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The Human Glucocorticoid Receptor (GR) Isoform ß Differentially Suppresses GR-Induced Transactivation Stimulated by Synthetic Glucocorticoids

Pediatric and Reproductive Endocrinology Branch (O.F., T.K., E.Z., S.A., M.D.M., G.C., Z.H.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Meyer Children’s Hospital (O.F., Z.H.), Rambam Medical Center, Haifa 31096, Israel

Address all correspondence and requests for reprints to: Oren Fruchter, M.D., Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892. E-mail: o_fruchter{at}rambam.health.gov.il

The ß-isoform of human glucocorticoid receptor ß (hGRß) acts as a natural dominant negative inhibitor of hGR-induced transactivation of glucocorticoid-responsive genes. We determined hGRß ability to suppress hGR 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. hGRß, at a 1:1 ratio to hGR, differentially suppressed hGR-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 hGRß on hGR-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 hGRß on hGR-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 hGRß modulates the sensitivity of tissues to glucocorticoids.

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