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

The cellular phospholipid, lysophosphatidic acid (LPA), released by activated 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 paracrine 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 further characterized by increased levels of mRNA transcripts encoding E-selectin, Intercellular Adhesion Molecule-1, Interleukin-8 and Monocyte Chemoattractant 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 observed in the presence of putative LPA receptor antagonists suramin or thrombospondin. LPA induces a proinflammatory activation of endothelial cells that (i) involves G(i) proteins; (ii) depends on phospholipase A(2) activity; (iii) is associated with the activation of NF-kappa B and (iv) results in increased expression of proinflammatory genes. We propose that LPA release by activated platelets may directly modulate vascular inflammatory responses.