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

Abstract

Gustin C, Van Steenbrugge M, Raes M. LPA modulates monocyte migration directly and via LPA-stimulated endothelial cells. Am J Physiol Cell Physiol 295: C905-C914, 2008. First published July 16, 2008 doi:10.1152/ajpcell.00544.2007.-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-, Gi/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 Ͻ1 M and to inhibit their migration at LPA concentrations Ͼ1 M, 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 M LPA, both cell types respond cooperatively, favoring monocyte migration. At higher LPA concentration (25 M), 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 LYSOPHOSPHATIDIC ACID (LPA) is a potent bioactive lipid mediator with multiple cellular effects (21) produced by activated platelets or by enzymatic cleavage of membrane phospholipids (3, 12). The concentration of LPA in the serum is estimated at 2 to 20 M, whereas the concentration in plasma is considerably lower (80 nM to 0.7 M) (10). LPA evokes many cellular responses by binding to five specific G protein-coupled receptors (GPCRs) known as LPA 1-5 that have been cloned and shown to be expressed in most mammalian cells and tissues (for a recent review see Ref. 20). Another GPCR (P2Y5) involved in the maintenance of human hair growth has been recently described as a member of a subgroup of LPA receptors, including LPA 4 and LPA 5 (28). Moreover, the McIntyre group (19) has shown that LPA is also a high-affinity ligand for the peroxisome proliferator-activator receptor ␥ (PPAR␥), suggesting the participation of LPA in intracellular signaling and cell regulation.LPA has recently attracted much interest due to its multiple roles in physiological and pathological co...

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