title: The non-genomic effects on Na+/H+-exchange 1 by progesterone and 20alpha-hydroxyprogesterone in human T cells.
abstract: 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.
authors.affiliation: Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China. eileen@ym.edu.tw
authors.forename: Eileen Jea
authors.initials: EJ
authors.lastname: Chien
authors.forename: Ching-Fong
authors.initials: CF
authors.lastname: Liao
authors.forename: Ching-Pang
authors.initials: CP
authors.lastname: Chang
authors.forename: Hsiao-Fung
authors.initials: HF
authors.lastname: Pu
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Lu
authors.forename: Mei-Chi
authors.initials: MC
authors.lastname: Shie
authors.forename: Dennis J-Y
authors.initials: DJ
authors.lastname: Hsieh
authors.forename: Ming-Ta
authors.initials: MT
authors.lastname: Hsu
mesh_terms: D004092:20-alpha-Dihydroprogesterone / Q000378:metabolism; D000328:Adult; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D001667:Binding, Competitive; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007155:Immunologic Factors / Q000378:metabolism* / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
chemical_list: D027682:Cation Transport Proteins; D007155:Immunologic Factors; D008934:Mitogens; D010835:Phytohemagglutinins; D012333:RNA, Messenger; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D004092:20-alpha-Dihydroprogesterone; C039465:5-dimethylamiloride; D011374:Progesterone; D000584:Amiloride