This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 25/5/976    most recent 01.ATV.0000162171.30089.f6v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend 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 Bolick, D. T. Articles by Hedrick, C. C. Search for Related Content PubMed PubMed Citation Articles by Bolick, D. T. Articles by Hedrick, C. C. Related Collections Lipid and lipoprotein metabolism Endothelium/vascular type/nitric oxide

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:976.)
© 2005 American Heart Association, Inc.

Vascular Biology

Sphingosine-1-Phosphate Prevents Tumor Necrosis Factor-–Mediated Monocyte Adhesion to Aortic Endothelium in Mice

David T. Bolick; Suseela Srinivasan; Kyu W. Kim; Melissa E. Hatley; Jeremy J. Clemens; Angela Whetzel; Nicole Ferger; Timothy L. Macdonald; Michael D. Davis; Philip S. Tsao; Kevin R. Lynch; Catherine C. Hedrick

From the Division of Endocrinology & Metabolism and Cardiovascular Research Center (D.T.B., S.S., M.E.H., A.W., N.F., C.C.H.), Department of Chemistry (J.J.C., T.L.M.), Department of Biochemistry & Molecular Genetics (M.D.D.), and Department of Pharmacology (K.W.K., K.R.L., C.C.H.), University of Virginia, Charlottesville, Va; Division of Cardiology (P.S.T.), Stanford University, Palo Alto, Calif.

Correspondence to Catherine C Hedrick, PhD, Cardiovascular Research Center, University of Virginia, 415 Lane Rd, MR5 G123, Charlottesville, VA 22908. E-mail cch6n{at}virginia.edu

Objective— Endothelial activation and monocyte adhesion to endothelium are key events in inflammation. Sphingosine-1-phosphate (S1P) is a sphingolipid that binds to G protein-coupled receptors on endothelial cells (ECs). We examined the role of S1P in modulating endothelial activation and monocyte–EC interactions in vivo.

Methods and Results— We injected C57BL/6J mice intravenously with tumor necrosis factor (TNF)- in the presence and absence of the S1P1 receptor agonist SEW2871 and examined monocyte adhesion. Aortas from TNF-–injected mice had a 4-fold increase in the number of monocytes bound, whereas aortas from TNF- plus SEW2871-treated mice had few monocytes bound (P<0.0001). Using siRNA, we found that inhibiting the S1P1 receptor in vascular ECs blocked the ability of S1P to prevent monocyte–EC interactions in response to TNF-. We examined signaling pathways downstream of S1P1 and found that 100 nM S1P increased phosphorylation of Akt and decreased activation of c-jun.

Conclusions— Thus, we provide the first evidence that S1P signaling through the endothelial S1P1 receptor protects the vasculature against TNF-–mediated monocyte–EC interactions in vivo.

We examined the role of sphingosine-1-phosphate (S1P) in modulating monocyte–endothelial cell (EC) interactions. S1P and a specific S1P1 receptor agonist prevented monocyte adhesion to aorta in tumor necrosis factor (TNF)-–treated mice in vivo. We provide the first evidence to our knowledge that S1P signaling through the endothelial S1P1 receptor protects the vasculature against TNF-–mediated monocyte–EC interactions in vivo.

Key Words: endothelium • sphingosine-1-phosphate • inflammation • Endothelium differentiation gene (Edg) receptors

This article has been cited by other articles:

				K. Sattler and B. Levkau Sphingosine-1-phosphate as a mediator of high-density lipoprotein effects in cardiovascular protection Cardiovasc Res, May 1, 2009; 82(2): 201 - 211. [Abstract] [Full Text] [PDF]

				A. M. Whetzel, D. T. Bolick, and C. C. Hedrick Sphingosine-1-phosphate inhibits high glucose-mediated ERK1/2 action in endothelium through induction of MAP kinase phosphatase-3 Am J Physiol Cell Physiol, February 1, 2009; 296(2): C339 - C345. [Abstract] [Full Text] [PDF]

				T. Kimura, C. Mogi, H. Tomura, A. Kuwabara, D.-S. Im, K. Sato, H. Kurose, M. Murakami, and F. Okajima Induction of Scavenger Receptor Class B Type I Is Critical for Simvastatin Enhancement of High-Density Lipoprotein-Induced Anti-Inflammatory Actions in Endothelial Cells J. Immunol., November 15, 2008; 181(10): 7332 - 7340. [Abstract] [Full Text] [PDF]

				D. Marsolais, B. Hahm, K. H. Edelmann, K. B. Walsh, M. Guerrero, Y. Hatta, Y. Kawaoka, E. Roberts, M. B. A. Oldstone, and H. Rosen Local Not Systemic Modulation of Dendritic Cell S1P Receptors in Lung Blunts Virus-Specific Immune Responses to Influenza Mol. Pharmacol., September 1, 2008; 74(3): 896 - 903. [Abstract] [Full Text] [PDF]

				B. R. Wamhoff, K. R. Lynch, T. L. Macdonald, and G. K. Owens Sphingosine-1-Phosphate Receptor Subtypes Differentially Regulate Smooth Muscle Cell Phenotype Arterioscler Thromb Vasc Biol, August 1, 2008; 28(8): 1454 - 1461. [Abstract] [Full Text] [PDF]

				A. I. Duenas, M. Aceves, I. Fernandez-Pisonero, C. Gomez, A. Orduna, M. S. Crespo, and C. Garcia-Rodriguez Selective attenuation of Toll-like receptor 2 signalling may explain the atheroprotective effect of sphingosine 1-phosphate Cardiovasc Res, August 1, 2008; 79(3): 537 - 544. [Abstract] [Full Text] [PDF]

