Glucocorticoid inhibition of zymosan-induced arachidonic acid release by rat alveolar macrophages.
The phospholipase-dependent liberation of arachidonic acid (AA) from membrane phospholipids has been proposed as the rate-limiting step in the synthesis of bioactive AA metabolites, which play an important role in the expression of inflammatory and immune reactions. We have examined the effects of steroids in vitro on the release of AA by rat alveolar macrophages exposed to zymosan. Fluocinolone (1 microM) significantly inhibited the zymosan-induced release of radiolabeled AA from phosphatidylcholine as well as the production of radiolabeled prostaglandin E2. (PGE2). Dose-response curves gave the following rank order of potency: fluocinolone greater than dexamethasone greater than hydrocortisone. The maximal degree of inhibition of radiolabeled AA release observed was approximately 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 microM) did not inhibit AA release. Concurrent incubation of macrophages 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.
D000818:Animals; D017302:Annexins; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002135:Calcium-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005446:Fluocinolone Acetonide / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006023:Glycoproteins; D012739:Gonadal Steroid Hormones / Q000494:pharmacology; D006854:Hydrocortisone / Q000494:pharmacology; D008222:Lymphokines / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D014176:Protein Biosynthesis; D011650:Pulmonary Alveoli / Q000166:cytology; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D015054:Zymosan / Q000494:pharmacology*
D017302:Annexins; D001095:Arachidonic Acids; D002135:Calcium-Binding Proteins; D005938:Glucocorticoids; D006023:Glycoproteins; D012739:Gonadal Steroid Hormones; D008222:Lymphokines; C030958:lipomodulin; D005446:Fluocinolone Acetonide; D016718:Arachidonic Acid; D003907:Dexamethasone; D015054:Zymosan; D006854:Hydrocortisone