Glucocorticoids inhibit prostaglandin synthesis not only at the level of phospholipase A2 but also at the level of cyclo-oxygenase/PGE isomerase.
1. Prostanoid synthesis was induced in bone marrow-derived macrophages by addition of exogenous arachidonic acid to the cell cultures. When the cells were preincubated with dexamethasone (10(-7) and 10(-6) M) overnight, prostaglandin synthesis was inhibited by 66.5 +/- 2.8% and 56.7 +/- 2.9% (mean +/- s.d.; n = 3) respectively. 2. Endogenous membrane bound phospholipase A2 was measured with labelled phospholipids used as substrates. The enzyme activity with phosphatidylcholine and phosphatidylethanolamine as substrates was inhibited by 27.0 +/- 8.3% and 23.3 +/- 11.1% (n = 4) respectively, in dexamethasone-treated macrophages compared to control cells. Neither the distribution of radiolabelled arachidonic acid among the different phospholipid species nor the release of arachidonic acid from prelabelled cells were significantly impaired by pretreatment of the macrophages with dexamethasone (1 microM). 3. The enzyme activity of the cyclo-oxygenase/prostaglandin E (PGE) isomerase was measured in cell membranes from control cells and dexamethasone-treated cells. It was inhibited by 40.0 +/- 8.4% (n = 4) in dexamethasone-treated cells as compared to control cells. Thus, glucocorticoids inhibit not only phospholipase A2 in these cells, but predominantly inhibit arachidonic acid metabolism subsequent to its release from phospholipids.
Goppelt-Struebe
M
M
Department of Pharmacology and Toxicology, Medical School Hannover, F.R.G.
Wolter
D
D
Resch
K
K
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells; D016861:Cyclooxygenase Inhibitors; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D007739:L Cells / Q000378:metabolism; D008566:Membranes / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010740:Phospholipases / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D010743:Phospholipids / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D011458:Prostaglandins E / Q000378:metabolism*
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D005938:Glucocorticoids; D010743:Phospholipids; D011453:Prostaglandins; D011458:Prostaglandins E; D003609:Dactinomycin; D003907:Dexamethasone; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2