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

Abstract

We have demonstrated previously that isolated guinea-pig alveolar macrophages (AM) synthesize type-II phospholipase A2 (PLA2-II) through a tumour necrosis factor-alpha (TNF-alpha)-dependent process. This synthesis is enhanced by lipopolysaccharide (LPS) and accompanied by a release of prostaglandin E2 (PGE2) into the medium. Because agents elevating intracellular cAMP, such as PGE2, have been shown to stimulate PLA2-II expression in various cell types, we investigated the modulation of PLA2-II synthesis by cAMP in AM. Surprisingly, incubation of AM with PGE2, dibutyryl-cAMP, cholera toxin or rolipram (an inhibitor of specific cAMP-phosphodiesterase) inhibited both basal and LPS-stimulated PLA2-II expression. The inhibitory effect of PGE2 was observed at concentrations similar to those released by AM. Moreover, treatment of AM with either aspirin or neutralizing PGE2 monoclonal antibody stimulated PLA2-II synthesis. These effects were closely correlated with the ability of these agents to modulate TNF-alpha release, which was decreased by dibutyryl-cAMP and exogenous PGE2, whereas neutralizing PGE2 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 PLA2-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 least in part, for the down-regulation of PLA2-II expression by endogenously produced prostaglandins and cAMP-elevating agents.

Protein Kinase A–Dependent Stimulation of Rat Type II Secreted Phospholipase A 2 Gene Transcription Involves C/EBP-β and -δ in Vascular Smooth Muscle Cells

“…This contrasts with the effect of forskolin on guinea pig alveolar macrophages, in which this drug inhibits LPSinduced type II sPLA 2 gene expression. 23 The forskolin effect does not need priming by an inflammatory cytokine, in agreement with previous studies on rat smooth muscle cells. 10 Smooth muscle cells have various adenylate cyclase-coupled receptors whose stimulation might increase cAMP in response to ␤ 2 -receptor agonists, 24 prostaglandins, 25 vasopressin, 26 angiotensin II, 27 and aldosterone.…”

Prostaglandin E2 concentrations in gingival crevicular fluid: observations in untreated chronic periodontitis

“…That is, prostaglandins acting via cAMP elevation downregulate macrophage function. PGE 2 also exerts a negative feedback effect on the synthesis of phospholipase A 2 (PLA 2 ) in guinea‐pig alveolar macrophages, probably via elevation of intracellular cAMP levels (Vial et al 1998). PLA 2 is important in prostanoid biosynthesis, as it acts on phosphatidyl choline to yield arachidonic acid, the precursor for prostaglandin synthesis (Glaser et al 1990).…”

Prostaglandin E2 Stimulates AP-1-Mediated CD14 Expression in Mouse Macrophages Via Cyclic AMP-Dependent Protein Kinase A

“…Therefore, for understanding the role of PGE 2 in the early stage of LPS-induced septic shock, it was of interest to us to explore whether PGE 2 stimulates CD14 expression in the cells. Several studies (11)(12)(13)(14) have shown that PGE 2 downregulates the production of some proinflammatory cytokines by macrophages. In contrast, PG was able to stimulate the expression of cytokines in other cells (32).…”

“…Interestingly, recent studies (8 -10) have shown that several Gram-negative bacteria stimulate PG production by interacting with several kinds of cells. In contrast, because many studies (11)(12)(13)(14)(15) have demonstrated that PG, acting in a paracrine fashion, is an important regulator of macrophages, the epithelial cell-derived PG formed after these bacterial infections may act as a potent modulator of macrophages in a given organ.…”