Lysophosphatidic acid activates nuclear factor kappa B and induces proinflammatory gene expression in endothelial cells

The cellular phospholipid, lysophosphatidic acid (LPA), released by activat ed platelets and fibroblasts or, at high levels, from ovarian and cervical carcinomas is a powerful serum mitogen that may modulate several signaling pathways in endothelial cells (EC). Hence, LPA could function in a paracrin e manner during EC-platelet interactions at sites of vascular injury. Here, we demonstrate activation of the transcription factor nuclear factor kappa B (NF-kappa B) in EC following exposure to LPA. EC activation was fur ther characterized by increased levels of mRNA transcripts encoding E-selec tin, Intercellular Adhesion Molecule-1, Interleukin-8 and Monocyte Chemoatt ractant Protein-1, These effects were inhibited by preincubating EC either in the presence of mepacrine (to block phospholipase A(2)) or of pertussis toxin (to increase ADP-ribosylation of G(i) proteins), No inhibition was ob served in the presence of putative LPA receptor antagonists suramin or thro mbospondin. LPA induces a proinflammatory activation of endothelial cells that (i) invo lves G(i) proteins; (ii) depends on phospholipase A(2) activity; (iii) is a ssociated with the activation of NF-kappa B and (iv) results in increased e xpression of proinflammatory genes. We propose that LPA release by activate d platelets may directly modulate vascular inflammatory responses.