Mechanism of cyclosporin A-induced inhibition of prostacyclin synthesis by macrophages.
In vitro studies of PG production over a 24 h period by adherent rat peritoneal macrophages activated by serum-opsonized zymosan revealed that CSA (0.3-10 micrograms/ml) caused a dose-related inhibition of PGI2 (assayed as 6-oxo-PGF1 alpha) formation. Indomethacin (IND, 0.01-10 micrograms/ml) and dexamethasone (DEX, 0.01-10 micrograms/ml) also inhibited the PG production in a dose-related manner. When arachidonic acid (10 micrograms/ml) was added together with the inhibitors, there was no change in the level of PGI2 produced by IND-treated cells whilst the PGI2 levels of DEX- and CSA-treated cells were elevated to the control level. Therefore CSA like DEX does not inhibit cyclo-oxygenase activity. However unlike DEX, CSA (1-30 micrograms/ml) caused inhibition of phospholipase A2 (PLA2) activity when assayed on the hydrolysis of a synthetic substrate by pancreatic PLA2 in a cell-free system. The direct inhibition of PLA2 might well be a manifestation of the fundamental activity of CSA on immunocompetent cells.
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002478:Cells, Cultured; D003524:Cyclosporins / Q000494:pharmacology*; D003864:Depression, Chemical; D003907:Dexamethasone / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D051381:Rats; D011919:Rats, Inbred Strains; D015054:Zymosan / Q000494:pharmacology
D001095:Arachidonic Acids; D003524:Cyclosporins; D016718:Arachidonic Acid; D015121:6-Ketoprostaglandin F1 alpha; D003907:Dexamethasone; D015054:Zymosan; D011464:Epoprostenol; D010741:Phospholipases A; D054467:Phospholipases A2; D007213:Indomethacin