Seminars in Immunopathology

, Volume 34, Issue 1, pp 73–91

Sphingosine 1-phosphate in coagulation and inflammation



Sphingosine 1-phosphate (S1P) is a lipid mediator produced from sphingomyelin by the sequential enzymatic actions of sphingomyelinase, ceramidase, and sphingosine kinase. Five subtypes of cell surface G-protein-coupled receptors, S1P1–5, mediate the actions of S1P in various organs systems, most notably cardiovascular, immune, and central nervous systems. S1P is enriched in blood and lymph but is present at much lower concentrations in interstitial fluids of tissues. This vascular S1P gradient is important for the regulation of trafficking of various immune cells. FTY720, which was recently approved for the treatment of relapsing-remitting multiple sclerosis, potently sequesters lymphocytes into lymph nodes by functionally antagonizing the activity of the S1P1 receptor. S1P also plays critical roles in the vascular barrier integrity, thereby regulating inflammation, tumor metastasis, angiogenesis, and atherosclerosis. Recent studies have also revealed the involvement of S1P signaling in coagulation and in tumor necrosis factor α-mediated signaling. This review highlights the importance of S1P signaling in these inflammatory processes as well as the contribution of each receptor subtype, which exhibits both cooperative and redundant functions.


Sphingosine 1-phosphate G-protein-coupled receptor Vascular barrier integrity Immune cell trafficking Coagulation Inflammation 


  1. 1.
    Westerlund B, Slotte JP (2009) How the molecular features of glycosphingolipids affect domain formation in fluid membranes. Biochim Biophys Acta 1788:194–201PubMedGoogle Scholar
  2. 2.
    Obeid LM, Linardic CM, Karolak LA, Hannun YA (1993) Programmed cell death induced by ceramide. Science 259:1769–1771PubMedGoogle Scholar
  3. 3.
    Venable ME, Lee JY, Smyth MJ, Bielawska A, Obeid LM (1995) Role of ceramide in cellular senescence. J Biol Chem 270:30701–30708PubMedGoogle Scholar
  4. 4.
    Hla T, Venkataraman K, Michaud J (2008) The vascular S1P gradient-cellular sources and biological significance. Biochim Biophys Acta 1781:477–482PubMedGoogle Scholar
  5. 5.
    Venkataraman K, Lee Y, Michaud J, Thangada S, Ai Y, Bonkovsky HL, Parikh NS, Habrukowich C, Hla T (2008) Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circ Res 102:669–676PubMedGoogle Scholar
  6. 6.
    Yatomi Y, Igarashi Y, Yang L, Hisano N, Qi R, Asazuma N, Satoh K, Ozaki Y, Kume S (1997) Sphingosine 1-phosphate, a bioactive sphingolipid abundantly stored in platelets, is a normal constituent of human plasma and serum. J Biochem (Tokyo) 121:969–973Google Scholar
  7. 7.
    Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, Camerer E, Zheng YW, Huang Y, Cyster JG, Coughlin SR (2007) Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316:295–298PubMedGoogle Scholar
  8. 8.
    Hänel P, Andréani P, Graler MH (2007) Erythrocytes store and release sphingosine 1-phosphate in blood. FASEB J 21:1202–1209PubMedGoogle Scholar
  9. 9.
    Spiegel S, Milstien S (2007) Functions of the multifaceted family of sphingosine kinases and some close relatives. J Biol Chem 282:2125–2129PubMedGoogle Scholar
  10. 10.
    Mizugishi K, Yamashita T, Olivera A, Miller GF, Spiegel S, Proia RL (2005) Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 25:11113–11121PubMedGoogle Scholar
  11. 11.
    Johnson KR, Becker KP, Facchinetti MM, Hannun YA, Obeid LM (2002) PKC-dependent activation of sphingosine kinase 1 and translocation to the plasma membrane. Extracellular release of sphingosine-1-phosphate induced by phorbol 12-myristate 13-acetate (PMA). J Biol Chem 277:35257–35262PubMedGoogle Scholar
  12. 12.
    Pitson SM, Moretti PAB, Zebol JR, Lynn HE, Xia P, Vadas MA, Wattenberg BW (2003) Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J 22:5491–5500PubMedGoogle Scholar
  13. 13.
    Pitson SM, Xia P, Leclercq TM, Moretti PAB, Zebol JR, Lynn HE, Wattenberg BW, Vadas MA (2005) Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. J Exp Med 201:49–54PubMedGoogle Scholar
  14. 14.
    Olivera A, Spiegel S (1993) Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 365:557–560PubMedGoogle Scholar
  15. 15.
    Shu X, Wu W, Mosteller RD, Broek D (2002) Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol Cell Biol 22:7758–7768PubMedGoogle Scholar
  16. 16.
    Edsall LC, Pirianov GG, Spiegel S (1997) Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation. J Neurosci 17:6952–6960PubMedGoogle Scholar
  17. 17.
    Sarkar S, Maceyka M, Hait NC, Paugh SW, Sankala H, Milstien S, Spiegel S (2005) Sphingosine kinase 1 is required for migration, proliferation and survival of MCF-7 human breast cancer cells. FEBS Lett 579:5313–5317PubMedGoogle Scholar
  18. 18.
    Ma MM, Chen JL, Wang GG, Wang H, Lu Y, Li JF, Yi J, Yuan YJ, Zhang QW, Mi J, Wang LS, Duan HF, Wu CT (2007) Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice. Diabetologia 50:891–900PubMedGoogle Scholar
  19. 19.
    El-Shewy HM, Johnson KR, Lee M, Jaffa AA, Obeid LM, Luttrell LM (2006) Insulin-like growth factors mediate heterotrimeric G protein-dependent ERK1/2 activation by transactivating sphingosine 1-phosphate receptors. J Biol Chem 281:31399–31407PubMedGoogle Scholar
  20. 20.
    Xia P, Wang L, Moretti PAB, Albanese N, Chai F, Pitson SM, D'Andrea RJ, Gamble JR, Vadas MA (2002) Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-alpha signaling. J Biol Chem 277:7996–8003PubMedGoogle Scholar
  21. 21.
    Pettus BJ, Bielawski J, Porcelli AM, Reames DL, Johnson KR, Morrow J, Chalfant CE, Obeid LM, Hannun YA (2003) The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-α. FASEB J 17:1411–1421PubMedGoogle Scholar
  22. 22.
    Billich A, Bornancin F, Mechtcheriakova D, Natt F, Huesken D, Baumruker T (2005) Basal and induced sphingosine kinase 1 activity in A549 carcinoma cells: function in cell survival and IL-1β and TNF-α induced production of inflammatory mediators. Cell Signal 17:1203–1217PubMedGoogle Scholar
  23. 23.
