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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/C905    most recent 00544.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gustin, C. Articles by Raes, M. PubMed PubMed Citation Articles by Gustin, C. Articles by Raes, M.

VASCULAR BIOLOGY

LPA modulates monocyte migration directly and via LPA-stimulated endothelial cells

Laboratory of Biochemistry and Cellular Biology, Unit of Research on Cellular Biology (URBC), Facultés Universitaires Notre-Dame de la Paix (FUNDP), University of Namur, Namur, Belgium

Submitted 15 November 2007 ; accepted in final form 11 July 2008

Lysophosphatidic acid (LPA) is a bioactive lysophospholipid ligand present in oxidized low-density lipoprotein. The effects of LPA were investigated, first separately on endothelial cells (EC) and monocytes. Using Ki16425 (an LPA₁ and LPA₃ receptor antagonist), GW9662 [a peroxisome proliferator-activator receptor (PPAR) antagonist], and pertussis toxin (that inhibits G_i/o), we demonstrate that LPA enhances IL-8 and monocyte chemoattractant protein-1 expression through a LPA₁-, LPA₃-, G_i/o- and PPAR-dependent manner in the EAhy926 cells. The effect of LPA on chemokine overexpression was confirmed in human umbilical vein endothelial cells. LPA was able to enhance monocyte migration at concentrations <1 µM and to inhibit their migration at LPA concentrations >1 µM, as demonstrated by using a chemotaxis assay. We then investigated the effects of LPA on the cross-talk between EC and monocytes by evaluating the chemotactic activity in the supernatants of LPA-treated EC. At 1 µM LPA, both cell types respond cooperatively, favoring monocyte migration. At higher LPA concentration (25 µM), the chemotactic response varies as a function of time. After 4 h, the chemotactic effect of the cytokines secreted by the EC is counteracted by the direct inhibitory effect of LPA on monocytes. For longer periods of time (24 h), we observe a monocyte migration, probably due to lowered concentrations of bioactive LPA, given the induction of lipid phosphate phosphatase-2 in monocytes that may inactivate LPA. These results suggest that LPA activates EC to secrete chemokines that in combination with LPA itself might favor or not favor interactions between endothelium and circulating monocytes.

lysophosphatidic acid; endothelial cells; monocytes; chemotaxis