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Anti-inflammatory glucocorticoids inhibit prostaglandin (PG) biosynthesis by preventing arachidonic acid release from phospholipids rather than inhibiting the cyclooxygenase. As in other cells, this steroid action depends on receptor occupation and de novo protein/RNA biosynthesis. We have previously shown in guinea pig perfused lungs and rat peritoneal leukocytes that the effect of steroids in PG generation is mediated by an uncharacterized 'second messenger'. Now, we report that this factor (which we have named 'macrocortin') is an intracellular polypeptide whose release and synthesis are stimulated by steroids. Macrocortin derived from rat peritoneal leukocytes is very similar to that released from guinea pig lungs.

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1 A simple double-isotope assay for phospholipase A2 activity of perfused organs is described. 2 Guinea-pig lungs perfused through the pulmonary circulation exhibit a low background enzyme activity. This activity is blocked by dexamethasone, betamethasone and hydrocortisone, mepacrine, procaine or chlorpromazine. Aspirin and indomethacin are without effect. 3 Mechanical trauma, antigen challenge or injections of bradykinin, rabbit aorta contracting substance-releasing factor (RCS-RF) or histamine increase 'basal' phospholipase activity. The effect of these agents, except that of bradykinin, is blocked by dexamethasone or mepacrine. 4 The blocking effect of steroids is cumulative and dose-dependent. They do not work in cell-free systems. Inhibition by mepacrine is rapid and is effective in cell-free lung homogenates. 5 It is suggested that agents which liberate prostaglandin endoperoxides and thromboxane A2 from perfused lungs do so by activating phospholipase A2.