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研究生:謝美琦
研究生(外文):Mei-Chi Shie
論文名稱:助孕酮透過非基因性抑制鈉氫交換蛋白免疫調節人類T細胞對PHA刺激所引發的細胞激素分泌和增生反應
論文名稱(外文):Progesterone Exerts Nongenomic Effects on Na+/H+ Exchange as to Immunomodulate Phytohemagglutinin (PHA)-induced Cytokine Secretion and Proliferation in Human Peripheral T Cells
指導教授:賈愛華
指導教授(外文):Eileen Jea Chien
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:中文
論文頁數:94
中文關鍵詞:助孕酮紅血球凝集素鈉氫交換蛋白人類T 淋巴細胞胞內鈣離子胞內pH值增生作用細胞激素
外文關鍵詞:progesteronePHANa+/H+ Exchangehuman T lymphocyteintracellular calciumintracellular pHproliferationcytokine
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先前發現助孕酮可透過非基因性作用促使T細胞胞內鈣離子濃度上升及細胞酸化的現象,而這兩個現象皆可受助孕酮拮抗劑-RU486前處理而阻斷,且助孕酮所造成細胞內pH值下降的現象可因鈉氫交換蛋白(Na+/H+-exchange,NHE)的抑制劑3-methylsulfony-4-piperdinobenzoyl guanidine (HOE694) 前處理T細胞,而有被減弱的現象,但令人質疑的是另一NHE抑制劑5-(N,N-dimethyl)-amiloride (DMA), 卻不會造成pH值下降被減弱的現象。 除此而外,助孕酮亦可抑制PHA所引發的胞內pH值上升,細胞激素的分泌,及增生等作用。 因此本研究旨在探討助孕酮是否透過抑制T細胞胞膜上之鈉氫交換蛋白造成其非基因性的作用使T細胞胞內酸化進而抑制PHA 所引發的細胞活化暨增生的反應。本研究係由健康男性捐贈的週邊血液分離T細胞為研究材料,並以人類淋巴胚瘤細胞株(Jurkat cells)為對照之研究材料。 以Fura-2螢光染劑觀測T細胞胞內鈣離子濃度的變化,並以BCECF測量T細胞胞內pH值的變化暨胞膜上NHE之活性﹔並以反轉錄聚合酶連鎖反應(RT-PCR) 分析胞內NHE之mRNA的表現﹔且以ELISA方法偵測 T細胞IL-10及IFN-γ的分泌量﹔以MTT assay研究活細胞粒腺體中酵素含量及3H-Thymidine攝取至DNA的計數量來評估T細胞增生的反應能力。 本研究結果發現 1) 在胞外無鈉的狀況下助孕酮仍能造成細胞內酸化的現象發生,且助孕酮會抑制PKC活化劑-PMA所引發的鹼化,然而PMA不影響助孕酮刺激T細胞的酸化。 2) PHA刺激T細胞4小時後,可刺激NHE的 mRNA表現量達到最大表現量。 3) NH4Cl可引發胞內酸化藉此可活化T細胞NHE之活性,當以助孕酮處理時,發現可抑制T細胞NHE之活性使得細胞回復至正常pH值的能力變弱,表示助孕酮可發揮其非基因性的作用直接抑制T細胞胞膜上之NHE之活性,而其抑制常數Ki值為13.48 μM﹔而助孕酮在T細胞胞膜上的代謝物20α-hydroxyprogesterone (20α-OHP) 並不會抑制T細胞胞膜上NHE之活性。 4) 助孕酮亦可刺激 Jurkat T cell促使其胞內鈣離子增加及細胞酸化的現象,而助孕酮對Jurkat T cell之NHE的抑制常數Ki值為8.93 μM。 5) 助孕酮及其拮抗劑RU486會抑制mitogen-PHA所引發T細胞的增生反應, 且RU486與助孕酮共同作用時,並不能減弱助孕酮抑制增生的作用。但20α-OHP則不會影響細胞增生反應。 6) 以NHE之抑制劑-DMA處理T細胞,亦發現可抑制PHA所引發T細胞增生的現象。 7) T細胞經PHA處理三天後,再加入助孕酮則發現助孕酮可呈現劑量抑制T細胞之增生作用,而其抑制的效果較助孕酮與PHA同時處理細胞三天的效果顯著,因發現助孕酮抑制PHA細胞增生所用之最低劑量可分別低至0.05 μM或1 μM。 8) PHA可增強細胞粒線體脫氫脢活性的表現,但以助孕酮5μM共同作用時即能有效降低細胞因PHA刺激所增加的活性表現。 由以上結果證明,T細胞具有NHE mRNA的表現,且抑制 NHE可抑制T細胞增生,然而助孕酮具有抑制NHE活性,造成細胞酸化,結果抑制T細胞的增生能力。 因此本研究推論助孕酮是藉由調控NHE的活性來執行其免疫調節的角色。
Progesterone is an endogenous immunomodulator, and can suppress T cell activation during pregnancy. When analyzed under a genome time scale, the classic steroid receptor pathway does not have any effect on ion fluxes. Our previous findings, progesterone antagonist, RU486, could block the intracellular calcium increases and pH (pHi) decrease in human peripheral T cells by progesterone. The acidification was blocked by Na+/H+ exchange inhibitor, 3-methylsulphonyl-4-piperidinobenzoyl, guanidine