title: Selective attenuation of Toll-like receptor 2 signalling may explain the atheroprotective effect of sphingosine 1-phosphate.
abstract: OBJECTIVE
  Vascular inflammation is a major atherogenic factor and Toll-like receptor (TLR) 2 ligands, including bacterial and serum lipoproteins, seem to be involved in atherogenesis. On this basis, we analysed the effect of lipoproteins and different lipid components on TLR2-dependent signalling.
  
  
  RESULTS
  In TLR2-transfected human embryonic kidney 293 cells and human monocytes, oxidized low-density lipoproteins inhibited nuclear factor (NF)-kappaB-driven transcriptional activity and chemokine gene expression in response to TLR2 ligands. Sphingosine 1-phosphate (S1P) and oxidized palmitoyl-arachidonoyl-phosphatidylcholine, but not lipoprotein-carried lysophospholipids, inhibited TLR2 activation. Silencing experiments in TLR2-transfected 293 cells showed that the S1P-mediated attenuation effect is mediated by S1P receptors type 1 and type 2. To address the physiological significance of these findings, additional experiments were performed in human peripheral blood monocytes and monocyte-derived macrophages. In both cell types, S1P selectively attenuated TLR2 signalling, as NF-kappaB and extracellular signal-regulated kinase activation, but not c-Jun amino terminal kinase phosphorylation, were inhibited by physiologically relevant concentrations of S1P. Moreover, the attenuation of TLR2 signalling was partially reverted by pharmacological inhibition of phosphoinositide 3-kinase (PI3K) and Ras pathways. In addition, S1P inhibited the chemokine gene expression elicited by TLR2, but not by TLR4 ligands.
  
  
  CONCLUSIONS
  These findings disclose a cross-talk mechanism between lipoprotein components and TLR in which engagement of S1P receptors exert selective attenuation of TLR2-dependent activation via PI3K and Ras signalling. A corollary to these data is that the negative cross-talk of S1P receptors and TLR2 signalling might be involved in the atheroprotective effects of S1P.
authors.affiliation: Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, C/Sanz y Forés s/n, 47003-Valladolid, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Dueñas
authors.forename: Mónica
authors.initials: M
authors.lastname: Aceves
authors.forename: Isabel
authors.initials: I
authors.lastname: Fernández-Pisonero
authors.forename: Cristina
authors.initials: C
authors.lastname: Gómez
authors.forename: Antonio
authors.initials: A
authors.lastname: Orduña
authors.forename: Mariano Sánchez
authors.initials: MS
authors.lastname: Crespo
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Rodríguez
mesh_terms: D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010586:Phagocytes / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018925:Chemokines; D004791:Enzyme Inhibitors; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; D016328:NF-kappa B; D010713:Phosphatidylcholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D051195:Toll-Like Receptor 2; D018631:ras Proteins; C495342:TLR2 protein, human; C099252:oxidized low density lipoprotein; C060506:sphingosine 1-phosphate