Inhibition by unsaturated fatty acids of type II secretory phospholipase A(2) 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 A(2) (sPLA(2)-II) by guinea-pig alveolar macrophages was i nvestigated. We show that incubation of these cells with 1-30 mu m of arach idonic acid inhibits the synthesis of sPLA(2)-II in a concentration-depende nt manner with an IC50 of approximate to 7.5 mu m. The inhibition by low co ncentrations (5 mu m) of arachidonic acid was partially reduced by pretreat ment of alveolar macrophages with cyclooxygenase or cytochrome P450 inhibit ors (aspirin and 1-aminobenzotriazole, respectively), but not by lipoxygena se inhibitor, BW A4C. However, these inhibitors failed to interfere with th e effect of high concentrations (30 mu m) of arachidonic acid, suggesting t hat the latter may act on the expression of sPLA(2)-II, at least in part, i ndependently of eicosanoid generation. Indeed, a similar inhibitory effect on sPLA(2)-II activity and mRNA expression was observed with other unsatura ted fatty acids such as eicosapentaenoic (C20:5) and oleic (C18:1) acids, b ut not with the saturated fatty acid, palmitic acid (C16:0). In addition, a rachidonic acid partially reduced the secretion of tumor necrosis factor al pha, an important intermediate in the induction of sPLA(2)-II synthesis by guinea-pig alveolar macrophages. However, addition of recombinant tumor nec rosis factor alpha failed to reverse the inhibitory effect of arachidonic a cid on sPLA(2)-II expression, suggesting that this process occurs downstrea m of tumor necrosis factor alpha secretion. We conclude that the expression of sPLA(2)-II in alveolar macrophages is down-regulated at the transcripti onal level by arachidonic acid either directly or via its cyclooxygenase an d cytochrome P450-derived metabolites.