    De Palma C, Meacci E, Perrotta C, Bruni P, Clementi E (2006) Endothelial nitric oxide synthase activation by tumor necrosis factor alpha through neutral sphingomyelinase 2, sphingosine kinase 1, and sphingosine 1 phosphate receptors: a novel pathway relevant to the pathophysiology of endothelium. Arterioscler Thromb Vasc Biol 26:99–105PubMedGoogle Scholar
  24. 24.
    Pyne S, Long JS, Ktistakis NT, Pyne NJ (2005) Lipid phosphate phosphatases and lipid phosphate signalling. Biochem Soc Trans 33:1370–1374PubMedGoogle Scholar
  25. 25.
    Alderton F, Darroch P, Sambi B, McKie A, Ahmed IS, Pyne N, Pyne S (2001) G-protein-coupled receptor stimulation of the p42/p44 mitogen-activated protein kinase pathway is attenuated by lipid phosphate phosphatases 1, 1a, and 2 in human embryonic kidney 293 cells. J Biol Chem 276:13452–13460PubMedGoogle Scholar
  26. 26.
    Long J, Darroch P, Wan KF, Kong KC, Ktistakis N, Pyne NJ, Pyne S (2005) Regulation of cell survival by lipid phosphate phosphatases involves the modulation of intracellular phosphatidic acid and sphingosine 1-phosphate pools. Biochem J 391:25–32PubMedGoogle Scholar
  27. 27.
    Le Stunff H, Galve-Roperh I, Peterson C, Milstien S, Spiegel S (2002) Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis. J Cell Biol 158:1039–1049PubMedGoogle Scholar
  28. 28.
    Ikeda M, Kihara A, Igarashi Y (2004) Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5′-phosphate binding domain exposed to the cytosol. Biochem Biophys Res Commun 325:338–343PubMedGoogle Scholar
  29. 29.
    Schwab SR, Pereira JP, Matloubian M, Xu Y, Huang Y, Cyster JG (2005) Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309:1735–1739PubMedGoogle Scholar
  30. 30.
    Marathe S, Schissel SL, Yellin MJ, Beatini N, Mintzer R, Williams KJ, Tabas I (1998) Human vascular endothelial cells are a rich and regulatable source of secretory sphingomyelinase. Implications for early atherogenesis and ceramide-mediated cell signaling. J Biol Chem 273:4081–4088PubMedGoogle Scholar
  31. 31.
    Romiti E, Meacci E, Tani M, Nuti F, Farnararo M, Ito M, Bruni P (2000) Neutral/alkaline and acid ceramidase activities are actively released by murine endothelial cells. Biochem Biophys Res Commun 275:746–751PubMedGoogle Scholar
  32. 32.
    Ancellin N, Colmont C, Su J, Li Q, Mittereder N, Chae S, Stefansson S, Liau G, Hla T (2002) Extracellular export of sphingosine kinase-1 enzyme. Sphingosine 1-phosphate generation and the induction of angiogenic vascular maturation. J Biol Chem 277:6667–6675PubMedGoogle Scholar
  33. 33.
    Venkataraman K, Thangada S, Michaud J, Oo ML, Ai Y, Lee YM, Wu M, Parikh NS, Khan F, Proia RL, Hla T (2006) Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient. Biochem J 397:461–471PubMedGoogle Scholar
  34. 34.
    Mitra P, Oskeritzian CA, Payne SG, Beaven MA, Milstien S, Spiegel S (2006) Role of ABCC1 in export of sphingosine-1-phosphate from mast cells. Proc Natl Acad Sci USA 103:16394–16399PubMedGoogle Scholar
  35. 35.
    Kobayashi N, Nishi T, Hirata T, Kihara A, Sano T, Igarashi Y, Yamaguchi A (2006) Sphingosine 1-phosphate is released from the cytosol of rat platelets in a carrier-mediated manner. J Lipid Res 47:614–621PubMedGoogle Scholar
  36. 36.
    Sato K, Malchinkhuu E, Horiuchi Y, Mogi C, Tomura H, Tosaka M, Yoshimoto Y, Kuwabara A, Okajima F (2007) Critical role of ABCA1 transporter in sphingosine 1-phosphate release from astrocytes. J Neurochem 103:2610–2619PubMedGoogle Scholar
  37. 37.
    Nieuwenhuis B, Lüth A, Chun J, Huwiler A, Pfeilschifter J, Schäfer-Korting M, Kleuser B (2009) Involvement of the ABC-transporter ABCC1 and the sphingosine 1-phosphate receptor subtype S1P3 in the cytoprotection of human fibroblasts by the glucocorticoid dexamethasone. J Mol Med 87:645–657PubMedGoogle Scholar
  38. 38.
    Takabe K, Kim RH, Allegood JC, Mitra P, Ramachandran S, Nagahashi M, Harikumar KB, Hait NC, Milstien S, Spiegel S (2010) Estradiol induces export of sphingosine 1-phosphate from breast cancer cells via ABCC1 and ABCG2. J Biol Chem 285:10477–10486PubMedGoogle Scholar
  39. 39.
    Lee Y, Venkataraman K, Hwang S, Han D, Hla T (2007) A novel method to quantify sphingosine 1-phosphate by immobilized metal affinity chromatography (IMAC). Prostaglandins Other Lipid Mediat 84:154–162PubMedGoogle Scholar
  40. 40.
    Kawahara A, Nishi T, Hisano Y, Fukui H, Yamaguchi A, Mochizuki N (2009) The sphingolipid transporter spns2 functions in migration of zebrafish myocardial precursors. Science 323:524–527PubMedGoogle Scholar
  41. 41.
    Hisano Y, Kobayashi N, Kawahara A, Yamaguchi A, Nishi T (2011) The sphingosine 1-phosphate transporter, SPNS2, functions as a transporter of the phosphorylated form of the immunomodulating agent FTY720. J Biol Chem 286:1758–1766PubMedGoogle Scholar
  42. 42.
    Murata N, Sato K, Kon J, Tomura H, Yanagita M, Kuwabara A, Ui M, Okajima F (2000) Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem J 352:809–815PubMedGoogle Scholar
  43. 43.
    Christoffersen C, Obinata H, Kumaraswamy SB, Galvani S, Ahnström J, Sevvana M, Egerer-Sieber C, Muller YA, Hla T, Nielsen LB, Dahlbäck B (2011) Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. Proc Natl Acad Sci USA 108:9613–9618Google Scholar
  44. 44.
    Xu N, Dahlbäck B (1999) A novel human apolipoprotein (apoM). J Biol Chem 274:31286–31290PubMedGoogle Scholar
  45. 45.
