The human glucocorticoid receptor (GR) isoform β differentially suppresses GRα-induced transactivation stimulated by synthetic glucocorticoids

The beta-isoform of human glucocorticoid receptor beta (hGR beta) acts as a natural dominant negative inhibitor of hGR alpha-induced transactivation of glucocorticoid-responsive genes. We determined hGR beta ability to suppress hGR alpha transactivation that was induced by commonly used synthetic glucocorticoids. HepG2/C3A cells were transiently cotransfected with GR cDNA and a glucocorticoid-responsive promoter, luciferase (MMTV-luc). Transfected cells were incubated for 16 h with glucocorticoid and luciferase. For each compound, a dose-response curve was constructed, and half-maximal effective concentrations and maximal transcriptional activities were compared. hGR beta, at a 1: 1 ratio to hGR alpha, differentially suppressed hGR alpha-induced maximal transcriptional activity stimulated by triamcinolone, dexamethasone, hydrocortisone, and betamethasone ( by 96, 68, 62, and 49%, respectively) but not by methylprednisolone. The suppressive effect of hGR beta on hGR alpha-induced transactivation was stronger at lower concentrations of all tested glucocorticoids, whereas it was blunted at higher concentrations. We conclude that the potency of the dominant negative effect of hGR beta on hGR alpha-induced transactivation depends on both the type and the dose of the synthetic glucocorticoids in use. These results may provide helpful information concerning the selection of synthetic glucocorticoids for treatment of pathological conditions in which hGR beta modulates the sensitivity of tissues to glucocorticoids.