Platelet-activating factor production in stimulated macrophages is down-regulated by concurrently produced prostaglandin E2.
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 extracellular prostaglandin E2 (PGE2) increased. In the presence of the cyclooxygenase inhibitor indomethacin, TPA-induced PAF production was further enhanced dose-dependently in accordance with decrease of PGE2 levels. In addition, indomethacin further enhanced PAF production that was stimulated by the protein kinase C activators, aplysiatoxin and teleocidin. Other cyclooxygenase inhibitors such as naproxen and ibuprofen also enhanced TPA-stimulated PAF production in accordance with inhibition of PGE2 production. Cyclooxygenase inhibitor-induced enhancement of PAF production was markedly prevented by exogenous PGE2. Exogenous arachidonic acid also inhibited TPA-induced PAF production in parallel with increase in PGE2 levels. Inhibition of PAF production by exogenous arachidonic acid was abolished by indomethacin. Furthermore, PAF production stimulated by the endomembrane Ca+2-ATPase inhibitors thapsigargin or thapsigargicin, or by the Ca+2 ionophore A23187, was also enhanced by indomethacin in compensation for the decrease in PGE2 production. In addition, the adenylate cyclase activator forskolin, or the cyclic adenosine monophosphate (cAMP) analogues 8-bromo cAMP and dibutyryl cAMP inhibited thapsigargin-induced PAF production. TPA-induced accumulation of intracellular cAMP was inhibited by indomethacin, and indomethacin-induced decrease of cAMP level was reversed by exogenous PGE2. These results suggested that concurrently produced PGE2 in stimulated macrophages down-regulates PAF production via adenylate cyclase and cAMP pathway.
Yamada
M
M
Department of Pathophysiological Biochemistry, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Watanabe
M
M
Mue
S
S
Ohuchi
K
K
D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D007213:Indomethacin / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D010972:Platelet Activating Factor / Q000096:biosynthesis / Q000378:metabolism*; D011493:Protein Kinase C / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D010972:Platelet Activating Factor; D011493:Protein Kinase C; D015232:Dinoprostone; D007213:Indomethacin