Dissociative glucocorticoid activity of medroxyprogesterone acetate in normal human lymphocytes

The immunosuppressive effects of glucocorticoids (GC) have led to their wid e application in the treatment of inflammatory and autoimmune states. Howev er, long term GC treatment is associated with severe side-effects. The deve lopment of agents displaying a more favorable ratio of wanted and unwanted GC effects, is, therefore, a major goal of pharmacological and clinical res earch. In this study, the progesterone receptor agonist medroxyprogesterone acetate (MPA), which also binds to the glucocorticoid receptor (GR), was t ested with regard to its immunosuppressive properties. Using a recently est ablished electroporation protocol, we show that MPA (but not progesterone) can suppress a human interleukin-a (IL-2) promoter-luciferase construct to the same extent as the synthetic GC dexamethasone in normal human lymphocyt es. MPA also markedly suppressed IL-2 las well as IL-1 and IL-6) release, a s assessed by specific enzyme-linked immunosorbent assays. In contrast, a h ighly dexamethasone-inducible glucocorticoid response element-driven promot er construct was only marginally stimulated by MPA in both normal human lym phocytes and HeLa cells. RT-PCR and Western blot analysis of normal human l ymphocytes revealed that they do not express progesterone receptor messenge r ribonucleic acid and protein, respectively. In contrast, the GR protein w as clearly detectable in all samples and was shown to mediate the effects o f MPA in transfected Jurkat T lymphoma cells. Our data indicate that 1) MPA can transrepress the human IL-2 gene in normal human lymphocytes in the ab sence of significant trans-activation; and 2) this effect is mediated by GR . Because of its dissociative GC activity, MPA is a highly promising substa nce for the treatment of inflammatory/autoimmune states.