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Medroxyprogesterone acetate impairs human dendritic cell activation and function
N E Quispe Calla1, M G Ghonime2, T L Cherpes2
1Departments of Microbial Infection & Immunity and Obstetrics & Gynecology, The Ohio State University College of Medicine, Columbus, OH 43210, USA quispecalla.1@osu.edu vicettimiguel.1@osu.edu.
Study Question:
Does medroxyprogesterone acetate (MPA) impair human dendritic cell (DC) activation and function?
Summary Answer:
In vitro MPA treatment suppressed expression of CD40 and CD80 by human primary DCs responding to Toll-like receptor 3 (TLR3) agonist stimulation (i.e. DC activation). Moreover, this MPA-mediated decrease in CD40 expression impaired DC capacity to stimulate T cell proliferation (i.e. DC function).
What Is Known Already:
MPA is the active molecule in Depo-Provera(®) (DMPA), a commonly used injectable hormonal contraceptive (HC). Although DMPA treatment of mice prior to viral mucosal tissue infection impaired the capacity of DCs to up-regulate CD40 and CD80 and prime virus-specific T cell proliferation, neither DC activation marker expression nor the ability of DCs to promote T cell proliferation were affected by in vitro progesterone treatment of human DCs generated from peripheral blood monocytes.
Study Design, Size, Duration:
This cross-sectional study examined MPA-mediated effects on the activation and function of human primary untouched peripheral blood DCs.
Participants/Materials, Setting, Methods:
Human DCs isolated from peripheral blood mononuclear cells by negative immunomagnetic selection were incubated for 24 h with various concentrations of MPA. After an additional 24 h incubation with the TLR3 agonist polyinosinic:polycytidylic acid (poly I:C), flow cytometry was used to evaluate DC phenotype (i.e. expression of CD40, CD80, CD86, and HLA-DR). In separate experiments, primary untouched human DCs were sequentially MPA-treated, poly I:C-activated, and incubated for 7 days with fluorescently labeled naïve allogeneic T cells. Flow cytometry was then used to quantify allogeneic T cell proliferation.
Main Results And The Role Of Chance:
Several pharmacologically relevant concentrations of MPA dramatically reduced CD40 and CD80 expression in human primary DCs responding to the immunostimulant poly I:C. In addition, MPA-treated DCs displayed a reduced capacity to promote allogeneic CD4(+) and CD8(+) T cell proliferation. In other DC: T cell co-cultures, the addition of antibody blocking the CD40-CD154 (CD40L) interaction mirrored the decreased T cell proliferation produced by MPA treatment, while addition of recombinant soluble CD154 restored the capacity of MPA-treated DCs to induce T cell proliferation to levels produced by non-MPA-treated controls.
Limitations, Reason For Caution:
While our results newly reveal that pharmacologically relevant MPA concentrations suppress human DC function in vitro, additional research is needed to learn if DMPA similarly inhibits DC maturation and function in the human female genital tract.
Wider Implications Of The Findings:
Identification of a mechanism by which MPA impairs human DC activation and function increases the biological plausibility for the relationships currently suspected between DMPA use and enhanced susceptibility to genital tract infection.
Study Funding/Competing Interests:
Funding provided by the NIH (grant R01HD072663) and The Ohio State University College of Medicine. The authors have no conflicts of interest to declare.
Insights
Medroxyprogesterone acetate (MPA) impairs human dendritic cell (DC) activation and function by suppressing key surface molecules. This impacts T cell proliferation, potentially increasing susceptibility to genital tract infections.
Area of Science:
- Immunology
- Endocrinology
- Cell Biology
Background:
- Medroxyprogesterone acetate (MPA) is the active component in Depo-Provera (DMPA), a widely used injectable hormonal contraceptive.
- Previous studies in mice suggested DMPA impairs dendritic cell (DC) function, but in vitro studies with human DCs and progesterone showed no effect.
Purpose of the Study:
- To investigate whether MPA affects the activation and function of human primary dendritic cells (DCs).
- To determine the impact of MPA on DC-mediated T cell proliferation.
Main Methods:
- Human peripheral blood DCs were isolated and treated with MPA in vitro.
- DCs were stimulated with a Toll-like receptor 3 (TLR3) agonist (poly I:C) to assess activation markers (CD40, CD80, CD86, HLA-DR) via flow cytometry.
- DC capacity to stimulate allogeneic T cell proliferation was measured through co-culture experiments.
Main Results:
- MPA significantly reduced the expression of CD40 and CD80 on human DCs stimulated with poly I:C.
- MPA-treated DCs showed a diminished ability to promote proliferation of both CD4+ and CD8+ T cells.
- Blocking CD40-CD154 interaction mimicked MPA's effect on T cell proliferation, while adding soluble CD154 restored it.
Conclusions:
- Pharmacologically relevant concentrations of MPA suppress human DC activation and function in vitro.
- MPA's impairment of DC function, particularly CD40 expression, reduces T cell proliferation.
- These findings suggest a mechanism linking DMPA use to increased susceptibility to genital tract infections.
