PLATELET-ACTIVATING-FACTOR PRODUCTION IN STIMULATED MACROPHAGES IS DOWN-REGULATED BY CONCURRENTLY PRODUCED PROSTAGLANDIN E(2)

When rat peritoneal macrophages were incubated in medium containing 12 -O-tetradecanoylphorbol 13-acetate (TPA), a protein kinase C activator , production of cell-associated platelet-activating factor (PAF) and e xtracellular prostaglandin E(2) (PGE(2)) increased. In the presence of the cyclooxygenase inhibitor indomethacin, TPA-induced PAF production was further enhanced dose-dependently in accordance with decrease of PGE(2) levels. In addition, indomethacin further enhanced PAF producti on that was stimulated by the protein kinase C activators, aplysiatoxi n and teleocidin. Other cyclooxygenase inhibitors such as naproxen and ibuprofen also enhanced TPA-stimulated PAF production in accordance w ith inhibition of PGE(2) production. Cyclooxygenase inhibitor-induced enhancement of PAF production was markedly prevented by exogenous PGE( 2). Exogenous arachidonic acid also inhibited TPA-induced PAF producti on in parallel with increase in PGE(2) levels. Inhibition of PAF produ ction by exogenous arachidonic acid was abolished by indomethacin. Fur thermore, PAF production stimulated by the endomembrane Ca++-ATPase in hibitors thapsigargin or thapsigargicin, or by the Ca++ ionophore A231 87, was also enhanced by indomethacin in compensation for the decrease in PGE(2) production. In addition, the adenylate cyclase activator fo rskolin, or the cyclic adenosine monophosphate (cAMP) analogues 8-brom o cAMP and dibutyryl cAMP inhibited thapsigargin-induced PAF productio n. TPA-induced accumulation of intracellular cAMP was inhibited by ind omethacin, and indomethacin-induced decrease of cAMP level was reverse d by exogenous PGE(2). These results suggested that concurrently produ ced PGE(2) in stimulated macrophages down-regulates PAF production via adenylate cyclase and cAMP pathway.