Mifepristone acts as progesterone antagonist of non-genomic responses but inhibits phytohemagglutinin-induced proliferation in human T cells.
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 ([Ca(2+)](i)) and decreased intracellular pH (pH(i)). 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 pH(i) and [Ca(2+)](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 [(3)H]-thymidine incorporation and MTT assay, respectively.


RESULTS
The mRNAs of mPRalpha, mPRbeta and mPRgamma were expressed in T cells. RU486 blocked progesterone-mediated rapid responses including, the [Ca(2+)](i) increase and pH(i) 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 microM 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.
Chien
C H
CH
Institute of Physiology, School of Medicine, National Yang-Ming University, Beitou, Taipei 11221, Taiwan, Republic of China.
Lai
J N
JN
Liao
C F
CF
Wang
O Y
OY
Lu
L M
LM
Huang
M I
MI
Lee
W F
WF
Shie
M C
MC
Chien
E J
EJ
D000328:Adult; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D010835:Phytohemagglutinins / Q000494:pharmacology*; D011374:Progesterone / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
D010835:Phytohemagglutinins; D012333:RNA, Messenger; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D015735:Mifepristone; D011374:Progesterone; D002118:Calcium