Inhibition by unsaturated fatty acids of type II secretory phospholipase A2 synthesis in guinea-pig alveolar macrophages evidence for the eicosanoid-independent pathway.
The effect of arachidonic acid (C20:4) on the production of secretory type II phospholipase A2 (sPLA2-II) by guinea-pig alveolar macrophages was investigated. We show that incubation of these cells with 1-30 microM of arachidonic acid inhibits the synthesis of sPLA2-II in a concentration-dependent manner with an IC50 of approximately 7.5 microM. The inhibition by low concentrations (5 microM) of arachidonic acid was partially reduced by pretreatment of alveolar macrophages with cyclooxygenase or cytochrome P450 inhibitors (aspirin and 1-aminobenzotriazole, respectively), but not by lipoxygenase inhibitor, BW A4C. However, these inhibitors failed to interfere with the effect of high concentrations (30 microM) of arachidonic acid, suggesting that the latter may act on the expression of sPLA2-II, at least in part, independently of eicosanoid generation. Indeed, a similar inhibitory effect on sPLA2-II activity and mRNA expression was observed with other unsaturated fatty acids such as eicosapentaenoic (C20:5) and oleic (C18:1) acids, but not with the saturated fatty acid, palmitic acid (C16:0). In addition, arachidonic acid partially reduced the secretion of tumor necrosis factor alpha, an important intermediate in the induction of sPLA2-II synthesis by guinea-pig alveolar macrophages. However, addition of recombinant tumor necrosis factor alpha failed to reverse the inhibitory effect of arachidonic acid on sPLA2-II expression, suggesting that this process occurs downstream of tumor necrosis factor alpha secretion. We conclude that the expression of sPLA2-II in alveolar macrophages is down-regulated at the transcriptional level by arachidonic acid either directly or via its cyclooxygenase and cytochrome P450-derived metabolites.
Alaoui El Azher
M
M
Unité de Pharmacologie Cellulaire, Unité Associée Pasteur/INSERM U485, Institut Pasteur, Paris, France.
Havet
N
N
Singer
M
M
Dumarey
C
C
Touqui
L
L
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D044482:Benzeneacetamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology*; D054501:Group II Phospholipases A2; D006168:Guinea Pigs; D006877:Hydroxamic Acids / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008084:Lipoxygenase / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology
D044482:Benzeneacetamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; C033020:1-aminobenzotriazole; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D001241:Aspirin