Dissociative Glucocorticoid Activity of Medroxyprogesterone Acetate in Normal Human Lymphocytes

Abstract

The immunosuppressive effects of glucocorticoids (GC) have led to their wide application in the treatment of inflammatory and autoimmune states. However, long term GC treatment is associated with severe side-effects. The development of agents displaying a more favorable ratio of wanted and unwanted GC effects, is, therefore, a major goal of pharmacological and clinical research. In this study, the progesterone receptor agonist medroxyprogesterone acetate (MPA), which also binds to the glucocorticoid receptor (GR), was tested with regard to its immunosuppressive properties. Using a recently established electroporation protocol, we show that MPA (but not progesterone) can suppress a human interleukin-2 (IL-2) promoter-luciferase construct to the same extent as the synthetic GC dexamethasone in normal human lymphocytes. MPA also markedly suppressed IL-2 (as well as IL-1 and IL-6) release, as assessed by specific enzyme-linked immunosorbent assays. In contrast, a highly dexamethasone-inducible glucocorticoid response element-driven promoter construct was only marginally stimulated by MPA in both normal human lymphocytes and HeLa cells. RT-PCR and Western blot analysis of normal human lymphocytes revealed that they do not express progesterone receptor messenger ribonucleic acid and protein, respectively. In contrast, the GR protein was clearly detectable in all samples and was shown to mediate the effects of 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 absence of significant trans-activation; and 2) this effect is mediated by GR. Because of its dissociative GC activity, MPA is a highly promising substance for the treatment of inflammatory/autoimmune states.

Fibrates and medroxyprogesterone acetate induce apoptosis of primary Burkitt's lymphoma cells and cell lines: potential for applying old drugs to a new disease

“…[38][39][40] We have demonstrated antiproliferative actions of MPA against both primary BL cells and cell lines, but, in contrast to Dex, did not detect significant caspase activation by L3055 cells after 24-48 h treatments with MPA alone. Furthermore, the antiproliferative effect of MPA alone was not as great as that of Dex alone against primary BL cells.…”

Estrogen: A Mitochrondrial Energizer That Keeps on Going

“…Like CEE, MPA was chosen because it is the most prescribed replacement. However, MPA displays unique pharmacological properties, including significantly greater activity at the glucocorticoid receptor than progesterone (Bamberger et al, 1999) and the ability to antagonize the beneficial effects of E2 in models of coronary vasospasm and neuroprotection in which progesterone exhibited beneficial effects (Miyagawa et al, 1997;Nilsen and Brinton, 2003). Thus, the distinct pharmacological profiles of the various hormone replacement regimens are a plausible explanation for the mystery; however, considerable basic and clinical research is required to resolve this issue.…”

Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate α-ENaC and sgk1 expression in renal collecting duct epithelia

“…Transactivation has been reported with both native genes and with transfected reporter genes and appears to be mediated via a classical GRE (1, 7). The GR-mediated trans-repression of target genes is less well understood and may involve a negative GRE (nGRE); nevertheless, in some cell culture systems, MPA is as potent as dexamethasone in transrepression (1,13). Both trans-activation and trans-repression may be enhanced by increasing GR receptor density and may explain the variable glucocorticoid effects of MPA in different tissues (33,39).…”