    Christoffersen C, Ahnström J, Axler O, Christensen EI, Dahlbäck B, Nielsen LB (2008) The signal peptide anchors apolipoprotein M in plasma lipoproteins and prevents rapid clearance of apolipoprotein M from plasma. J Biol Chem 283:18765–18772PubMedGoogle Scholar
  46. 46.
    Axler O, Ahnström J, Dahlbäck B (2008) Apolipoprotein M associates to lipoproteins through its retained signal peptide. FEBS Lett 582:826–828PubMedGoogle Scholar
  47. 47.
    Sevvana M, Ahnström J, Egerer-Sieber C, Lange HA, Dahlbäck B, Muller YA (2009) Serendipitous fatty acid binding reveals the structural determinants for ligand recognition in apolipoprotein M. J Mol Biol 393:920–936PubMedGoogle Scholar
  48. 48.
    Christoffersen C, Nielsen LB, Axler O, Andersson A, Johnsen AH, Dahlbäck B (2006) Isolation and characterization of human apolipoprotein M-containing lipoproteins. J Lipid Res 47:1833–1843PubMedGoogle Scholar
  49. 49.
    Lee M, Van Brocklyn J, Thangada S, Liu C, Hand A, Menzeleev R, Spiegel S, Hla T (1998) Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279:1552PubMedGoogle Scholar
  50. 50.
    Chun J, Goetzl EJ, Hla T, Igarashi Y, Lynch KR, Moolenaar W, Pyne S, Tigyi G (2002) International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol Rev 54:265–269PubMedGoogle Scholar
  51. 51.
    Gräler MH, Bernhardt G, Lipp M (1998) EDG6, a novel G-protein-coupled receptor related to receptors for bioactive lysophospholipids, is specifically expressed in lymphoid tissue. Genomics 53:164–169PubMedGoogle Scholar
  52. 52.
    Graeler M, Goetzl EJ (2002) Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J 16:1874–1878PubMedGoogle Scholar
  53. 53.
    Jolly PS, Rosenfeldt HM, Milstien S, Spiegel S (2002) The roles of sphingosine-1-phosphate in asthma. Mol Immunol 38:1239–1245PubMedGoogle Scholar
  54. 54.
    Im DS, Heise CE, Ancellin N, O'Dowd BF, Shei GJ, Heavens RP, Rigby MR, Hla T, Mandala S, McAllister G, George SR, Lynch KR (2000) Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. J Biol Chem 275:14281–14286PubMedGoogle Scholar
  55. 55.
    Terai K, Soga T, Takahashi M, Kamohara M, Ohno K, Yatsugi S, Okada M, Yamaguchi T (2003) Edg-8 receptors are preferentially expressed in oligodendrocyte lineage cells of the rat CNS. Neuroscience 116:1053–1062PubMedGoogle Scholar
  56. 56.
    Lee MJ, Thangada S, Paik JH, Sapkota GP, Ancellin N, Chae SS, Wu M, Morales-Ruiz M, Sessa WC, Alessi DR, Hla T (2001) Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis. Mol Cell 8:693–704PubMedGoogle Scholar
  57. 57.
    Ryu Y, Takuwa N, Sugimoto N, Sakurada S, Usui S, Okamoto H, Matsui O, Takuwa Y (2002) Sphingosine-1-phosphate, a platelet-derived lysophospholipid mediator, negatively regulates cellular Rac activity and cell migration in vascular smooth muscle cells. Circ Res 90:325–332PubMedGoogle Scholar
  58. 58.
    Sugimoto N, Takuwa N, Okamoto H, Sakurada S, Takuwa Y (2003) Inhibitory and stimulatory regulation of Rac and cell motility by the G12/13-Rho and Gi pathways integrated downstream of a single G protein-coupled sphingosine-1-phosphate receptor isoform. Mol Cell Biol 23:1534–1545PubMedGoogle Scholar
  59. 59.
    Sanchez T, Thangada S, Wu M, Kontos CD, Wu D, Wu H, Hla T (2005) PTEN as an effector in the signaling of antimigratory G protein-coupled receptor. Proc Natl Acad Sci USA 102:4312–4317PubMedGoogle Scholar
  60. 60.
    Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK, Luo C, Marmorstein R, Kordula T, Milstien S, Spiegel S (2009) Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325:1254–1257PubMedGoogle Scholar
  61. 61.
    Alvarez SE, Harikumar KB, Hait NC, Allegood J, Strub GM, Kim EY, Maceyka M, Jiang H, Luo C, Kordula T, Milstien S, Spiegel S (2010) Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 465:1084–1088PubMedGoogle Scholar
  62. 62.
    Liu Y, Wada R, Yamashita T, Mi Y, Deng CX, Hobson JP, Rosenfeldt HM, Nava VE, Chae SS, Lee MJ, Liu CH, Hla T, Spiegel S, Proia RL (2000) Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest 106:951–961PubMedGoogle Scholar
  63. 63.
    Allende ML, Yamashita T, Proia RL (2003) G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood 102:3665–3667PubMedGoogle Scholar
  64. 64.
    Paik J, Skoura A, Chae S, Cowan AE, Han DK, Proia RL, Hla T (2004) Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev 18:2392–2403PubMedGoogle Scholar
  65. 65.
    Camerer E, Regard JB, Cornelissen I, Srinivasan Y, Duong DN, Palmer D, Pham TH, Wong JS, Pappu R, Coughlin SR (2009) Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice. J Clin Invest 119:1871–1879PubMedGoogle Scholar
  66. 66.
    Ishii I, Friedman B, Ye X, Kawamura S, McGiffert C, Contos JJ, Kingsbury MA, Zhang G, Brown JH, Chun J (2001) Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LPB3/EDG-3. J Biol Chem 276:33697–33704PubMedGoogle Scholar
  67. 67.
    Ishii I, Ye X, Friedman B, Kawamura S, Contos JJ, Kingsbury MA, Yang AH, Zhang G, Brown JH, Chun J (2002) Marked perinatal lethality and cellular signaling deficits in mice null for the two sphingosine 1-phosphate (S1P) receptors, S1P2/LPB2/EDG-5 and S1P3/LPB3/EDG-3. J Biol Chem 277:25152–25159PubMedGoogle Scholar
  68. 68.
    Kono M, Mi Y, Liu Y, Sasaki T, Allende ML, Wu Y, Yamashita T, Proia RL (2004) The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J Biol Chem 279:29367–29373PubMedGoogle Scholar
  69. 69.
    MacLennan AJ, Carney PR, Zhu WJ, Chaves AH, Garcia J, Grimes JR, Anderson KJ, Roper SN, Lee N (2001) An essential role for the H218/AGR16/Edg-5/LPB2 sphingosine 1-phosphate receptor in neuronal excitability. Eur J Neurosci 14:203–209PubMedGoogle Scholar
  70. 70.
