Differential effects of RU486 reveal distinct mechanisms for glucocorticoid repression of prostaglandin E₂ release

In A549 pulmonary cells, the dexamethasone‐ and budesonide‐dependent repression of interleukin‐1β‐induced prostaglandin E 2 release was mimicked by the steroid antagonist, RU486. Conversely, whereas dexamethasone and budesonide were highly effective inhibitors of interleukin‐1β‐induced cyclooxygenase (COX)/prostaglandin E synthase (PGES) activity and COX‐2 expression, RU486 (< 1 µ m ) was a poor inhibitor, but was able to efficiently antagonize the effects of dexamethasone and budesonide. In addition, both dexamethasone and RU486 repressed [ 3 H]arachidonate release, which is consistent with an effect at the level of phospholipase A 2 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‐κB‐dependent transcription was maximally 30–40% and RU486 (< 1 µ m ) was without significant effect. Thus, two pharmacologically distinct mechanisms of glucocorticoid‐dependent repression of prostaglandin E 2 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‐κB in the repression of COX‐2 is indicated.