Down-regulation by prostaglandins of type-II phospholipase A2 expression in guinea-pig alveolar macrophages: a possible involvement of cAMP

We have demonstrated previously that isolated guinea-pig alveolar macrophages (AM) synthesize type-II phospholipase A 2 (PLA 2 -II) through a tumour necrosis factor-α (TNF-α)-dependent process. This synthesis is enhanced by lipopolysaccharide (LPS) and accompanied by a release of prostaglandin E 2 (PGE 2 ) into the medium. Because agents elevating intracellular cAMP, such as PGE 2 , have been shown to stimulate PLA 2 -II expression in various cell types, we investigated the modulation of PLA 2 -II synthesis by cAMP in AM. Surprisingly, incubation of AM with PGE 2 , dibutyryl-cAMP, cholera toxin or rolipram (an inhibitor of specific cAMP-phosphodiesterase) inhibited both basal and LPS-stimulated PLA 2 -II expression. The inhibitory effect of PGE 2 was observed at concentrations similar to those released by AM. Moreover, treatment of AM with either aspirin or neutralizing PGE 2 monoclonal antibody stimulated PLA 2 -II synthesis. These effects were closely correlated with the ability of these agents to modulate TNF-α release, which was decreased by dibutyryl-cAMP and exogenous PGE 2 , whereas neutralizing PGE 2 antibody markedly increased this release. Hence, in contrast to other cell systems, we report that: (i) agents elevating intracellular cAMP levels down-regulate both basal and LPS-induced PLA 2 -II synthesis, (ii) prostaglandins exert a negative feedback effect on this synthesis, probably through an elevation of intracellular cAMP levels, and (iii) inhibition of TNF-α release may account, at least in part, for the down-regulation of PLA 2 -II expression by endogenously produced prostaglandins and cAMP-elevating agents.