    Herr DR, Grillet N, Schwander M, Rivera R, Müller U, Chun J (2007) Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2. J Neurosci 27:1474–1478PubMedGoogle Scholar
  71. 71.
    Kono M, Belyantseva IA, Skoura A, Frolenkov GI, Starost MF, Dreier JL, Lidington D, Bolz SS, Friedman TB, Hla T, Proia RL (2007) Deafness and stria vascularis defects in S1P2 receptor-null mice. J Biol Chem 282:10690–10696PubMedGoogle Scholar
  72. 72.
    Ishii M, Kikuta J, Shimazu Y, Meier-Schellersheim M, Germain RN (2010) Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo. J Exp Med 207:2793–2798PubMedGoogle Scholar
  73. 73.
    Michaud J, Im D, Hla T (2010) Inhibitory role of sphingosine 1-phosphate receptor 2 in macrophage recruitment during inflammation. J Immunol 184:1475–1483PubMedGoogle Scholar
  74. 74.
    Skoura A, Sanchez T, Claffey K, Mandala SM, Proia RL, Hla T (2007) Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina. J Clin Invest 117:2506–2516PubMedGoogle Scholar
  75. 75.
    Du W, Takuwa N, Yoshioka K, Okamoto Y, Gonda K, Sugihara K, Fukamizu A, Asano M, Takuwa Y (2010) S1P2, the G protein-coupled receptor for sphingosine-1-phosphate, negatively regulates tumor angiogenesis and tumor growth in vivo in mice. Cancer Res 70:772–781PubMedGoogle Scholar
  76. 76.
    Wang F, Okamoto Y, Inoki I, Yoshioka K, Du W, Qi X, Takuwa N, Gonda K, Yamamoto Y, Ohkawa R, Nishiuchi T, Sugimoto N, Yatomi Y, Mitsumori K, Asano M, Kinoshita M, Takuwa Y (2010) Sphingosine-1-phosphate receptor-2 deficiency leads to inhibition of macrophage proinflammatory activities and atherosclerosis in apoE-deficient mice. J Clin Invest 120:3979–3995PubMedGoogle Scholar
  77. 77.
    Skoura A, Michaud J, Im D, Thangada S, Xiong Y, Smith JD, Hla T (2011) Sphingosine-1-phosphate receptor-2 function in myeloid cells regulates vascular inflammation and atherosclerosis. Arterioscler Thromb Vasc Biol 31:81–85PubMedGoogle Scholar
  78. 78.
    Sanna MG, Liao J, Jo E, Alfonso C, Ahn MY, Peterson MS, Webb B, Lefebvre S, Chun J, Gray N, Rosen H (2004) Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem 279:13839–13848PubMedGoogle Scholar
  79. 79.
    Forrest M, Sun SY, Hajdu R, Bergstrom J, Card D, Doherty G, Hale J, Keohane C, Meyers C, Milligan J, Mills S, Nomura N, Rosen H, Rosenbach M, Shei GJ, Singer II, Tian M, West S, White V, Xie J, Proia RL, Mandala S (2004) Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J Pharmacol Exp Ther 309:758–768PubMedGoogle Scholar
  80. 80.
    Levkau B, Hermann S, Theilmeier G, van der Giet M, Chun J, Schober O, Schäfers M (2004) High-density lipoprotein stimulates myocardial perfusion in vivo. Circulation 110:3355–3359PubMedGoogle Scholar
  81. 81.
    Theilmeier G, Schmidt C, Herrmann J, Keul P, Schäfers M, Herrgott I, Mersmann J, Larmann J, Hermann S, Stypmann J, Schober O, Hildebrand R, Schulz R, Heusch G, Haude M, von Wnuck Lipinski K, Herzog C, Schmitz M, Erbel R, Chun J, Levkau B (2006) Sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. Circulation 114:1403–1409PubMedGoogle Scholar
  82. 82.
    Means CK, Xiao C, Li Z, Zhang T, Omens JH, Ishii I, Chun J, Brown JH (2007) Sphingosine 1-phosphate S1P2 and S1P3 receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 292:H2944–H2951PubMedGoogle Scholar
  83. 83.
    Nofer J, Giet MVD, Tölle M, Wolinska I, von Wnuck Lipinski K, Baba HA, Tietge UJ, Gödecke A, Ishii I, Kleuser B, Schäfers M, Fobker M, Zidek W, Assmann G, Chun J, Levkau B (2004) HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest 113:569–581PubMedGoogle Scholar
  84. 84.
    Takuwa N, Ohkura S, Takashima S, Ohtani K, Okamoto Y, Tanaka T, Hirano K, Usui S, Wang F, Du W, Yoshioka K, Banno Y, Sasaki M, Ichi I, Okamura M, Sugimoto N, Mizugishi K, Nakanuma Y, Ishii I, Takamura M, Kaneko S, Kojo S, Satouchi K, Mitumori K, Chun J, Takuwa Y (2010) S1P3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species. Cardiovasc Res 85:484–493PubMedGoogle Scholar
  85. 85.
    Girkontaite I, Sakk V, Wagner M, Borggrefe T, Tedford K, Chun J, Fischer K (2004) The sphingosine-1-phosphate (S1P) lysophospholipid receptor S1P3 regulates MAdCAM-1+ endothelial cells in splenic marginal sinus organization. J Exp Med 200:1491–1501PubMedGoogle Scholar
  86. 86.
    Walter DH, Rochwalsky U, Reinhold J, Seeger F, Aicher A, Urbich C, Spyridopoulos I, Chun J, Brinkmann V, Keul P, Levkau B, Zeiher AM, Dimmeler S, Haendeler J (2007) Sphingosine-1-phosphate stimulates the functional capacity of progenitor cells by activation of the CXCR4-dependent signaling pathway via the S1P3 receptor. Arterioscler Thromb Vasc Biol 27:275–282PubMedGoogle Scholar
  87. 87.
    Niessen F, Schaffner F, Furlan-Freguia C, Pawlinski R, Bhattacharjee G, Chun J, Derian CK, Andrade-Gordon P, Rosen H, Ruf W (2008) Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature 452:654–658PubMedGoogle Scholar
  88. 88.
    Keul P, Lucke S, von Wnuck Lipinski K, Bode C, Gräler M, Heusch G, Levkau B (2011) Sphingosine-1-phosphate receptor 3 promotes recruitment of monocyte/macrophages in inflammation and atherosclerosis. Circ Res 108:314–323PubMedGoogle Scholar
  89. 89.
    Wang W, Graeler MH, Goetzl EJ (2005) Type 4 sphingosine 1-phosphate G protein-coupled receptor (S1P4) transduces S1P effects on T cell proliferation and cytokine secretion without signaling migration. FASEB J 19:1731–1733PubMedGoogle Scholar
  90. 90.
