Differential effects of RU486 reveal distinct mechanisms for glucocorticoid repression of prostaglandin E release.
In A549 pulmonary cells, the dexamethasone- and budesonide-dependent repression of interleukin-1beta-induced prostaglandin E2 release was mimicked by the steroid antagonist, RU486. Conversely, whereas dexamethasone and budesonide were highly effective inhibitors of interleukin-1beta-induced cyclooxygenase (COX)/prostaglandin E synthase (PGES) activity and COX-2 expression, RU486 (<1 microm) was a poor inhibitor, but was able to efficiently antagonize the effects of dexamethasone and budesonide. In addition, both dexamethasone and RU486 repressed [3H]arachidonate release, which is consistent with an effect at the level of phospholipase A2 activity. By contrast, glucocorticoid response element-dependent transcription was unaffected by RU486 but induced by dexamethasone and budesonide, whilst dexamethasone- and budesonide-dependent repression of nuclear factor-kappaB-dependent transcription was maximally 30-40% and RU486 (<1 microm) was without significant effect. Thus, two pharmacologically distinct mechanisms of glucocorticoid-dependent repression of prostaglandin E2 release are revealed. First, glucocorticoid-dependent repression of arachidonic acid is mimicked by RU486 and, second, repression of COX/PGES is antagonized by RU486. Finally, whilst all compounds induced glucocorticoid receptor translocation, no role for glucocorticoid response element-dependent transcription is supported in these inhibitory processes and only a limited role for glucocorticoid-dependent inhibition of nuclear factor-kappaB in the repression of COX-2 is indicated.
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College London, Faculty of Medicine, London, UK.
Joanna E
JE
Chivers
Lisa M
LM
Cambridge
Matthew C
MC
Catley
Judith C
JC
Mak
Louise E
LE
Donnelly
Peter J
PJ
Barnes
Robert
R
Newton
D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D001667:Binding, Competitive; D019819:Budesonide / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology; D008156:Luciferases / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D016861:Cyclooxygenase Inhibitors; D005938:Glucocorticoids; D007375:Interleukin-1; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D016718:Arachidonic Acid; D015735:Mifepristone; D019819:Budesonide; D003907:Dexamethasone; D008156:Luciferases; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone