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

• Published in: Journal of cellular physiology 2007-05, Vol.211 (2), p.544-550
• Main Authors: Chien, Eileen Jea, Liao, Ching-Fong, Chang, Ching-Pang, Pu, Hsiao-Fung, Lu, Li-Ming, Shie, Mei-Chi, Hsieh, Dennis J-Y, Hsu, Ming-Ta
• Format: Article
• Language: English
• Subjects: 20-alpha-Dihydroprogesterone - metabolism; Adult; Amiloride - analogs & derivatives; Amiloride - pharmacology; Binding, Competitive; Cation Transport Proteins - antagonists & inhibitors; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Hydrogen-Ion Concentration; Immunologic Factors - metabolism; Immunologic Factors - pharmacology; Intracellular Fluid - metabolism; Lymphocyte Activation - drug effects; Male; Mitogens - pharmacology; Phytohemagglutinins - pharmacology; Progesterone - metabolism; Progesterone - pharmacology; RNA, Messenger - analysis; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers - antagonists & inhibitors; Sodium-Hydrogen Exchangers - genetics; Sodium-Hydrogen Exchangers - metabolism; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Time Factors
• ISSN: 0021-9541

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 20alpha-hydroxyprogesterone (20alpha-OHP). Furthermore, 20alpha-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 20alpha-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 20alpha-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 20alpha-OHP may possibly be able to quickly release the suppression when T cells circulated away from the interface.