運(yùn)動(dòng)、胸腺細(xì)胞凋亡與機(jī)制研究

楊貴明，王雪芹

(1.中山大學(xué)南方學(xué)院，廣東 廣州　510000；2.臨沂大學(xué)，山東 臨沂　276005)

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運(yùn)動(dòng)、胸腺細(xì)胞凋亡與機(jī)制研究

楊貴明1，王雪芹2

(1.中山大學(xué)南方學(xué)院，廣東 廣州510000；2.臨沂大學(xué)，山東 臨沂276005)

主要通過(guò)文獻(xiàn)資料法，對(duì)細(xì)胞凋亡的機(jī)制及運(yùn)動(dòng)與胸腺細(xì)胞凋亡的關(guān)系等進(jìn)行了述評(píng)，其中細(xì)胞凋亡與死亡受體信號(hào)轉(zhuǎn)導(dǎo)途徑、細(xì)胞凋亡與線粒體凋亡途徑和細(xì)胞凋亡與內(nèi)質(zhì)網(wǎng)凋亡途徑是本文論述的重點(diǎn)。結(jié)果顯示，有關(guān)胸腺細(xì)胞凋亡的死亡受體信號(hào)轉(zhuǎn)導(dǎo)途徑機(jī)制和線粒體機(jī)制研究不多，有關(guān)胸腺細(xì)胞凋亡的內(nèi)質(zhì)網(wǎng)機(jī)制甚少?，F(xiàn)有研究顯示運(yùn)動(dòng)誘導(dǎo)胸腺細(xì)胞凋亡與線粒體凋亡途徑關(guān)系密切，其他有待進(jìn)一步研究證實(shí)。

運(yùn)動(dòng)；胸腺；凋亡；死亡受體；線粒體；內(nèi)質(zhì)網(wǎng)

細(xì)胞的程序化死亡是1965 年被第一次提出，而有關(guān)細(xì)胞凋亡則是1972年第一次被提出[1][2]。細(xì)胞凋亡是細(xì)胞在基因調(diào)控下有序死亡的形式，是一個(gè)遺傳性的程序性過(guò)程[3]。胸腺細(xì)胞的發(fā)育過(guò)程需要經(jīng)過(guò)多次篩選，在篩選中，約有95%的胸腺細(xì)胞被篩掉，篩掉的細(xì)胞會(huì)發(fā)生凋亡，凋亡的情況直接關(guān)系到胸腺細(xì)胞的分化和成熟情況。從而推斷篩掉細(xì)胞的量可能與免疫機(jī)能有關(guān)，比如在大強(qiáng)度運(yùn)動(dòng)刺激下，胸腺細(xì)胞的凋亡量增加，可能是引起機(jī)體免疫力下降的原因之一。有研究顯示，大強(qiáng)度運(yùn)動(dòng)會(huì)導(dǎo)致胸腺細(xì)胞發(fā)育情況受阻，細(xì)胞失常，并伴有機(jī)體免疫功能紊亂等[4][5]。為了探討運(yùn)動(dòng)對(duì)機(jī)體免疫機(jī)能的影響，本文從胸腺細(xì)胞凋亡及凋亡的機(jī)制出發(fā)，希望找到運(yùn)動(dòng)過(guò)程中胸腺細(xì)胞凋亡情況及胸腺細(xì)胞凋亡的機(jī)理，為運(yùn)動(dòng)免疫抑制及調(diào)理提供理論基礎(chǔ)。

