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

• Published in: Thrombosis and haemostasis Vol. 82; no. 5; p. 1532
• Main Authors: Palmetshofer, A, Robson, S C, Nehls, V
• Format: Journal Article
• Language: English
• Published: Germany 01.11.1999
• Subjects: Animals; Cells, Cultured; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - genetics; Drug Synergism; E-Selectin - biosynthesis; E-Selectin - genetics; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Gene Expression Regulation - drug effects; Inflammation - genetics; Intercellular Adhesion Molecule-1 - biosynthesis; Intercellular Adhesion Molecule-1 - genetics; Interleukin-8 - biosynthesis; Interleukin-8 - genetics; Lysophospholipids - pharmacology; MAP Kinase Signaling System - drug effects; NF-kappa B - metabolism; Quinacrine - pharmacology; Receptors, Cell Surface - antagonists & inhibitors; Receptors, G-Protein-Coupled; Receptors, Lysophosphatidic Acid; Recombinant Proteins - pharmacology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Suramin - pharmacology; Swine; Thrombospondins - pharmacology; Transcription, Genetic - drug effects; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0340-6245

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-kappaB) 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 A2) or of pertussis toxin (to increase ADP-ribosylation of Gi 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 Gi proteins; (ii) depends on phospholipase A2 activity; (iii) is associated with the activation of NF-kappaB and (iv) results in increased expression of proinflammatory genes. We propose that LPA release by activated platelets may directly modulate vascular inflammatory responses.