Differential effects of RU486 reveal distinct mechanisms for glucocorticoid repression of prostaglandin E release

Eur J Biochem. 2004 Oct;271(20):4042-52. doi: 10.1111/j.1432-1033.2004.04342.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonic Acid / antagonists & inhibitors
  • Arachidonic Acid / metabolism
  • Binding, Competitive
  • Budesonide / pharmacology
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Cyclooxygenase Inhibitors / pharmacology
  • Dexamethasone / pharmacology
  • Dinoprostone / antagonists & inhibitors*
  • Dinoprostone / metabolism
  • Dose-Response Relationship, Drug
  • Glucocorticoids / genetics
  • Glucocorticoids / metabolism*
  • Humans
  • Inhibitory Concentration 50
  • Interleukin-1 / pharmacology
  • Interleukin-1 / physiology
  • Luciferases / metabolism
  • Mifepristone / pharmacology*
  • NF-kappa B / metabolism
  • Prostaglandin-Endoperoxide Synthases / drug effects
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Radioligand Assay
  • Receptors, Glucocorticoid / drug effects
  • Receptors, Glucocorticoid / metabolism
  • Response Elements / drug effects
  • Response Elements / physiology
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology


  • Cyclooxygenase Inhibitors
  • Glucocorticoids
  • Interleukin-1
  • NF-kappa B
  • Receptors, Glucocorticoid
  • Arachidonic Acid
  • Mifepristone
  • Budesonide
  • Dexamethasone
  • Luciferases
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone