Medroxyprogesterone acetate impairs human dendritic cell activation and function.
OBJECTIVE
Does medroxyprogesterone acetate (MPA) impair human dendritic cell (DC) activation and function?


CONCLUSIONS
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).


BACKGROUND
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.


METHODS
This cross-sectional study examined MPA-mediated effects on the activation and function of human primary untouched peripheral blood DCs.


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.


RESULTS
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.


CONCLUSIONS
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.


CONCLUSIONS
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.


BACKGROUND
Funding provided by the NIH (grant R01HD072663) and The Ohio State University College of Medicine. The authors have no conﬂicts of interest to declare.
Departments 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.
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Quispe Calla
Departments of Microbial Infection & Immunity and Obstetrics & Gynecology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
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Ghonime
Departments of Microbial Infection & Immunity and Obstetrics & Gynecology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
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TL
Cherpes
Departments 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.
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Vicetti Miguel
D018122:B7-1 Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D003271:Contraceptive Agents, Female / Q000737:chemistry; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects*; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000737:chemistry*; D009000:Monocytes / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology; D051196:Toll-Like Receptor 3 / Q000378:metabolism
D018122:B7-1 Antigen; D019013:CD40 Antigens; D003271:Contraceptive Agents, Female; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D017258:Medroxyprogesterone Acetate
T cell proliferation; costimulatory molecule expression; dendritic cell activation; medroxyprogesterone acetate