    Golfier S, Kondo S, Schulze T, Takeuchi T, Vassileva G, Achtman AH, Graler MH, Abbondanzo SJ, Wiekowski M, Kremmer E, Endo Y, Lira SA, Bacon KB, Lipp M (2010) Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine-1-phosphate receptor S1P4. FASEB J 24:4701–4710PubMedGoogle Scholar
  91. 91.
    Jaillard C, Harrison S, Stankoff B, Aigrot MS, Calver AR, Duddy G, Walsh FS, Pangalos MN, Arimura N, Kaibuchi K, Zalc B, Lubetzki C (2005) Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci 25:1459–1469PubMedGoogle Scholar
  92. 92.
    Walzer T, Chiossone L, Chaix J, Calver A, Carozzo C, Garrigue-Antar L, Jacques Y, Baratin M, Tomasello E, Vivier E (2007) Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat Immunol 8:1337–1344PubMedGoogle Scholar
  93. 93.
    Jenne CN, Enders A, Rivera R, Watson SR, Bankovich AJ, Pereira JP, Xu Y, Roots CM, Beilke JN, Banerjee A, Reiner SL, Miller SA, Weinmann AS, Goodnow CC, Lanier LL, Cyster JG, Chun J (2009) T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow. J Exp Med 206:2469–2481PubMedGoogle Scholar
  94. 94.
    Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, Vera AD, Jin J, Stites T, Wu S, Aradhye S, Kappos L (2010) Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362:402–415PubMedGoogle Scholar
  95. 95.
    Kappos L, Radue EW, O'connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P (2010) A placebo-controlled trial of oral Fingolimod in relapsing multiple sclerosis. N Engl J Med 362:387PubMedGoogle Scholar
  96. 96.
    Schwab SR, Cyster JG (2007) Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol 8:1295–1301PubMedGoogle Scholar
  97. 97.
    Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P (2010) Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 9:883–897PubMedGoogle Scholar
  98. 98.
    Adachi K, Kohara T, Nakao N, Arita M, Chiba K, Mishina T, Sasaki S, Fujita T (1995) Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1,3-propanediols: discovery of a novel immunosuppressant, FTY720. Bioorg Med Chem Lett 5:853–856Google Scholar
  99. 99.
    Fujita T, Inoue K, Yamamoto S, Ikumoto T, Sasaki S, Toyama R, Chiba K, Hoshino Y, Okumoto T (1994) Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J Antibiot 47:208–215PubMedGoogle Scholar
  100. 100.
    Chiba K, Yanagawa Y, Masubuchi Y, Kataoka H, Kawaguchi T, Ohtsuki M, Hoshino Y (1998) FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol 160:5037–5044PubMedGoogle Scholar
  101. 101.
    Yanagawa Y, Sugahara K, Kataoka H, Kawaguchi T, Masubuchi Y, Chiba K (1998) FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. J Immunol 160:5493–5499PubMedGoogle Scholar
  102. 102.
    Sanchez T, Estrada-Hernandez T, Paik J, Wu MT, Venkataraman K, Brinkmann V, Claffey K, Hla T (2003) Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. J Biol Chem 278:47281–47290PubMedGoogle Scholar
  103. 103.
    Kharel Y, Lee S, Snyder AH, Sheasley-O'neill SL, Morris MA, Setiady Y, Zhu R, Zigler MA, Burcin TL, Ley K, Tung KS, Engelhard VH, Macdonald TL, Pearson-White S, Lynch KR (2005) Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720. J Biol Chem 280:36865–36872PubMedGoogle Scholar
  104. 104.
    Zemann B, Kinzel B, Müller M, Reuschel R, Mechtcheriakova D, Urtz N, Bornancin F, Baumruker T, Billich A (2006) Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720. Blood 107:1454–1458PubMedGoogle Scholar
  105. 105.
    Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, Foster CA, Zollinger M, Lynch KR (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277:21453–21457PubMedGoogle Scholar
  106. 106.
    Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W, Rosen H (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296:346–349PubMedGoogle Scholar
  107. 107.
    Liu CH, Thangada S, Lee MJ, Van Brocklyn JR, Spiegel S, Hla T (1999) Ligand-induced trafficking of the sphingosine-1-phosphate receptor EDG-1. Mol Biol Cell 10:1179–1190PubMedGoogle Scholar
  108. 108.
    Oo ML, Thangada S, Wu M, Liu CH, Macdonald TL, Lynch KR, Lin C, Hla T (2007) Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem 282:9082–9089PubMedGoogle Scholar
  109. 109.
    Oo ML, Chang S, Thangada S, Wu MT, Rezaul K, Blaho V, Hwang S, Han DK, Hla T (2011) Engagement of S1P1-degradative mechanisms leads to vascular leak in mice. J Clin Invest 121:2290–2300Google Scholar
  110. 110.
    Thangada S, Khanna KM, Blaho VA, Oo ML, Im D, Guo C, Lefrancois L, Hla T (2010) Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics. J Exp Med 207:1475–1483PubMedGoogle Scholar
  111. 111.
    Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427:355–360PubMedGoogle Scholar
  112. 112.
    Czeloth N, Bernhardt G, Hofmann F, Genth H, Förster R (2005) Sphingosine-1-phosphate mediates migration of mature dendritic cells. J Immunol 175:2960–2967PubMedGoogle Scholar
  113. 113.
    Massberg S, Schaerli P, Knezevic-Maramica I, Köllnberger M, Tubo N, Moseman EA, Huff IV, Junt T, Wagers AJ, Mazo IB, von Andrian UH (2007) Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131:994–1008PubMedGoogle Scholar
  114. 114.
    Brinkmann V (2007) Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 115:84–105PubMedGoogle Scholar
  115. 115.
    Rivera J, Proia RL, Olivera A (2008) The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol 8:753–763PubMedGoogle Scholar
  116. 116.
    Nixon GF (2009) Sphingolipids in inflammation: pathological implications and potential therapeutic targets. Br J Pharmacol 158:982–993PubMedGoogle Scholar
  117. 117.
    Okajima F, Sato K, Kimura T (2009) Anti-atherogenic actions of high-density lipoprotein through sphingosine 1-phosphate receptors and scavenger receptor class B type I. Endocr J 56:317–334PubMedGoogle Scholar
  118. 118.
    Ruf W, Furlan-Freguia C, Niessen F (2009) Vascular and dendritic cell coagulation signaling in sepsis progression. J Thromb Haemost 7(Suppl 1):118–121PubMedGoogle Scholar
  119. 119.
    Lucke S, Levkau B (2010) Endothelial functions of sphingosine-1-phosphate. Cell Physiol Biochem 26:87–96PubMedGoogle Scholar
  120. 120.
