DOWN-REGULATION BY PROSTAGLANDINS OF TYPE-II PHOSPHOLIPASE A(2) EXPRESSION IN GUINEA-PIG ALVEOLAR MACROPHAGES - A POSSIBLE INVOLVEMENT OF CAMP

We have demonstrated previously that isolated guinea-pig alveolar macr ophages (AM) synthesize type-II phospholipase A, (PLA(2)-II) through a tumour necrosis factor-alpha (TNF-alpha)-dependent process. This synt hesis is enhanced by lipopolysaccharide (LPS) and accompanied by a rel ease of prostaglandin E-2 (PGE(2)) into the medium. Because agents ele vating intracellular cAMP, such as PGE(2), have been shown to stimulat e PLA(2)-II expression in various cell types, we investigated the modu lation of PLA(2)-II synthesis by cAMP in AM. Surprisingly, incubation of AM with PGE(2), dibutyryl-cAMP, cholera toxin or rolipram (an inhib itor of specific cAMP-phosphodiesterase) inhibited both basal and LPS- stimulated PLA(2)-II expression. The inhibitory effect of PGE? was obs erved at concentrations similar to those released by AM. Moreover, tre atment of AM with either aspirin or neutralizing PGE(2) monoclonal ant ibody stimulated PLA(2)-II synthesis. These effects were closely corre lated with the ability of these agents to modulate TNF-alpha release, which was decreased by dibutyryl-cAMP and exogenous PGE(2), whereas ne utralizing PGE(2) antibody markedly increased this release. Hence, in contrast to other cell systems, we report that: (i) agents elevating i ntracellular 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-alpha release may account, at lea st in part, for the down-regulation of PLA(2)-II expression by endogen ously produced prostaglandins and cAMP-elevating agents.