GLUCOCORTICOID INHIBITION OF ZYMOSAN-INDUCED ARACHIDONIC-ACID RELEASE BY RAT ALVEOLAR MACROPHAGES

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Abstract
The phospholipase-dependent arachidonic acid (AA) liberation from membrane phosphlipids has been proposed as the rate limiting step in bioactive AA metabolite synthesis, which plays an important role in inflammatory and immune reaction expression. The effects of steroids in vitro on AA release by rat alveolar macrophages exposed to zymosan were examined. Fluocinolone (1 .mu.M) significantly inhibited the zymosan-induced radiolabeled AA release from phosphatidylcholine and radiolabeled prostaglandin E2 (PGE2) production. Dose-response curves gave the following rank potency order: fluocinolone > dexamethasone > hydrocortisone. The maximal degree of radiolabeled AA release inhibition observed was .apprx. 70%. Inhibition was not observed after 3 h of glucocorticoid pretreatment, but maximal inhibition was achieved after 10 h of pretreatment. Pretreatment with gonadal sex hormones (1 .mu.M) did not inhibit AA release. Concurrent macrophage incubation with hydrocortisone and excess concentrations of the partial glucocorticoid agonist, progesterone, blunted the degree of inhibition observed with hydrocortisone alone. These data are consistent with a receptor-mediated process. The time course suggests a response dependent on new protein synthesis, and the increased concentration of the phospholipase-inhibitory protein, lipomodulin, in steroid-treated cultures is putative evidence of new protein synthesis.