Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells.
Sphingosine 1-phosphate (S1P) stimulates expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human umbilical vein endothelial cells. S1P-induced actions were associated with nuclear factor kappa-B activation and inhibited by pertussis toxin as well as by antisense oligonucleotides specific to S1P receptors, especially, S1P(3). S1P also stimulated endothelial nitric oxide synthase (eNOS) and its activation was markedly inhibited by the antisense oligonucleotide for the S1P(1) receptor rather than that for the S1P(3) receptor. The dose-response curve of S1P to stimulate adhesion molecule expression was shifted to the left in the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin and the NOS inhibitor Nomega-nitro-l-arginine methyl ester. NO donor S-nitroso-N-acetylpenicillamine inhibited S1P-induced adhesion molecule expression. Moreover, tumor necrosis factor-alpha-induced adhesion molecule expression was markedly inhibited by S1P in a manner sensitive to inhibitors for PI3-K and NOS. These results suggest that S1P receptors are coupled to both stimulatory and inhibitory pathways for adhesion molecule expression. The stimulatory pathway involves nuclear factor kappa-B and inhibitory one does phosphatidylinositol 3-kinase and NOS.
Kimura
Takao
T
Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan.
Tomura
Hideaki
H
Mogi
Chihiro
C
Kuwabara
Atsushi
A
Ishiwara
Mitsuteru
M
Shibasawa
Kunihiko
K
Sato
Koichi
K
Ohwada
Susumu
S
Im
Doon-Soon
DS
Kurose
Hitoshi
H
Ishizuka
Tamotsu
T
Murakami
Masami
M
Okajima
Fumikazu
F
D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000502:physiology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D016328:NF-kappa B; D049349:Receptors, Lysosphingolipid; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D052250:Nitric Oxide Synthase Type III; D019206:GTP-Binding Protein alpha Subunits, Gi-Go