title: Sphingosine-1-phosphate receptor-2 mediated NFκB activation contributes to tumor necrosis factor-α induced VCAM-1 and ICAM-1 expression in endothelial cells.
abstract: Sphingosine-1-phosphate (S1P) regulates a wide array of biological functions in endothelial cells. We previously showed that S1P receptor subtype 2 (S1P2) is significantly up-regulated in the atherosclerotic endothelium (J. Biol. Chem. 283:30363, 2008). In this study, we investigated the roles of S1P2-mediated signaling in the proinflammatory responses of endothelial cells. Treatment with tumor necrosis factor-α (TNFα), a proinflammatory cytokine, increased the expression of S1P2 receptors in endothelial cells. TNFα treatment also enhanced sphingosine kinase 1 expression and increased S1P production. Pharmacological inhibition or knockdown of S1P2 receptors completely abrogated the TNFα-induced VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) expression in endothelial cells. In contrast, pharmacological inhibition or knockdown of other S1P receptor subtypes had no effect on the TNFα-stimulated ICAM-1 and VCAM-1 expression. Moreover, ectopic expression of S1P2 receptors increased VCAM-1 and ICAM-1 expression in endothelial cells in response to S1P stimulation. Mechanistically, we show that antagonizing S1P2 signaling markedly inhibited the TNFα-stimulated NFκB activation. Utilizing the NFκB reporter luciferase assay, the S1P/S1P2 signaling was shown to stimulate NFκB activation. Moreover, the S1P/S1P2-stimulated VCAM-1/ICAM-1 expression was completely abolished by the pharmacological inhibitor of NFκB. Collectively, our data suggest that TNFα treatment activates autocrine S1P/S1P2 signaling, which subsequently activates NFκB and leads to the proinflammatory responses in endothelial cells.
authors.affiliation: Bioactive Lipid Research Program, Wayne State University School of Medicine, Detroit, MI 48202, United States; Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48202, United States.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Zhang
authors.forename: Jin
authors.initials: J
authors.lastname: An
authors.forename: Hiba
authors.initials: H
authors.lastname: Jawadi
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Siow
authors.forename: Jen-Fu
authors.initials: JF
authors.lastname: Lee
authors.forename: Jiawei
authors.initials: J
authors.lastname: Zhao
authors.forename: Allison
authors.initials: A
authors.lastname: Gartung
authors.forename: Krishna Rao
authors.initials: KR
authors.lastname: Maddipati
authors.forename: Kenneth V
authors.initials: KV
authors.lastname: Honn
authors.forename: Binks W
authors.initials: BW
authors.lastname: Wattenberg
authors.forename: Menq-Jer
authors.initials: MJ
authors.lastname: Lee
mesh_terms: D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D008246:Lysophospholipids / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
chemical_list: D008246:Lysophospholipids; D016328:NF-kappa B; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: ECs; G-protein coupled receptor; GPCR; HUVEC; ICAM-1; S1P; S1P family of G-protein coupled receptor; S1P(1–5); SphK; Sphingolipids; Sphingosine kinase; Sphingosine-1-phosphate; TNFα; VCAM-1; Vasculature; cultured endothelial cells; high affinity GPCRs for S1P; human umbilical vein endothelial cells; intercellular adhesion molecule 1; sphingosine kinase; sphingosine-1-phosphate; tumor necrosis factor-α; vascular cell adhesion molecule 1