Cyclosporin A and FK506 are potent activators of proopiomelanocortin-derived peptide secretion without affecting corticotrope glucocorticoid receptor function.
Unliganded glucocorticoid receptors (GR) are localized in the cytoplasm and are associated with heat shock protein (hsp)90, hsp70, and a member of the immunophilin family, FK506 binding protein 59 (FKBP59). Several members of the cyclophilin and FKBP families have now been shown to associate with unactivated steroid receptors, however the physiological role these immunophilins play in steroid receptor function is questionable. In the present study we have measured GR binding and nuclear translocation of activated receptor in corticotrope cells following treatment with the immunophilin ligands FK506 and cyclospcrin A (CsA). Extensive GR binding studies in AtT20 cells, a mouse corticotrope tumor cell line failed to demonstrate an effect of FK506 or CsA on either the ability of GR to bind ligand, or on nuclear translocation of the liganded receptor at either a saturating or subsaturating dose of dexamethasone (DEX). Consistent with the binding data, functionally, neither CsA nor FK506 altered the glucocorticoid induced decrease in either proopiomelanocortin (POMC) derived peptide secretion or POMC heteronuclear (hn) RNA expression. Despite the fact these drugs did not modulate the actions of glucocorticoids on corticotrope cells, both FK506 and CsA were potent stimulators of basal beta-endorphin secretion (4-6 fold) from rat anterior pituitary cultures and AtT20 cells. In addition, FK506 and CsA potentiated beta-endorphin secretion induced by corticotropin releasing factor (CRF) and phorbol ester, but had no apparent acute (60 min) effect on POMC hnRNA levels. Unlike the acute actions of these immunosuppressant drugs, chronic (24 h) treatment lead to a decrease in cytoplasmic POMC mRNA with no apparent change in the amount of secreted beta-endorphin. Taken together these data suggest that FK506 and CsA do not alter GR activation or function in corticotrope cells, however, they are potent but short lived stimulators of POMC-derived peptide secretion. The observation that CsA and FK506 stimulate POMC-derived peptide secretion, and potentiate both phorbol ester and CRF induced secretion, suggests that these immunosuppressant drugs are acting upon a common point within these intracellular pathways.
Sheppard
K E
KE
Baker Medical Research Institute, Prahan, Victoria, Australia.
D000324:Adrenocorticotropic Hormone / Q000502:physiology; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D010455:Peptides / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000819:agonists* / Q000235:genetics; D012332:RNA, Heterogeneous Nuclear / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001615:beta-Endorphin / Q000378:metabolism
D010455:Peptides; D012332:RNA, Heterogeneous Nuclear; D011965:Receptors, Glucocorticoid; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin; D016572:Cyclosporine; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D013755:Tetradecanoylphorbol Acetate; D016559:Tacrolimus