1　死亡受體信號(hào)轉(zhuǎn)導(dǎo)途徑與胸腺細(xì)胞凋亡的相關(guān)研究

死亡受體具有胞外結(jié)構(gòu)域和胞內(nèi)死亡結(jié)構(gòu)域，是腫瘤壞死因子受體(TNFR)基因超家族的成員[6]。現(xiàn)已發(fā)現(xiàn)的死亡受體的種類很多，其中研究較多的是CD95(Fas)[7] [8] [9]。CD95(Fas或Apol)的配體是CD95L，TNFR1的配體是TNF、DR31的配體是淋巴毒素A、DR4的配體是Apo3L。細(xì)胞凋亡途徑之一是死亡受體信號(hào)轉(zhuǎn)導(dǎo)途徑。死亡受體在誘導(dǎo)細(xì)胞凋亡中必須與特定的死亡配體結(jié)合[10]。死亡受體信號(hào)通路作用過(guò)程以Fas和FasL為例進(jìn)行介紹。(1)死亡受體Fas啟動(dòng)凋亡過(guò)程；(2)死亡信號(hào)誘導(dǎo)復(fù)合體(DISC)的形成[11]；(3)FasL配體與三分子Fas結(jié)合；(4)然后接頭蛋白FADD在細(xì)胞內(nèi)聚集成簇，其C端的DD結(jié)合Fas，其N端招募caspase-8前體，結(jié)合caspase-8前體后，進(jìn)行寡聚化，形成DISC。使caspase-8發(fā)生同源活化。進(jìn)一步活化caspase-3、7和4等[12][13]。細(xì)胞DNA完整性被破壞，最終導(dǎo)致細(xì)胞凋亡。

死亡受體凋亡通路的各成分都能從大鼠胸腺中檢測(cè)到[14]。有研究發(fā)現(xiàn)Fas途徑參與了三丁基氯化錫(TBTC)誘導(dǎo)的胸腺細(xì)胞凋亡過(guò)程[15]。Liang等通過(guò)體外培養(yǎng)的胸腺細(xì)胞，發(fā)現(xiàn)脫氫表雄酮(DHEA)可使胸腺細(xì)胞Fas和FasL的表達(dá)提高，表明Fas/FasL的途徑可能參與了DHEA誘導(dǎo)的胸腺細(xì)胞凋亡[16]。Yao等研究發(fā)現(xiàn)壬基酚可能通過(guò)改變Fas和FasLmRNA的表達(dá)介導(dǎo)細(xì)胞凋亡，進(jìn)而影響免疫功能[17]。有研究發(fā)現(xiàn)Fas途徑與不成熟的CD4+8+胸腺細(xì)胞凋亡有關(guān)[18]。體外、體內(nèi)和原位實(shí)驗(yàn)已被證實(shí)，雙陽(yáng)性不成熟CD4+8+胸腺細(xì)胞最容易受到Fas誘導(dǎo)而出現(xiàn)細(xì)胞凋亡。Aquino Esperanza等在觀察體內(nèi)5-氟脲嘧啶(5-FU,一種抗癌藥物)誘導(dǎo)小鼠胸腺細(xì)胞凋亡中，CF-1小鼠單劑量注射的5-FU(150毫克/公斤的IP )，實(shí)驗(yàn)持續(xù)10天，發(fā)現(xiàn)細(xì)胞死亡在第二天最多，此外，在第2天，F(xiàn)as和Bax等促凋亡蛋白強(qiáng)烈上調(diào)，且伴隨著在同一期間內(nèi)caspase-3的激活[19]。Song等將40只SD大鼠隨機(jī)分成對(duì)照組、嗎啡戒斷綜合征1組(第21天處死)、嗎啡戒斷綜合征2組(第27天處死)和嗎啡戒斷綜合征電針刺組(EA，電針刺7天處死)，發(fā)現(xiàn)電刺激足三里能抑制嗎啡誘導(dǎo)的Bcl-2下調(diào)和Fas和FasL表達(dá)上調(diào)，這可能有助于抵抗嗎啡戒斷大鼠胸腺細(xì)胞的凋亡[20]。以上的研究表明，F(xiàn)as和FasL死亡信號(hào)通路在胸腺細(xì)胞凋亡過(guò)程中可能起著重要作用。