    Pyne NJ, Pyne S (2010) Sphingosine 1-phosphate and cancer. Nat Rev Cancer 10:489–503PubMedGoogle Scholar
  121. 121.
    Spiegel S, Milstien S (2011) The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol 11:403–415Google Scholar
  122. 122.
    Yatomi Y, Ruan F, Hakomori S, Igarashi Y (1995) Sphingosine-1-phosphate: a platelet-activating sphingolipid released from agonist-stimulated human platelets. Blood 86:193–202PubMedGoogle Scholar
  123. 123.
    Yatomi Y, Yamamura S, Ruan F, Igarashi Y (1997) Sphingosine 1-phosphate induces platelet activation through an extracellular action and shares a platelet surface receptor with lysophosphatidic acid. J Biol Chem 272:5291–5297PubMedGoogle Scholar
  124. 124.
    Caligan TB, Peters K, Ou J, Wang E, Saba J, Merrill AH (2000) A high-performance liquid chromatographic method to measure sphingosine 1-phosphate and related compounds from sphingosine kinase assays and other biological samples. Anal Biochem 281:36–44PubMedGoogle Scholar
  125. 125.
    Ruwisch L, Schäfer-Korting M, Kleuser B (2001) An improved high-performance liquid chromatographic method for the determination of sphingosine-1-phosphate in complex biological materials. Naunyn Schmiedebergs Arch Pharmacol 363:358–363PubMedGoogle Scholar
  126. 126.
    Yatomi Y, Ruan F, Ohta J, Welch RJ, Hakomori S, Igarashi Y (1995) Quantitative measurement of sphingosine 1-phosphate in biological samples by acylation with radioactive acetic anhydride. Anal Biochem 230:315–320PubMedGoogle Scholar
  127. 127.
    Pham TH, Baluk P, Xu Y, Grigorova I, Bankovich AJ, Pappu R, Coughlin SR, McDonald DM, Schwab SR, Cyster JG (2010) Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. J Exp Med 207:17–27PubMedGoogle Scholar
  128. 128.
    Lee MJ, Thangada S, Claffey KP, Ancellin N, Liu CH, Kluk M, Volpi M, Sha'afi RI, Hla T (1999) Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 99:301–312PubMedGoogle Scholar
  129. 129.
    Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA, Gerthoffer WT, Bamberg JR, English D (2001) Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J Clin Invest 108:689–701PubMedGoogle Scholar
  130. 130.
    Singleton PA, Dudek SM, Ma S, Garcia JG (2006) Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation. Novel role for hyaluronan and CD44 receptor family. J Biol Chem 281:34381–34393PubMedGoogle Scholar
  131. 131.
    Singleton PA, Moreno-Vinasco L, Sammani S, Wanderling SL, Moss J, Garcia JG (2007) Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation. Am J Respir Cell Mol Biol 37:222–231PubMedGoogle Scholar
  132. 132.
    Spindler V, Schlegel N, Waschke J (2010) Role of GTPases in control of microvascular permeability. Cardiovasc Res 87:243–253PubMedGoogle Scholar
  133. 133.
    Sanchez T, Skoura A, Wu MT, Casserly B, Harrington EO, Hla T (2007) Induction of vascular permeability by the sphingosine-1-phosphate receptor-2 (S1P2R) and its downstream effectors ROCK and PTEN. Arterioscler Thromb Vasc Biol 27:1312–1318PubMedGoogle Scholar
  134. 134.
    Peng X, Hassoun PM, Sammani S, McVerry BJ, Burne MJ, Rabb H, Pearse D, Tuder RM, Garcia JG (2004) Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury. Am J Respir Crit Care Med 169:1245–1251PubMedGoogle Scholar
  135. 135.
    Sammani S, Moreno-Vinasco L, Mirzapoiazova T, Singleton PA, Chiang ET, Evenoski CL, Wang T, Mathew B, Husain A, Moitra J, Sun X, Nunez L, Jacobson JR, Dudek SM, Natarajan V, Garcia JG (2010) Differential effects of sphingosine 1-phosphate receptors on airway and vascular barrier function in the murine lung. Am J Respir Cell Mol Biol 43:394–402PubMedGoogle Scholar
  136. 136.
    Sanna MG, Wang SK, Gonzalez-Cabrera PJ, Don A, Marsolais D, Matheu MP, Wei SH, Parker I, Jo E, Cheng WC, Cahalan MD, Wong CH, Rosen H (2006) Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat Chem Biol 2:434–441PubMedGoogle Scholar
  137. 137.
    Tauseef M, Kini V, Knezevic N, Brannan M, Ramchandaran R, Fyrst H, Saba J, Vogel SM, Malik AB, Mehta D (2008) Activation of sphingosine kinase-1 reverses the increase in lung vascular permeability through sphingosine-1-phosphate receptor signaling in endothelial cells. Circ Res 103:1164–1172PubMedGoogle Scholar
  138. 138.
    Zhao YD, Ohkawara H, Rehman J, Wary KK, Vogel SM, Minshall RD, Zhao YY, Malik AB (2009) Bone marrow progenitor cells induce endothelial adherens junction integrity by sphingosine-1-phosphate-mediated Rac1 and Cdc42 signaling. Circ Res 105:696–704PubMedGoogle Scholar
  139. 139.
    Wang F, Van Brocklyn JR, Hobson JP, Movafagh S, Zukowska-Grojec Z, Milstien S, Spiegel S (1999) Sphingosine 1-phosphate stimulates cell migration through a Gi-coupled cell surface receptor. Potential involvement in angiogenesis. J Biol Chem 274:35343–35350PubMedGoogle Scholar
  140. 140.
    Kimura T, Watanabe T, Sato K, Kon J, Tomura H, Tamama K, Kuwabara A, Kanda T, Kobayashi I, Ohta H, Ui M, Okajima F (2000) Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3. Biochem J 348(Pt 1):71–76PubMedGoogle Scholar
  141. 141.
    Morales-Ruiz M, Lee MJ, Zöllner S, Gratton JP, Scotland R, Shiojima I, Walsh K, Hla T, Sessa WC (2001) Sphingosine 1-phosphate activates Akt, nitric oxide production, and chemotaxis through a Gi protein/phosphoinositide 3-kinase pathway in endothelial cells. J Biol Chem 276:19672–19677PubMedGoogle Scholar
  142. 142.
    Paik JH, Chae SS, Lee MJ, Thangada S, Hla T (2001) Sphingosine 1-phosphate-induced endothelial cell migration requires the expression of EDG-1 and EDG-3 receptors and Rho-dependent activation of αvβ3- and β1-containing integrins. J Biol Chem 276:11830–11837PubMedGoogle Scholar
  143. 143.
