Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage.
OBJECTIVE
To examine the effects of dydrogesterone on the production of Th1 and Th2 cytokines by lymphocytes from women undergoing unexplained recurrent spontaneous miscarriage (RSM).


METHODS
Controlled prospective, clinical study conducted in a maternity hospital and a university-based immunology laboratory.


METHODS
Faculty of Medicine, Kuwait University and Kuwait Maternity Hospital.


METHODS
Thirty women with unexplained RSM.


METHODS
Peripheral blood mononuclear cells (PBMC) from women with unexplained RSM were isolated from venous blood by density gradient sedimentation and stimulated with phytohaemagglutinin (PHA). Culture supernatants assayed for interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-4, IL-6 and IL-10 by ELISA. Levels of the progesterone-induced blocking factor (PIBF) were also measured.


METHODS
Cytokine production in the presence and absence of progesterone and dydrogesterone.


RESULTS
Dydrogesterone significantly inhibited the production of the Th1 cytokines IFN-gamma (P= 0.0001) and TNF-alpha (P= 0.005) and induced an increase in the levels of the Th2 cytokines IL-4 (P= 0.03) and IL-6 (P= 0.017) resulting in a substantial shift in the ratio of Th1/Th2 cytokines. The effect of dydrogesterone was blocked by the addition of the progesterone-receptor antagonist mifepristone, indicating that dydrogesterone was acting via the progesterone receptor. Dydrogesterone induced the production of PIBF.


CONCLUSIONS
Dydrogesterone inhibits the production of the Th1 cytokines IFN-gamma and TNF-alpha from lymphocytes and up-regulates the production of the Th2 cytokines IL-4 and IL-6, inducing a Th1 to Th2 cytokine shift.
Raghupathy
Raj
R
Department of Microbiology, Faculty of Medicine, Kuwait University, Kuwait.
Al Mutawa
Esraa
E
Makhseed
Ma'asoumah
M
Azizieh
Fawaz
F
Szekeres-Bartho
Julia
J
D000026:Abortion, Habitual / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects*; D004394:Dydrogesterone / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D015735:Mifepristone / Q000494:pharmacology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000096:biosynthesis; D011446:Prospective Studies; D013491:Suppressor Factors, Immunologic; D018417:Th1 Cells / Q000187:drug effects* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000096:biosynthesis; D015854:Up-Regulation
D016207:Cytokines; D006727:Hormone Antagonists; D015850:Interleukin-6; C110058:PIBF1 protein, human; D011257:Pregnancy Proteins; D013491:Suppressor Factors, Immunologic; D048069:Tumor Necrosis Factors; D015847:Interleukin-4; D015735:Mifepristone; D007371:Interferon-gamma; D004394:Dydrogesterone