2　線粒體凋亡途徑與胸腺細(xì)胞凋亡的相關(guān)研究

線粒體主要由基質(zhì)、內(nèi)膜、外膜和膜間隙組成，是三羧酸循環(huán)和氧化磷酸化的重要場(chǎng)所，猶如細(xì)胞的動(dòng)力工廠。脊椎動(dòng)物細(xì)胞的凋亡過(guò)程中線粒體起最基本的調(diào)節(jié)作用。即線粒體凋亡途徑調(diào)節(jié)著脊柱動(dòng)物細(xì)胞的凋亡，在caspase依賴線粒體凋亡途徑中，Bcl-2家族成員(如Bax、 Bak等)能與激活的Bcl-2相應(yīng)的家族成員Bid、Bad、Bim、Harikari和Noxa等作用，如Bax導(dǎo)致線粒體跨膜電位減弱甚至丟失，進(jìn)而導(dǎo)致細(xì)胞中細(xì)胞色素C的釋放等[21]。細(xì)胞色素C的釋放在細(xì)胞凋亡過(guò)程中起著關(guān)鍵作用，是細(xì)胞線粒體膜電位通透性改變的結(jié)果[22] [23]。Bax寡聚體能整合到線粒體外膜上，使膜通透性增加, 使細(xì)胞色素C釋放至細(xì)胞質(zhì)[24]。在細(xì)胞質(zhì)中，色素C會(huì)激活酶激活因子-1( Apaf-1)，并活化半胱氨酸蛋白酶procaspase-9及caspase-3 等導(dǎo)致細(xì)胞出現(xiàn)凋亡增加[25][26][27]。

已有研究發(fā)現(xiàn)，線粒體凋亡途徑在小鼠胸腺的細(xì)胞凋亡中起著重要作用[28]。其中，嘌呤核苷磷酸化酶與胸腺細(xì)胞發(fā)育關(guān)系密切，嘌呤核苷磷酸化酶缺乏會(huì)導(dǎo)致胸腺DP細(xì)胞凋亡改變，并檢測(cè)到了線粒體膜電位的丟失。即線粒體凋亡途徑與DP胸腺細(xì)胞的凋亡關(guān)系密切[29]。Pálinkás等發(fā)現(xiàn)DP胸腺細(xì)胞凋亡與外源性糖皮質(zhì)激素(GC)刺激有關(guān)， DP胸腺細(xì)胞線粒體功能作用減弱，胸腺細(xì)胞中Bcl-2顯著減少等DP胸腺細(xì)胞的凋亡有關(guān)[30]。Xie等對(duì)(60)Coγ射線誘導(dǎo)細(xì)胞凋亡的機(jī)制進(jìn)行了研究，發(fā)現(xiàn)紫薯素能顯著抑制線粒體介導(dǎo)的細(xì)胞凋亡[31]。Han等也發(fā)現(xiàn)紫薯素能清除ROS，在非caspase依賴的線粒體途徑中對(duì)細(xì)胞凋亡起著調(diào)節(jié)作用[32]。Yan等發(fā)現(xiàn)櫛孔扇貝(PCF)能降低紫外線照射條件下的胸腺細(xì)胞凋亡，這個(gè)過(guò)程也檢測(cè)到了線粒體凋亡途徑上因子變化，說(shuō)明線粒體凋亡途徑參與了紫外線照射導(dǎo)致的胸腺細(xì)胞凋亡過(guò)程[33]。在胸腺細(xì)胞的發(fā)育選擇過(guò)程中線粒體凋亡途徑起著重要作用，調(diào)控胸腺DP細(xì)胞的分化方向與把握線粒體凋亡途徑關(guān)系密切。

