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 1 (NHE1) by progesterone and correlate this with immunosuppressive phytohemagglutinin (PHA)‐induced T‐cell proliferation. The presence of amiloride‐sensitive NHE 1 was identified in T cells. The activity of NHE1 was inhibited by progesterone but not by 20α‐hydroxyprogesterone (20α‐OHP). Furthermore, 20α‐OHP was able to compete with progesterone and release the inhibitory effect on the NHE1. The inhibition of NHE1 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 20α‐OHP and PHA co‐stimulation. However, when DMA was applied 72 h after PHA stimulation, it was able to suppress PHA‐induced T‐cell proliferation. This is the first study to show that progesterone causes a rapid non‐genomic inhibition of plasma membrane NHE1 activity in T cells within minutes which is released by 20α‐OHP. The inhibition of NHE1 leads to immunosuppressive T‐cell proliferation and suggests that progesterone might exert a major rapid non‐genomic suppressive effect on NHE1 activity at the maternal–fetal interface in vivo and that 20α‐OHP may possibly be able to quickly release the suppression when T cells circulated away from the interface. J. Cell. Physiol. 211: 544–550, 2007. © 2007 Wiley‐Liss, Inc.