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Journal of Lipid Research, Vol. 46, 2488-2496, November 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

PGE₂ release is independent of upregulation of Group V phospholipase A₂ during long-term stimulation of P388D₁ cells with LPS¹

Ursula A. Kessen, Ralph H. Schaloske, Daren L. Stephens, Karin Killermann Lucas and Edward A. Dennis²

Departments of Chemistry and Biochemistry and Pharmacology, University of California–San Diego, La Jolla, CA 92093

¹ Trudy Forte served as Guest Editor for this manuscript.

Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500325-JLR200

² To whom correspondence should be addressed. e-mail: edennis{at}ucsd.edu

P388D₁ cells release arachidonic acid (AA) and produce prostaglandin E₂ (PGE₂) upon long-term stimulation with lipopolysaccharide (LPS). The cytosolic Group IVA (GIVA) phospholipase A₂ (PLA₂) has been implicated in this pathway. LPS stimulation also results in increased expression and secretion of a secretory PLA₂, specifically GV PLA₂. To test whether GV PLA₂ contributes to PGE₂ production and whether GIVA PLA₂ activation increases the expression of GV PLA₂, we utilized the specific GIVA PLA₂ inhibitor pyrrophenone and second generation antisense oligonucleotides (AS-ONs) designed to specifically inhibit expression and activity of GV PLA₂. Treatment of P388D₁ cells with antisense caused a marked decrease in basal GV PLA₂ mRNA and prevented the LPS-induced increase in GV PLA₂ mRNA. LPS-stimulated cells release active GV PLA₂ into the medium, which is inhibited to background levels by antisense treatment. However, LPS-induced PGE₂ release by antisense-treated cells and by control cells are not significantly different.

Collectively, the results suggest that the upregulation of GV PLA₂ during long-term LPS stimulation is not required for PGE₂ production by P388D₁ cells. Experiments employing pyrrophenone suggested that GIVA PLA₂ is the dominant player involved in AA release, but it appears not to be involved in the regulation of LPS-induced expression of GV PLA₂ or cyclooxygenase-2.

Abbreviations: AA, arachidonic acid; AS-ON, antisense oligonucleotide; GIVA, Group IVA; LPS, lipopolysaccharide; MAFP, methyl arachidonyl fluorophosphonate; PGE₂, prostaglandin E₂; PLA₂, phospholipase A₂; S-ON, sense oligonucleotide; sPLA₂, secreted phospholipase A₂

Supplementary key words antisense inhibitor • macrophage • lipopolysaccharide • prostaglandin E₂ • arachidonic acid • eicosanoid

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