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Group V Phospholipase A₂-Derived Lysophosphatidylcholine Mediates Cyclooxygenase-2 Induction in Lipopolysaccharide-Stimulated Macrophages¹

Institute of Molecular Biology and Genetics, Spanish National Research Council and University of Valladolid School of Medicine, Valladolid, Spain

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 A₂ (sPLA₂-V) was required for COX-2 induction, but the nature of the sPLA₂-V metabolite involved was not defined. In this study, we identify lysophosphatidylcholine (lysoPC) as the sPLA₂-V downstream mediator involved in COX-2 induction by LPS-stimulated macrophages. Inhibition of sPLA₂-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 sPLA₂-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 sPLA₂-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Spanish Ministry of Education and Science (Grants BFU2004-01886/BMC and SAF2004-04676), the Fundación La Caixa (Grant BM05-248-0), and the Spanish Ministry of Health (ISCIII-RETIC RD06).

² Address correspondence and reprint requests to Dr. Jesús Balsinde, Instituto de Biología y Genética Molecular, Calle Sanz y Forés s/n, 47003 Valladolid, Spain. E-mail address: jbalsinde{at}ibgm.uva.es

³ Abbreviations used in this paper: AA, arachidonic acid; BEL, bromoenol lactone; COX-2, cyclooxygenase-2; cPLA₂, cytosolic phospholipase A₂; cPLA₂, group IV cPLA₂; iPLA₂, Ca²⁺-independent phospholipase A₂; lysoPC, lysophosphatidylcholine; MAFP, methyl arachidonyl fluorophosphonate; methyl-lysoPC, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine; OA, oleic acid; PLA₂, phospholipase A₂; siRNA, small interfering RNA; sPLA₂, secreted PLA₂; sPLA₂-V, group V sPLA₂.

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