M. Yamada et al., PLATELET-ACTIVATING-FACTOR PRODUCTION IN STIMULATED MACROPHAGES IS DOWN-REGULATED BY CONCURRENTLY PRODUCED PROSTAGLANDIN E(2), The Journal of pharmacology and experimental therapeutics, 277(3), 1996, pp. 1607-1614
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.