosphate.J Immunol. 2002; 169: 4084-4087Crossref PubMed Google Scholar an effect that is mediated through S1P1 but not S1P4 receptors.65.Graeler M. Shankar G. Goetzl E.J. Cutting edge: suppression of T cell chemotaxis by sphingosine 1-phosphate.J Immunol. 2002; 169: 4084-4087Crossref PubMed Google Scholar In addition, S1P at a concentration range of 1 nM to 1 μM can inhibit CD4 T-cell proliferation and production of interferon-γ and IL-4 without affecting IL-2.66.Dorsam G. Graeler M.H. Seroogy C. et al.Transduction of multiple effects of sphingosine 1-phosphate (S1P) on T cell functions by the S1P1 G protein-coupled receptor.J Immunol. 2003; 171: 3500-3507Crossref PubMed Scopus (79) Google Scholar These multiple immune modulatory functions of S1P are mediated through S1P1 activation.66.Dorsam G. Graeler M.H. 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