Group V phospholipase A2-derived lysophosphatidylcholine mediates cyclooxygenase-2 induction in lipopolysaccharide-stimulated macrophages.
Activation of macrophages and macrophage cell lines by bacterial LPS elicits a delayed phase of PG biosynthesis that appears to be entirely mediated by cyclooxygenase-2 (COX-2). In previous work, we found that a catalytically active group V secreted phospholipase A(2) (sPLA(2)-V) was required for COX-2 induction, but the nature of the sPLA(2)-V metabolite involved was not defined. In this study, we identify lysophosphatidylcholine (lysoPC) as the sPLA(2)-V downstream mediator involved in COX-2 induction by LPS-stimulated macrophages. Inhibition of sPLA(2)-V by RNA interference or by the cell-permeable compound scalaradial blocked LPS-induced COX-2 expression, and this inhibition was overcome by incubating the cells with a nonhydrolyzable lysoPC analog, but not by arachidonic acid or oleic acid. Moreover, inhibition of sPLA(2)-V by scalaradial also prevented the activation of the transcription factor c-Rel, and such an inhibition was also selectively overcome by the lysoPC analog. Collectively, these results support a model whereby sPLA(2)-V hydrolysis of phospholipids upon LPS stimulation results in lysoPC generation, which in turn regulates COX-2 expression by a mechanism involving the transcriptional activity of c-Rel.
Ruipérez
Violeta
V
Institute of Molecular Biology and Genetics, Spanish National Research Council and University of Valladolid School of Medicine, Valladolid, Spain.
Casas
Javier
J
Balboa
María A
MA
Balsinde
Jesús
J
D000818:Animals; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D004790:Enzyme Induction / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054505:Group V Phospholipases A2; D006718:Homosteroids / Q000494:pharmacology; D007941:Leukemia P388 / Q000201:enzymology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D054467:Phospholipases A2; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology; D054830:Sesterterpenes; D013729:Terpenes / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006718:Homosteroids; D008070:Lipopolysaccharides; D008244:Lysophosphatidylcholines; D020569:Proto-Oncogene Proteins c-rel; D054830:Sesterterpenes; D013729:Terpenes; C071197:scalaradial; D051546:Cyclooxygenase 2; D010741:Phospholipases A; D054505:Group V Phospholipases A2; D054467:Phospholipases A2; C516300:Pla2g5 protein, mouse