Molecular mechanisms of dissociative glucocorticoid activity

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Abstract
Background Glucocorticoids mediate their effects on target cells via transactivation and transrepression of certain target genes. While conventional glucocorticoids do not distinguish between transactivation and transrepression, new glucocoticoids should be able to dissociate these effects, thus lowering the potential of unwanted side‐effects of glucocorticoids in clinical use. In this study, we developed a new experimental system to test potentially selective glucocorticoids in normal lymphocytes. Materials and methods Following pretreatment with phytohaemagglutinin, normal lymphocytes were transfected, using electroporation, with pGL3 luciferase reporter vectors under the control: (1) of the human IL‐2 promoter; and (2) of a glucocorticoid response element (GRE). Luciferase activity was measured in response to various steroid compounds, including the potentially dissociative glucocorticoid medroxyprogesterone acetate (MPA). Results The IL‐2 promoter was induced 267.2 ± 27.5‐fold (mean ± SD) by phorbol ester and ionomycin. In these cells, hydrocortisone and dexamethasone caused a 22.9 ± 3.6% and a 38.4 ± 10% reduction in luciferase activity, respectively. Under GRE control, hydrocortisone stimulated luciferase activity 6.4 ± 0.50‐fold and dexamethasone 8.2 ± 0.4‐fold. MPA‐induced transrepression was 73.3 ± 7.2% for the IL‐2 promoter, and transactivation was 2.4 ± 0.4‐fold with the GRE‐driven construct. The natural progestin progesterone did not have significant effects on either construct. Conclusions This is the first system that allows efficient analysis of glucocorticoid‐dependent transactivation and transrepression in normal human lymphocytes. Compared to conventional glucocorticoids, MPA can be reffered to as a dissociative glucocorticoid, its transrepression/transactivation ratio being 6.6 (transrepression 1.91/transactivation 0.29), with dexamethasone being the standard (transrepression 1/transactivation 1). We conclude that MPA is a highly promising substance for the treatment of autoimmune/inflammatory diseases.

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