Functional dissociation between glucocorticoid-induced decrease in arachidonic acid release and inhibition of adrenocorticotropic hormone secretion in AtT-20 corticotrophs.
The biochemical basis of the short-term inhibitory effects of glucocorticoids on corticotropin release from pituitary corticotrophs is still obscure. A well-characterized effect of glucocorticoids in several cell types is the inhibition of arachidonic acid (AA) generation by phospholipase A2 (PLA2). Arachidonic acid and its metabolites have been implicated in the secretory process from a number of pituitary cells, such as the corticotrophs. We have thus examined the role of AA in the anti-secretagogue effects of glucocorticoids in a corticotropin-secreting clonal corticotroph line (AtT-20 D16/16). Glucocorticoids decreased AA release induced by melittin, a bee venom protein related to extracellular PLA2. When a possible role of AA in corticotropin release was studied, the following results were obtained: (a) all corticotropin secretagogues tested, including corticotropin-releasing factor (CRF), did not alter AA generation; (b) calcium and guanine nucleotides, which stimulate corticotropin release in permeabilized cells, inhibited the release of AA under the same conditions; (c) administration of melittin or of exogenous AA had no effect on basal and CRF-stimulated corticotropin release; (d) administration of large amounts of exogenous AA was unable to restore the ability to secrete corticotropin under suppression by glucocorticoids. Altogether, the data suggest that whereas glucocorticoids can inhibit both AA generation and corticotropin release, these two effects appear to be causally unrelated.
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Istituto di Richerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Department of Cell Biology and Oncology, Chieti, Italy.
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D000324:Adrenocorticotropic Hormone / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008555:Melitten / Q000494:pharmacology; D051379:Mice; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D005938:Glucocorticoids; D008555:Melitten; D016718:Arachidonic Acid; D000001:Calcimycin; D011189:Potassium Chloride; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate