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Science 296 (5566): 346-349

Copyright © 2002 by the American Association for the Advancement of Science

Alteration of Lymphocyte Trafficking by Sphingosine-1-Phosphate Receptor Agonists

Suzanne Mandala,1 Richard Hajdu,1 James Bergstrom,1 Elizabeth Quackenbush,2 Jenny Xie,2 James Milligan,1 Rosemary Thornton,1 Gan-Ju Shei,1 Deborah Card,1 CarolAnn Keohane,1 Mark Rosenbach,1 Jeffrey Hale,3 Christopher L. Lynch,3 Kathleen Rupprecht,3 William Parsons,3 Hugh Rosen1*

Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.

Departments of
1 Immunology and Rheumatology,
2 zaff;2>Pharmacology, and
3 zaff;3>Medicinal Chemistry, Merck Research Laboratories, Post Office Box 2000, Rahway, NJ 07065, USA.
*   To whom correspondence should be addressed. E-mail: hugh_rosen{at}

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   Abstract »    Full Text »    PDF »
T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow.
C. N. Jenne, A. Enders, R. Rivera, S. R. Watson, A. J. Bankovich, J. P. Pereira, Y. Xu, C. M. Roots, J. N. Beilke, A. Banerjee, et al. (2009)
J. Exp. Med. 206, 2469-2481
   Abstract »    Full Text »    PDF »
The Survival of Memory CD4+ T Cells within the Gut Lamina Propria Requires OX40 and CD30 Signals.
D. R. Withers, E. Jaensson, F. Gaspal, F. M. McConnell, B. Eksteen, G. Anderson, W. W. Agace, and P. J. L. Lane (2009)
J. Immunol. 183, 5079-5084
   Abstract »    Full Text »    PDF »
Synthetic Analogs of FTY720 [2-Amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] Differentially Regulate Pulmonary Vascular Permeability in Vivo and in Vitro.
S. M. Camp, R. Bittman, E. T. Chiang, L. Moreno-Vinasco, T. Mirzapoiazova, S. Sammani, X. Lu, C. Sun, M. Harbeck, M. Roe, et al. (2009)
J. Pharmacol. Exp. Ther. 331, 54-64
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Discontinued Postnatal Thymocyte Development in Sphingosine 1-Phosphate-Lyase-Deficient Mice.
C. Weber, A. Krueger, A. Munk, C. Bode, P. P. Van Veldhoven, and M. H. Graler (2009)
J. Immunol. 183, 4292-4301
   Abstract »    Full Text »    PDF »
Dynamic accumulation of plasmacytoid dendritic cells in lymph nodes is regulated by interferon-{beta}.
Y. Gao, B. Majchrzak-Kita, E. N. Fish, and J. L. Gommerman (2009)
Blood 114, 2623-2631
   Abstract »    Full Text »    PDF »
Ceramide Synthesis Is Modulated by the Sphingosine Analog FTY720 via a Mixture of Uncompetitive and Noncompetitive Inhibition in an Acyl-CoA Chain Length-de pend ent Manner.
S. Lahiri, H. Park, E. L. Laviad, X. Lu, R. Bittman, and A. H. Futerman (2009)
J. Biol. Chem. 284, 16090-16098
   Abstract »    Full Text »    PDF »
Immunosuppressive human anti-lymphocyte autoantibodies specific for the type 1 sphingosine 1-phosphate receptor.
J.-J. Liao, M.-C. Huang, K. Fast, K. Gundling, M. Yadav, J. R. Van Brocklyn, M. R. Wabl, and E. J. Goetzl (2009)
FASEB J 23, 1786-1796
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Targeting Protein Serine/Threonine Phosphatases for Drug Development.
J. L. McConnell and B. E. Wadzinski (2009)
Mol. Pharmacol. 75, 1249-1261
   Abstract »    Full Text »    PDF »
G Protein-Coupled Receptors as Potential Drug Targets for Lymphangiogenesis and Lymphatic Vascular Diseases.
W. P. Dunworth and K. M. Caron (2009)
Arterioscler Thromb Vasc Biol 29, 650-656
   Abstract »    Full Text »    PDF »
Sphingosine-1-phosphate and modulation of vascular tone.
J. Igarashi and T. Michel (2009)
Cardiovasc Res 82, 212-220
   Abstract »    Full Text »    PDF »
Sphingosine-1-phosphate as a mediator of high-density lipoprotein effects in cardiovascular protection.
K. Sattler and B. Levkau (2009)
Cardiovasc Res 82, 201-211
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