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-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.
Palmetshofer
A
A
Institut für Klinische Biochemie und Pathobiochemie, Medizinische Kliniken Würzburg, Germany. palme@klin-biochem.uni-wuerzburg.de
Robson
S C
SC
Nehls
V
V
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D004357:Drug Synergism; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D007249:Inflammation / Q000235:genetics*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008246:Lysophospholipids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D011796:Quinacrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D011994:Recombinant Proteins / Q000494:pharmacology; D013498:Suramin / Q000494:pharmacology; D013552:Swine; D019699:Thrombospondins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018932:Chemokine CCL2; D019040:E-Selectin; D016209:Interleukin-8; D008246:Lysophospholipids; D016328:NF-kappa B; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D011994:Recombinant Proteins; D019699:Thrombospondins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D013498:Suramin; D011796:Quinacrine