Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 14, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn087
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Selective attenuation of Toll-like receptor 2 signaling may explain the atheroprotective effect of sphingosine 1-phosphate
a Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid
b Hospital Clinico Universitario, Valladolid, Spain
* Correspondence to: Carmen García-Rodríguez Instituto de Biología y Genética Molecular C/ Sanz y Forés s/n, 47003-Valladolid, SPAIN Phone: +34-983-184841 Fax: +34-983-184800 E-mail: cgarcia{at}ibgm.uva.es
Aims: 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 analyzed the effect of lipoproteins and different lipid components on TLR2-dependent signaling.
Methods and Results: In TLR2-transfected human embryonic kidney 293 cells and human monocytes, oxidized low-density lipoproteins inhibited nuclear factor (NF)-
B-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 signaling, as NF-B 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 signaling 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 signaling. A corollary to these data is that the negative cross-talk of S1P receptors and TLR2 signaling might be involved in the atheroprotective effects of S1P.
Time for primary review: 28 days