				G. Gollmann, H. Neuwirt, C. H. Tripp, H. Mueller, G. Konwalinka, C. Heufler, N. Romani, and M. Tiefenthaler Sphingosine-1-phosphate receptor type-1 agonism impairs blood dendritic cell chemotaxis and skin dendritic cell migration to lymph nodes under inflammatory conditions Int. Immunol., July 1, 2008; 20(7): 911 - 923. [Abstract] [Full Text] [PDF]

				J. E. Hughes, S. Srinivasan, K. R. Lynch, R. L. Proia, P. Ferdek, and C. C. Hedrick Sphingosine-1-Phosphate Induces an Antiinflammatory Phenotype in Macrophages Circ. Res., April 25, 2008; 102(8): 950 - 958. [Abstract] [Full Text] [PDF]

				S. Srinivasan, D. T. Bolick, D. Lukashev, C. Lappas, M. Sitkovsky, K. R. Lynch, and C. C. Hedrick Sphingosine-1-Phosphate Reduces CD4+ T-Cell Activation in Type 1 Diabetes Through Regulation of Hypoxia-Inducible Factor Short Isoform I.1 and CD69 Diabetes, February 1, 2008; 57(2): 484 - 493. [Abstract] [Full Text] [PDF]

				M. Kim, M. Kim, N. Kim, V. D. D'Agati, C. W. Emala Sr, and H. T. Lee Isoflurane mediates protection from renal ischemia-reperfusion injury via sphingosine kinase and sphingosine-1-phosphate-dependent pathways Am J Physiol Renal Physiol, December 1, 2007; 293(6): F1827 - F1835. [Abstract] [Full Text] [PDF]

				D. Graham, M. W. McBride, M. Gaasenbeek, K. Gilday, E. Beattie, W. H. Miller, J. D. McClure, J. M. Polke, A. Montezano, R. M. Touyz, et al. Candidate Genes That Determine Response to Salt in the Stroke-Prone Spontaneously Hypertensive Rat: Congenic Analysis Hypertension, December 1, 2007; 50(6): 1134 - 1141. [Abstract] [Full Text] [PDF]

				T. Sanchez, A. Skoura, M. T. Wu, B. Casserly, E. O. Harrington, and T. Hla Induction of Vascular Permeability by the Sphingosine-1-Phosphate Receptor-2 (S1P2R) and its Downstream Effectors ROCK and PTEN Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1312 - 1318. [Abstract] [Full Text] [PDF]

				E. Tellier, A. Negre-Salvayre, B. Bocquet, S. Itohara, Y. A. Hannun, R. Salvayre, and N. Auge Role for Furin in Tumor Necrosis Factor Alpha-Induced Activation of the Matrix Metalloproteinase/Sphingolipid Mitogenic Pathway Mol. Cell. Biol., April 15, 2007; 27(8): 2997 - 3007. [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]

				D. T. Bolick, A. M. Whetzel, M. Skaflen, T. L. Deem, J. Lee, and C. C. Hedrick Absence of the G Protein-Coupled Receptor G2A in Mice Promotes Monocyte/Endothelial Interactions in Aorta Circ. Res., March 2, 2007; 100(4): 572 - 580. [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]

				J.-R. Nofer, M. Bot, M. Brodde, P. J. Taylor, P. Salm, V. Brinkmann, T. van Berkel, G. Assmann, and E. A.L. Biessen FTY720, a Synthetic Sphingosine 1 Phosphate Analogue, Inhibits Development of Atherosclerosis in Low-Density Lipoprotein Receptor Deficient Mice Circulation, January 30, 2007; 115(4): 501 - 508. [Abstract] [Full Text] [PDF]

				T. Kimura, H. Tomura, C. Mogi, A. Kuwabara, A. Damirin, T. Ishizuka, A. Sekiguchi, M. Ishiwara, D.-S. Im, K. Sato, et al. 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., December 8, 2006; 281(49): 37457 - 37467. [Abstract] [Full Text] [PDF]

				A. M. Whetzel, D. T. Bolick, S. Srinivasan, T. L. Macdonald, M. A. Morris, K. Ley, and C. C. Hedrick Sphingosine-1 Phosphate Prevents Monocyte/Endothelial Interactions in Type 1 Diabetic NOD Mice Through Activation of the S1P1 Receptor Circ. Res., September 29, 2006; 99(7): 731 - 739. [Abstract] [Full Text] [PDF]

				G. Theilmeier, C. Schmidt, J. Herrmann, P. Keul, M. Schafers, I. Herrgott, J. Mersmann, J. Larmann, S. Hermann, J. Stypmann, et al. High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P3 Lysophospholipid Receptor Circulation, September 26, 2006; 114(13): 1403 - 1409. [Abstract] [Full Text] [PDF]

				A. S. Awad, H. Ye, L. Huang, L. Li, F. W. Foss Jr., T. L. Macdonald, K. R. Lynch, and M. D. Okusa Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney Am J Physiol Renal Physiol, June 1, 2006; 290(6): F1516 - F1524. [Abstract] [Full Text] [PDF]

				C. De Palma, E. Meacci, C. Perrotta, P. Bruni, and E. Clementi 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, January 1, 2006; 26(1): 99 - 105. [Abstract] [Full Text] [PDF]

				D. T. Bolick, A. W. Orr, A. Whetzel, S. Srinivasan, M. E. Hatley, M. A. Schwartz, and C. C. Hedrick 12/15-Lipoxygenase Regulates Intercellular Adhesion Molecule-1 Expression and Monocyte Adhesion to Endothelium Through Activation of RhoA and Nuclear Factor-{kappa}B Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2301 - 2307. [Abstract] [Full Text] [PDF]