hydrochloride (HOE694); but not by 5-(N,N- dimethyl)-amiloride (DMA). Therefore, the aim of this study was to investigate whether progesterone exerted nongenomic effects through the inhibition of Na+/H+ exchange (NHE) activities and how it suppressed cytokine secretion and proliferation in human peripheral T cells. T cells from human peripheral blood and leukemia cell line-Jurkat were used to determine the pHi by the fluorescent dye, BCECF. The changes in intracellular calcium ([Ca2+]i) by fluorescent dye, Fura-2. In this study, the expression of NHE1 mRNA was detected by RT-PCR. IL-10 and IFN-γ were determined by ELISA. The proliferation was determined by [3H]-thymidine uptake into DNA or 3-[4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide (MTT) reduction. The new findings indicated that 1) progesterone prevented PMA-induced alkalinization, but PMA did not affect the acidification induced by progesterone. 2) The mRNA expression of NHE was reached peak at 4 h after PHA stimulation. 3) The recovery capability of NHE from acidification following application of a NH3 pulse by addition NH4Cl was suppressed by progesterone (Ki=13.48 μM), but the inactive steroid, 20α-hydroxyprogesterone (20α-OHP), could not affect NHE. 4) Progesterone also resulted an elevation of [Ca2+]i, a decrease of pHi and a suppression of NHE activation(K i =8.93 μM) in Jurkat T cells. 5) Both progesterone and its antagonist, RU486 suppressed T cell proliferation. RU486 did not reverse the suppressive effects by progesterone on PHA-induced [3H]-thymidine uptake. However, DMA could mimic the action of progesterone to suppress PHA-induced [3H]-thymidine uptake. 20α-OHP did not suppress PHA-induced [3H]-thymidine uptake. 6) Progesterone exhibited less effective on suppression PHA-induced [3H]-thymidine uptake when addition of PHA with progesterone at same time than 72 h apart. 7) Progesterone attenuated PHA-induced MTT reduction, but it attenuated [3H]-thymidine uptake with much more extent. In conclusion, the nongenomic effect on inhibition of NHE activity by progesterone did lead to suppress PHA-induced T cell proliferation. These facts indicated that the nongenomic effect on inhibition of NHE activity by progesterone might direct an immunomodulation on human T cells.
中文摘要……………………………………… 1
英文摘要……………………………………… 3
緒 言……………………………………… 5
材料方法………………………………………15
結 果………………………………………31
討 論………………………………………43
參考資料………………………………………55
圖表說明………………………………………64
附 錄………………………………………88
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