Life Sciences, Vol. 36, pp. 1225-1231 Pergamon Press Printed in the U.S.A. HYDROCORTISQNE AND 'MACROCORTIN' INHIBIT THE ZYMOSAN-INDUCED RELEASE OF LYSO-PAF FROM RAT PERITONEAL LEUCOCYTES L. Parente and R.J. Flower* Dept. of Prostaglandin Research, Wellcome Research Laboratories, Langley Court, Beckenham, Kent BR3 3BS. (Received in final form January 22, 1985) SUMMARY Hydroc ortisone and the glue oc or tic old-in duced anti-phospholipase protein macrocortin, were tested as inhibitors of PAFgeneration. The steroid produced a dose- dependent inhibition of the release of the PAF precursor 2-lyso-PAF, and this effect was mimicked by affinity-purified macrocortin. Neither agent had any effect on the acetylation of lyso-PAF to PAF. Of other drugs tested only phospholipase inhibitors blocked lyso-PAF release and sulphydryl reagents blocked the acetylation step. It is concluded that glucocorticoids inhibit the generation of PAF and this could be an important component of their anti-anaphylactic and anti-inflammatory action. Platelet activating factor (PAF; AGEPC; 1-O-octadecyl (or hexadecyl), 2-acetyl- sn-glycerol-]-phosphorylcholine) is formed by a two stage process in which the 1-O- alkyl-2-ac yl-sn-glycerot-3-phosphorylc holine ether phosphatide precursor is catalytically degraded to lyso-PAF (1-O-alkyl-2 lyso-sn-glycerol-3-phosphorylcholine by the enzyme phospholipase A~ and then acetylated by a specific Co-A dependent acetyl transferase (1-4). The latte} reaction is apparently the rate-limiting step. Mepacrine, and the active site directed alkylating reagent p-bramophenacyl bromide (p-BPB), inhibit phospholipase A~ and prevent the release of the 2-lyso-PAF from pre-labelled macrophages (4). We~have previously demonstrated that glucocorticoids suppress phospholipase A~. activity in macrophages by inducing the synthesis/release of an inhibitor protein~('macrocortin ') (5) and we now report that both hydrocortisone itself, and purified preparations of macrocortin, suppress the release of 2-1yso-PAF from rat peritoneal macrophages induced by zymosan. This observation could be important in understanding the anti-inflammatory action of steroids as well as their suppressive effect on host defence systems. * Present address: Dept. of Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, U.K. 0024-3025/85 $3.00 + .00 Copyright (c) 1985 Pergamon Press Ltd.