    Liu F, Verin AD, Wang P, Day R, Wersto RP, Chrest FJ, English DK, Garcia JG (2001) Differential regulation of sphingosine-1-phosphate- and VEGF-induced endothelial cell chemotaxis. Involvement of Giα2-linked Rho kinase activity. Am J Respir Cell Mol Biol 24:711–719PubMedGoogle Scholar
  144. 144.
    English D, Welch Z, Kovala AT, Harvey K, Volpert OV, Brindley DN, Garcia JG (2000) Sphingosine 1-phosphate released from platelets during clotting accounts for the potent endothelial cell chemotactic activity of blood serum and provides a novel link between hemostasis and angiogenesis. FASEB J 14:2255–2265PubMedGoogle Scholar
  145. 145.
    Yatomi Y, Ohmori T, Rile G, Kazama F, Okamoto H, Sano T, Satoh K, Kume S, Tigyi G, Igarashi Y, Ozaki Y (2000) Sphingosine 1-phosphate as a major bioactive lysophospholipid that is released from platelets and interacts with endothelial cells. Blood 96:3431–3438PubMedGoogle Scholar
  146. 146.
    English D, Garcia JG, Brindley DN (2001) Platelet-released phospholipids link haemostasis and angiogenesis. Cardiovasc Res 49:588–599PubMedGoogle Scholar
  147. 147.
    Chae S, Paik J, Furneaux H, Hla T (2004) Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference. J Clin Invest 114:1082–1089PubMedGoogle Scholar
  148. 148.
    Takeya H, Gabazza EC, Aoki S, Ueno H, Suzuki K (2003) Synergistic effect of sphingosine 1-phosphate on thrombin-induced tissue factor expression in endothelial cells. Blood 102:1693–1700PubMedGoogle Scholar
  149. 149.
    Matsushita K, Morrell CN, Lowenstein CJ (2004) Sphingosine 1-phosphate activates Weibel–Palade body exocytosis. Proc Natl Acad Sci USA 101:11483–11487PubMedGoogle Scholar
  150. 150.
    Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407:258–264PubMedGoogle Scholar
  151. 151.
    Riewald M, Ruf W (2001) Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc Natl Acad Sci USA 98:7742–7747PubMedGoogle Scholar
  152. 152.
    Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W (2002) Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296:1880–1882PubMedGoogle Scholar
  153. 153.
    Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL, Esmon CT (1996) The endothelial cell protein C receptor augments protein C activation by the thrombin–thrombomodulin complex. Proc Natl Acad Sci USA 93:10212–10216PubMedGoogle Scholar
  154. 154.
    Feistritzer C, Riewald M (2005) Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 105:3178–3184PubMedGoogle Scholar
  155. 155.
    Finigan JH, Dudek SM, Singleton PA, Chiang ET, Jacobson JR, Camp SM, Ye SQ, Garcia JG (2005) Activated protein C mediates novel lung endothelial barrier enhancement: role of sphingosine 1-phosphate receptor transactivation. J Biol Chem 280:17286–17293PubMedGoogle Scholar
  156. 156.
    Feistritzer C, Schuepbach RA, Mosnier LO, Bush LA, Di Cera E, Griffin JH, Riewald M (2006) Protective signaling by activated protein C is mechanistically linked to protein C activation on endothelial cells. J Biol Chem 281:20077–20084PubMedGoogle Scholar
  157. 157.
    Bae J, Yang L, Manithody C, Rezaie AR (2007) The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood 110:3909–3916PubMedGoogle Scholar
  158. 158.
    Bae J, Yang L, Rezaie AR (2008) Lipid raft localization regulates the cleavage specificity of protease activated receptor 1 in endothelial cells. J Thromb Haemost 6:954–961PubMedGoogle Scholar
  159. 159.
    Castellino FJ, Liang Z, Volkir SP, Haalboom E, Martin JA, Sandoval-Cooper MJ, Rosen ED (2002) Mice with a severe deficiency of the endothelial protein C receptor gene develop, survive, and reproduce normally, and do not present with enhanced arterial thrombosis after challenge. Thromb Haemost 88:462–472PubMedGoogle Scholar
  160. 160.
    Weiler H, Lindner V, Kerlin B, Isermann BH, Hendrickson SB, Cooley BC, Meh DA, Mosesson MW, Shworak NW, Post MJ, Conway EM, Ulfman LH, von Andrian UH, Weitz JI (2001) Characterization of a mouse model for thrombomodulin deficiency. Arterioscler Thromb Vasc Biol 21:1531–1537PubMedGoogle Scholar
  161. 161.
    Niessen F, Furlan-Freguia C, Fernández JA, Mosnier LO, Castellino FJ, Weiler H, Rosen H, Griffin JH, Ruf W (2009) Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality. Blood 113:2859–2866PubMedGoogle Scholar
  162. 162.
    Dawicki W, Marshall JS (2007) New and emerging roles for mast cells in host defence. Curr Opin Immunol 19:31–38PubMedGoogle Scholar
  163. 163.
    Choi OH, Kim JH, Kinet JP (1996) Calcium mobilization via sphingosine kinase in signalling by the Fc epsilon RI antigen receptor. Nature 380:634–636PubMedGoogle Scholar
  164. 164.
    Prieschl EE, Csonga R, Novotny V, Kikuchi GE, Baumruker T (1999) The balance between sphingosine and sphingosine-1-phosphate is decisive for mast cell activation after Fc epsilon receptor I triggering. J Exp Med 190:1–8PubMedGoogle Scholar
  165. 165.
    Melendez AJ, Khaw AK (2002) Dichotomy of Ca2+ signals triggered by different phospholipid pathways in antigen stimulation of human mast cells. J Biol Chem 277:17255–17262PubMedGoogle Scholar
  166. 166.
    Olivera A, Urtz N, Mizugishi K, Yamashita Y, Gilfillan AM, Furumoto Y, Gu H, Proia RL, Baumruker T, Rivera J (2006) IgE-dependent activation of sphingosine kinases 1 and 2 and secretion of sphingosine 1-phosphate requires Fyn kinase and contributes to mast cell responses. J Biol Chem 281:2515–2525PubMedGoogle Scholar
  167. 167.
    Olivera A, Mizugishi K, Tikhonova A, Ciaccia L, Odom S, Proia RL, Rivera J (2007) The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis. Immunity 26:287–297PubMedGoogle Scholar
  168. 168.
    Jolly PS, Bektas M, Olivera A, Gonzalez-Espinosa C, Proia RL, Rivera J, Milstien S, Spiegel S (2004) Transactivation of sphingosine-1-phosphate receptors by FcεRI triggering is required for normal mast cell degranulation and chemotaxis. J Exp Med 199:959–970PubMedGoogle Scholar
  169. 169.
