Mechanism of cyclosporin A-induced inhibition of prostacyclin synthesis by macrophages

Abstract

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 μg/ml) caused a dose-related inhibition of PGI 2 (assayed as 6-oxo-PGF 1α) formation. Indomethacin (IND, 0.01 – 10 μg/ml) and dexamethasone (DEX, 0.01 – 10 μg/ml) also inhibited the PG production in a dose-related manner. When arachidonic acid (10 μg/ml) was added together with the inhibitors, there was no change in the level of PGI 2 produced by IND-treated cells whilst the PGI 2 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 μg/ml) caused inhibition of phospholipase A 2 (PLA 2) activity when assayed on the hydrolysis of a synthetic substrate by pancreatic PLA 2 in a cell-free system. The direct inhibition of PLA 2 might well be a manifestation of the fundamental activity of CSA on immunocompetent cells.