Hum. Reprod. Advance Access originally published online on April 28, 2009
Human Reproduction 2009 24(8):1968-1975; doi:10.1093/humrep/dep099
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Mifepristone acts as progesterone antagonist of non-genomic responses but inhibits phytohemagglutinin-induced proliferation in human T cells
1 Institute of Physiology, School of Medicine, National Yang-Ming University, Beitou, Taipei 11221, Taiwan, Republic of China 2 Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Beitou, Taipei 11221, Taiwan, Republic of China 3 Department of Obstetrics and Gynecology, Taipei Municipal Yang-Ming Hospital, Taipei 11260, Taiwan, Republic of China 4 Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China
5 Correspondence address. Fax: +886-2-2826-4049 E-mail: eileen{at}ym.edu.tw
BACKGROUND: Progesterone is an endogenous immunomodulator that suppresses T cell activation during pregnancy. The stimulation of membrane progesterone receptors (mPRs) would seem to be the cause of rapid non-genomic responses in human peripheral T cells, such as an elevation of intracellular calcium ([Ca2+]i) and decreased intracellular pH (pHi). Mifepristone (RU486) produces mixed agonist/antagonist effects on immune cells compared with progesterone. We explored whether RU486 is an antagonist to mPRs and can block rapid non-genomic responses and the induction by phytohemagglutinin (PHA) of cell proliferation.
METHODS: Human male peripheral T cell responses in terms of pHi and [Ca2+]i changes were measured using the fluorescent dyes, 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) and fura-2, respectively. Expression of mPR mRNA was determined by RT–PCR analysis. Cell proliferation and cell toxicity were determined by [3H]-thymidine incorporation and MTT assay, respectively.
RESULTS: The mRNAs of mPR
, mPRβ and mPR
were expressed in T cells. RU486 blocked progesterone-mediated rapid responses including, the [Ca2+]i increase and pHi decrease, in a dose related manner. RU486 did not block, but enhanced, the inhibitory effect of progesterone on PHA induced cell proliferation. RU486 alone inhibited proliferation induced by PHA and at >25 µM seems to be cytotoxic against resting T cells (P < 0.01).
CONCLUSIONS: RU486 is antagonistic to the rapid mPR-mediated non-genomic responses, but is synergistic with progesterone with respect to the inhibition of PHA-induced cell proliferation. Our findings shine new light on RU486's clinical application and how this relates to the non-genomic rapid physiological responses caused by progesterone.
Key words: progesterone/mifepristone/RU486/membrane progesterone receptors/T cells
Submitted on November 11, 2008; resubmitted on February 4, 2009; accepted on March 20, 2009.