HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Singer, I. I. Articles by Quackenbush, E. J. Search for Related Content PubMed PubMed Citation Articles by Singer, I. I. Articles by Quackenbush, E. J.

Sphingosine-1-Phosphate Agonists Increase Macrophage Homing, Lymphocyte Contacts, and Endothelial Junctional Complex Formation in Murine Lymph Nodes

Irwin I. Singer^1,*, Min Tian^*, L. Alexandra Wickham, Jeffrey Lin, Scaria S. Matheravidathu, Michael J. Forrest, Suzanne Mandala^* and Elizabeth J. Quackenbush^1,

^* Immunology and Rheumatology, Pharmacology, and Cardiovascular Disease, Merck and Co., Inc., Merck Research Laboratories, Rahway, NJ 07065

The sphingosine-1-phosphate (S1P) receptor agonist, phosphorylated FTY720 (FTY-P), causes lymphopenia, lymphocyte sequestration in mesenteric lymph nodes (MLNs), and immunosuppression. Using multiple techniques to analyze MLN cells harvested from mice treated with S1P receptor agonists, we saw a redistribution of lymphocytes out of nodal sinuses and an expansion of follicles. Although changes in circulating monocytes were not observed with overnight exposure to FTY720, we saw a significant increase in S1P receptor 1 (S1P₁)-expressing CD68⁺ macrophages in subcapsular sinuses of FTY-P-treated MLNs. This was confirmed by quantitative analysis of F4/80⁺ cells in MLN suspensions. The sinus volume and number of S1P₁-positive cells within sinuses were also increased by FTY-P. High endothelial venules and lymphatic endothelium expressed high levels of S1P₁, and treatment with FTY-P resulted in intense staining and colocalization of CD31, -catenin, and zona occludens 1 in junctions between sinus cells. Transmission electron microscopy showed that FTY-P greatly reduced lymphocyte microvilli and increased cell-cell contacts in the parenchyma. Immunoelectron microscopy revealed that intranodal lymphocytes lacked surface expression of S1P₁, whereas S1P₁ was evident on the surface and within the cytoplasm of macrophages, endothelial cells, and stromal cells. This subcellular pattern of intranodal receptor distribution was unchanged by treatment with FTY-P. We conclude that S1P₁ agonists have profound effects on macrophages and endothelial cells, in addition to inducing lymphopenia.

This article has been cited by other articles:

				W. P. Dunworth and K. M. Caron G Protein-Coupled Receptors as Potential Drug Targets for Lymphangiogenesis and Lymphatic Vascular Diseases Arterioscler Thromb Vasc Biol, May 1, 2009; 29(5): 650 - 656. [Abstract] [Full Text] [PDF]

				D. R. Gude, S. E. Alvarez, S. W. Paugh, P. Mitra, J. Yu, R. Griffiths, S. E. Barbour, S. Milstien, and S. Spiegel Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal FASEB J, August 1, 2008; 22(8): 2629 - 2638. [Abstract] [Full Text] [PDF]

				T. Kohno and Y. Igarashi Attenuation of cell motility observed with high doses of sphingosine 1-phosphate or phosphorylated FTY720 involves RGS2 through its interactions with the receptor S1P. Genes Cells, July 1, 2008; 13(7): 747 - 757. [Abstract] [Full Text] [PDF]

				R. Klingenberg, J.-R. Nofer, M. Rudling, F. Bea, E. Blessing, M. Preusch, H. J. Grone, H. A. Katus, G. K. Hansson, and T. J. Dengler Sphingosine-1-Phosphate Analogue FTY720 Causes Lymphocyte Redistribution and Hypercholesterolemia in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2392 - 2399. [Abstract] [Full Text] [PDF]

				M. L. Oo, S. Thangada, M.-T. Wu, C. H. Liu, T. L. Macdonald, K. R. Lynch, C.-Y. Lin, and T. Hla Immunosuppressive and Anti-angiogenic Sphingosine 1-Phosphate Receptor-1 Agonists Induce Ubiquitinylation and Proteasomal Degradation of the Receptor J. Biol. Chem., March 23, 2007; 282(12): 9082 - 9089. [Abstract] [Full Text] [PDF]

				C. Nombela-Arrieta, T. R. Mempel, S. F. Soriano, I. Mazo, M. P. Wymann, E. Hirsch, C. Martinez-A., Y. Fukui, U. H. von Andrian, and J. V. Stein A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress J. Exp. Med., March 19, 2007; 204(3): 497 - 510. [Abstract] [Full Text] [PDF]

				P. J. Gonzalez-Cabrera, T. Hla, and H. Rosen Mapping Pathways Downstream of Sphingosine 1-Phosphate Subtype 1 by Differential Chemical Perturbation and Proteomics J. Biol. Chem., March 9, 2007; 282(10): 7254 - 7264. [Abstract] [Full Text] [PDF]

				P. Keul, M. Tolle, S. Lucke, K. von Wnuck Lipinski, G. Heusch, M. Schuchardt, M. van der Giet, and B. Levkau The Sphingosine-1-Phosphate Analogue FTY720 Reduces Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 607 - 613. [Abstract] [Full Text] [PDF]

				D. H. Walter, U. Rochwalsky, J. Reinhold, F. Seeger, A. Aicher, C. Urbich, I. Spyridopoulos, J. Chun, V. Brinkmann, P. Keul, et al. 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, February 1, 2007; 27(2): 275 - 282. [Abstract] [Full Text] [PDF]