Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils

We previously have demonstrated that oxidized 1-palmitoyl-2-arachidonoyl-sn -glycero-3-phosphorylcholine (OxPAPC), a component of minimally modified lo w density lipoprotein (MM-LDL), activates endothelial cells to bind monocyt es. 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC) an d 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine (PGPC), which are present in OxPAPC, MM-LDL, and atherosclerotic lesions, were shown to have a major role in the activation of endothelial cells. We now demonstrate tha t these two highly similar molecules have dramatically different effects on leukocyte endothelial interactions. POVPC is a potent regulator of monocyt e-specific endothelial interactions. Treatment of endothelial cells with PO VPC increased monocyte binding by inducing the surface expression of the co nnecting segment 1 domain of fibronectin; no increase in neutrophil binding was observed. In addition, POVPC strongly inhibited lipopolysaccharide-med iated induction of neutrophil binding and expression of E-selectin protein and mRNA. This inhibition was mediated by a protein kinase A-dependent path way, resulting in down-regulation of NF-kappa B-dependent transcription. In contrast, PGPC induced both monocyte and neutrophil binding and expression of E-selectin and vascular cell adhesion molecule 1. We present evidence t o suggest that the two phospholipids act by different novel receptors prese nt in Xenopus laevis oocytes and that POVPC, but not PGPC, stimulates a cAM P-mediated pathway. At concentrations equal to that present in MM-LDL, the effect of POVPC dominates and inhibits PGPC-induced neutrophil binding and E-selectin expression in endothelial cells. In summary, our data provide ev idence that both POVPC and PGPC are important regulators of leukocyte-endot helial interactions and that POVPC may play a dominant role in a number of chronic inflammatory processes where oxidized phospholipids are known to be present.