Mifepristone acts as progesterone antagonist of non-genomic responses but inhibits phytohemagglutinin-induced proliferation in human T cells  

Oleh:

Chien, C.H. ; Lai, J.N. ; Liao, C.F. ; Wang, O.Y.

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: Human Reproduction vol. 24 no. 08 (Aug. 2009), page 1968-1975.
Topik: progesterone/mifepristone/RU486/membrane progesterone receptors/T cells

Ketersediaan

Perpustakaan FK Nomor Panggil: H07.K Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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Isi artikel

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, mPRß 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.

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