The effects of glucocorticoids are mediated by cytosolic glucocorticoid receptors and result from both genomic and nongenomic mechanisms that also have a role in the therapeutic effects of these agents [ 1-3 ]. The AEs appear to result largely from transactivation that leads to increased expression of regulatory and antiinflammatory proteins [ 2 ]; by contrast, many of the clinically desirable effects appear to result primarily from transrepression, which results in the decreased production of proinflammatory proteins. Nongenomic effects of glucocorticoids include rapid, nonspecific interactions of glucocorticoids with cellular membranes, nongenomic effects medicated by cytosolic glucocorticoid receptors, and specific interactions with membrane-bound glucocorticoid receptors [ 2 ].
By co-expressing glucocorticoid receptor (GR) and transcriptional reporter systems in GR-deficient Cos-7 cells, we profiled potency and efficacy of a panel of GR ligands as a function of GR expression levels (density). Our results show that potency and efficacy for GR full agonists, such as dexamethasone, in these transrepression assays are affected by receptor density. Intriguingly, receptor density dramatically influenced the behavior of the GR antagonist RU486 or the GR agonist medroxyprogesterone acetate (MPA). At high receptor density, both MPA and RU486 behaved as full agonists in transrepression: reducing GR density, however, resulted in conversion of these ligands from full agonist to full antagonists. In contrast, varying GR density could not convert cortisol and budesonide from GR agonists to antagonists. These results have clearly demonstrated, for the first time, an effect of receptor density on the agonist and antagonist properties of RU486 and MPA in GR-mediated transrepression.