Sphingosine-1-phosphate prevents tumor necrosis factor-{alpha}-mediated monocyte adhesion to aortic endothelium in mice.
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.


RESULTS
We injected C57BL/6J mice intravenously with tumor necrosis factor (TNF)-alpha in the presence and absence of the S1P1 receptor agonist SEW2871 and examined monocyte adhesion. Aortas from TNF-alpha-injected mice had a 4-fold increase in the number of monocytes bound, whereas aortas from TNF-alpha 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-alpha. 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-alpha-mediated monocyte-EC interactions in vivo.
Bolick
David T
DT
Division of Endocrinology & Metabolism and Cardiovascular Research Center, University of Virginia, Charlottesville, Va 22908, USA.
Srinivasan
Suseela
S
Kim
Kyu W
KW
Hatley
Melissa E
ME
Clemens
Jeremy J
JJ
Whetzel
Angela
A
Ferger
Nicole
N
Macdonald
Timothy L
TL
Davis
Michael D
MD
Tsao
Philip S
PS
Lynch
Kevin R
KR
Hedrick
Catherine C
CC
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology* / Q000276:immunology; D010069:Oxadiazoles / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014657:Vasculitis / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control
D018925:Chemokines; D019040:E-Selectin; D008246:Lysophospholipids; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C060506:sphingosine 1-phosphate; D013110:Sphingosine