The non-genomic effects on Na+/H+-exchange 1 by progesterone and 20α-hydroxyprogesterone in human T cells
The non-genomic effects on Na+/H+-exchange 1 by progesterone and 20α-hydroxyprogesterone in human T cells
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DOI：
10.1002/jcp.20962
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发表时间：
2007-05-01
影响因子：
5.6
通讯作者：
Hsu, Ming-Ta
中科院分区：
文献类型：
--
作者：
Chien, Eileen Jea;Liao, Ching-Fong;Hsu, Ming-Ta
孕激素是一种内源性免疫调节剂，可以抑制妊娠期间的T细胞活化。我们以前已经表明，孕酮的非基因组效应，特别是酸化，是通过质膜位点发挥作用，并抑制细胞基因组对有丝分裂原的反应。本研究旨在表明，酸化是由于非基因组抑制Na+/H+-交换I（NHEI）的孕酮和相关的免疫抑制植物血凝素（PHA）诱导的T细胞增殖。在T细胞中鉴定出阿米洛利敏感的NHE I的存在。孕酮对NHEI活性有抑制作用，但20 α-羟孕酮（20 α-OHP）对NHEI活性无抑制作用。此外，20 alpha-OHP能够与黄体酮竞争并释放对NHEI的抑制作用。甾酮-BSA对NHEI活性的抑制证明了通过质膜位点的非基因组作用。最后，与PHA和孕酮或阿米洛利（5-（N，N-二甲基）-阿米洛利，DMA）的共刺激，抑制PHA诱导的T细胞增殖，但这种抑制没有发生与20 α-OHP和PHA的共刺激。然而，当DMA应用PHA刺激后72小时，它能够抑制PHA-included T细胞增殖。这是第一项研究表明孕酮在几分钟内引起T细胞中质膜NHEI活性的快速非基因组抑制，其由20 α-OHP释放。NHE I的抑制导致免疫抑制性T细胞增殖，并表明孕酮可能在体内母胎界面对NHE I活性产生主要的快速非基因组抑制作用，并且当T细胞从界面循环离开时，20 α-OHP可能能够快速释放抑制。
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.