The non-genomic effects on Na+/H+-exchange 1 by progesterone and 20α-hydroxyprogesterone in human T cells

Progesterone is an endogenous immunomodulator and can suppress T-cell activation during pregnancy. We have previously shown that the non-genomic effects of progesterone, especially acidification, are exerted via plasma membrane sites and suppress cellular genomic responses to mitogens. This study aimed to show that acidification is due to a non-genomic inhibition of Na+/H+-exchange I (NHEI) by progesterone and correlate this with immunosuppressive phytohemagglutinin (PHA)-induced T-cell proliferation. The presence of amiloride-sensitive NHE I was identified in T cells. The activity of NHEI was inhibited by progesterone but not by 20 alpha-hydroxyprogesterone (20 alpha-OHP). Furthermore, 20 alpha-OHP was able to compete with progesterone and release the inhibitory effect on the NHEI. The inhibition of NHEI activity by progesterone-BSA demonstrated non-genomic action via plasma membrane sites. Finally, co-stimulation with PHA and progesterone or amiloride, (5-(N, N-dimethyl)-amiloride, DMA), inhibited PHA-induced T-cell proliferation, but this inhibition did not occur with 20 alpha-OHP and PHA co-stimulation. However, when DMA was applied 72 h after PHA stimulation, it was able to suppress PHA-incluced T-cell proliferation. This is the first study to show that progesterone causes a rapid non-genomic inhibition of plasma membrane NHEI activity in T cells within minutes which is released by 20 alpha-OHP. The inhibition of NHE I leads to immunosuppressive T-cell proliferation and suggests that progesterone might exert a major rapid non-genomic suppressive effect on NHE I activity at the maternal-fetal interface in vivo and that 20 alpha-OHP may possibly be able to quickly release the suppression when T cells circulated away from the interface.