    Oskeritzian CA, Price MM, Hait NC, Kapitonov D, Falanga YT, Morales JK, Ryan JJ, Milstien S, Spiegel S (2010) Essential roles of sphingosine-1-phosphate receptor 2 in human mast cell activation, anaphylaxis, and pulmonary edema. J Exp Med 207:465–474PubMedGoogle Scholar
  170. 170.
    Chen L, Woszczek G, Nagineni S, Logun C, Shelhamer JH (2008) Cytosolic phospholipase A2α activation induced by S1P is mediated by the S1P3 receptor in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 295:L326–L335PubMedGoogle Scholar
  171. 171.
    Melendez AJ, Ibrahim FB (2004) Antisense knockdown of sphingosine kinase 1 in human macrophages inhibits C5a receptor-dependent signal transduction, Ca2+ signals, enzyme release, cytokine production, and chemotaxis. J Immunol 173:1596–1603PubMedGoogle Scholar
  172. 172.
    Hammad SM, Crellin HG, Wu BX, Melton J, Anelli V, Obeid LM (2008) Dual and distinct roles for sphingosine kinase 1 and sphingosine 1 phosphate in the response to inflammatory stimuli in RAW macrophages. Prostaglandins Other Lipid Mediat 85:107–114PubMedGoogle Scholar
  173. 173.
    Snider AJ, Kawamori T, Bradshaw SG, Orr KA, Gilkeson GS, Hannun YA, Obeid LM (2009) A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis. FASEB J 23:143–152PubMedGoogle Scholar
  174. 174.
    Lai W, Irwan AW, Goh HH, Melendez AJ, McInnes IB, Leung BP (2009) Distinct roles of sphingosine kinase 1 and 2 in murine collagen-induced arthritis. J Immunol 183:2097–2103PubMedGoogle Scholar
  175. 175.
    Baker DA, Barth J, Chang R, Obeid LM, Gilkeson GS (2010) Genetic sphingosine kinase 1 deficiency significantly decreases synovial inflammation and joint erosions in murine TNF-α-induced arthritis. J Immunol 185:2570–2579PubMedGoogle Scholar
  176. 176.
    Puneet P, Yap CT, Wong L, Yulin L, Koh DR, Moochhala S, Pfeilschifter J, Huwiler A, Melendez AJ (2010) SphK1 regulates proinflammatory responses associated with endotoxin and polymicrobial sepsis. Science 328:1290–1294PubMedGoogle Scholar
  177. 177.
    Bolick DT, Srinivasan S, Kim KW, Hatley ME, Clemens JJ, Whetzel A, Ferger N, Macdonald TL, Davis MD, Tsao PS, Lynch KR, Hedrick CC (2005) Sphingosine-1-phosphate prevents tumor necrosis factor-α-mediated monocyte adhesion to aortic endothelium in mice. Arterioscler Thromb Vasc Biol 25:976–981PubMedGoogle Scholar
  178. 178.
    Kimura T, Tomura H, Mogi C, Kuwabara A, Ishiwara M, Shibasawa K, Sato K, Ohwada S, Im DS, Kurose H, Ishizuka T, Murakami M, Okajima F (2006) Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells. Cell Signal 18:841–850PubMedGoogle Scholar
  179. 179.
    De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA, Shin WS, Liao JK (1995) Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96:60–68PubMedGoogle Scholar
  180. 180.
    Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford RM (1996) Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci USA 93:9114–9119PubMedGoogle Scholar
  181. 181.
    Assmann G, Gotto AM (2004) HDL cholesterol and protective factors in atherosclerosis. Circulation 109:III8–III14PubMedGoogle Scholar
  182. 182.
    Choi BG, Vilahur G, Yadegar D, Viles-Gonzalez JF, Badimon JJ (2006) The role of high-density lipoprotein cholesterol in the prevention and possible treatment of cardiovascular diseases. Curr Mol Med 6:571–587PubMedGoogle Scholar
  183. 183.
    Rohrer L, Hersberger M, Eckardstein VA (2004) High density lipoproteins in the intersection of diabetes mellitus, inflammation and cardiovascular disease. Curr Opin Lipidol 15:269–278PubMedGoogle Scholar
  184. 184.
    Kimura T, Sato K, Kuwabara A, Tomura H, Ishiwara M, Kobayashi I, Ui M, Okajima F (2001) Sphingosine 1-phosphate may be a major component of plasma lipoproteins responsible for the cytoprotective actions in human umbilical vein endothelial cells. J Biol Chem 276:31780–31785PubMedGoogle Scholar
  185. 185.
    Kimura T, Sato K, Malchinkhuu E, Tomura H, Tamama K, Kuwabara A, Murakami M, Okajima F (2003) High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors. Arterioscler Thromb Vasc Biol 23:1283–1288PubMedGoogle Scholar
  186. 186.
    Kimura T, Tomura H, Mogi C, Kuwabara A, Damirin A, Ishizuka T, Sekiguchi A, Ishiwara M, Im DS, Sato K, Murakami M, Okajima F (2006) Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells. J Biol Chem 281:37457–37467PubMedGoogle Scholar
  187. 187.
    Kimura T, Tomura H, Sato K, Ito M, Matsuoka I, Im DS, Kuwabara A, Mogi C, Itoh H, Kurose H, Murakami M, Okajima F (2010) Mechanism and role of high density lipoprotein-induced activation of AMP-activated protein kinase in endothelial cells. J Biol Chem 285:4387–4397PubMedGoogle Scholar
  188. 188.
    Argraves KM, Gazzolo PJ, Groh EM, Wilkerson BA, Matsuura BS, Twal WO, Hammad SM, Argraves WS (2008) High density lipoprotein-associated sphingosine 1-phosphate promotes endothelial barrier function. J Biol Chem 283:25074–25081PubMedGoogle Scholar
  189. 189.
    Keul P, Tölle M, Lucke S, von Wnuck Lipinski K, Heusch G, Schuchardt M, der Giet VM, Levkau B (2007) The sphingosine-1-phosphate analogue FTY720 reduces atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 27:607–613PubMedGoogle Scholar
  190. 190.
    Nofer J, Bot M, Brodde M, Taylor PJ, Salm P, Brinkmann V, Van Berkel T, Assmann G, Biessen EA (2007) FTY720, a synthetic sphingosine 1 phosphate analogue, inhibits development of atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 115:501–508PubMedGoogle Scholar
  191. 191.
    Allende ML, Bektas M, Lee BG, Bonifacino E, Kang J, Tuymetova G, Chen W, Saba JD, Proia RL (2011) Sphingosine-1-phosphate lyase deficiency produces a pro-inflammatory response while impairing neutrophil trafficking. J Biol Chem 286:7348–7358PubMedGoogle Scholar

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© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical CollegeCornell UniversityNew YorkUSA

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