ENDOTOXIN-INDUCED MIGRATION OF MONOCYTES AND PECAM-1 PHOSPHORYLATION ARE ABROGATED BY PAF RECEPTOR ANTAGONISTS

The trafficking of monocytes across the endothelial lining of the bloo d vessel increases in response to bacterial infection at sites of infl ammation. However, the molecular events involved in the diapedesis of monocytes in response to endotoxin are not completely understood. Our studies revealed that signaling by Lipopolysaccharide (LPS) in human u mbilical vein endothelial cells (HUVEC) resulted in a threefold increa se in the transendothelial migration of monocyte-like HL-60 cells and a sevenfold increase in the phosphorylation of platelet endothelial ce ll adhesion molecule-1 (PECAM-1). The transmigration induced by LPS wa s inhibited by an antibody to PECAM-1. Both the phosphorylation of PEC AM-1 and transendothelial migration of monocytes were inhibited by a p latelet-activating factor (PAF) receptor antagonist, indicating the au tocrine effect of PAF in these events. Treatment of HUVEC with LPS cau sed a fourfold increase in PAF receptor mRNA expression that was compl etely blocked by the PAF receptor antagonist. We conclude that PAF, ge nerated by HUVEC in response to LPS or gram-negative bacterial infecti on, acts in an autocrine manner, causing PECAM-1 phosphorylation and t hus the transendothelial migration of monocytes.