3　內(nèi)質(zhì)網(wǎng)凋亡途徑與胸腺細(xì)胞凋亡的相關(guān)研究

運(yùn)動(dòng)等作為一種刺激，會(huì)導(dǎo)致機(jī)體缺血、缺氧和乳酸堆積等，而乳酸堆積等會(huì)導(dǎo)致機(jī)體內(nèi)環(huán)境的改變，在內(nèi)環(huán)境變化的基礎(chǔ)上，內(nèi)質(zhì)網(wǎng)也會(huì)發(fā)生改變，內(nèi)質(zhì)網(wǎng)改變或功能失調(diào)的一個(gè)中重要狀態(tài)我們稱之為內(nèi)質(zhì)網(wǎng)應(yīng)激[34]。當(dāng)運(yùn)動(dòng)等刺激持續(xù)的時(shí)間夠長(zhǎng)或強(qiáng)度夠大時(shí)，內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)越大，會(huì)導(dǎo)致細(xì)胞發(fā)生凋亡。內(nèi)質(zhì)網(wǎng)應(yīng)激與凋亡關(guān)系途徑包括(1)Caspase-12激活，這是內(nèi)質(zhì)網(wǎng)依賴性的細(xì)胞凋亡信號(hào)轉(zhuǎn)導(dǎo)通路[35]。另有研究也發(fā)現(xiàn)核酶抑制Caspase-12后, 可有效減少內(nèi)質(zhì)網(wǎng)應(yīng)激引起的細(xì)胞凋亡[36]。(2)CHOP/GADD153表達(dá)上調(diào)；內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)引起的細(xì)胞凋亡中，CHOP是最具代表性的分子。內(nèi)質(zhì)網(wǎng)應(yīng)激后，ATF6、PERK/elF-2α和IRE1/XBP-1幾條信號(hào)途徑均被激活，激活后會(huì)導(dǎo)致細(xì)胞凋亡[37][38]。(3)c-jun氨基末端激酶激活(JNK)等[39]。JNK的激活與Ⅰ型雌激素受體跨膜蛋白激酶(IRE1)激活有關(guān)[37]。

當(dāng)機(jī)體受到刺激而導(dǎo)致內(nèi)質(zhì)網(wǎng)應(yīng)激時(shí)，與刺激的強(qiáng)度關(guān)系密切，內(nèi)質(zhì)網(wǎng)應(yīng)激主要包括適度的應(yīng)激和過(guò)度應(yīng)激兩種。當(dāng)內(nèi)質(zhì)網(wǎng)應(yīng)激適度時(shí)對(duì)機(jī)體的生理機(jī)能影響是正向的，有利于提高機(jī)體細(xì)胞的生理狀態(tài)，但是內(nèi)質(zhì)網(wǎng)應(yīng)激過(guò)度時(shí)對(duì)機(jī)體生理機(jī)能的影響是負(fù)向的，會(huì)導(dǎo)致機(jī)體細(xì)胞發(fā)生損傷，甚至出現(xiàn)凋亡[40]。如大強(qiáng)度運(yùn)動(dòng)是誘導(dǎo)內(nèi)質(zhì)網(wǎng)發(fā)生應(yīng)激的刺激形式之一。研究發(fā)現(xiàn)給新生小鼠腹膜內(nèi)注射MCF13MLV，MCF13MLV可使小鼠胸腺細(xì)胞中內(nèi)質(zhì)網(wǎng)伴侶分子GRP78和GRP58表達(dá)的升高，即逆轉(zhuǎn)錄病毒感染可誘導(dǎo)小鼠胸腺細(xì)胞內(nèi)質(zhì)網(wǎng)應(yīng)激(ERS)的發(fā)生[41]。另有研究顯示，小鼠的肌肉、肝臟、腎臟、脾臟和肺中堅(jiān)持到了內(nèi)質(zhì)網(wǎng)應(yīng)激介導(dǎo)細(xì)胞凋亡的一些主要因子[35][42]。但有關(guān)內(nèi)質(zhì)網(wǎng)應(yīng)激凋亡途徑介導(dǎo)胸腺細(xì)胞凋亡的研究非常少，需加強(qiáng)這方面的研究。

4　運(yùn)動(dòng)與胸腺細(xì)胞凋亡的相關(guān)研究

大量實(shí)驗(yàn)結(jié)果證實(shí)大強(qiáng)度運(yùn)動(dòng)對(duì)免疫機(jī)能有強(qiáng)烈的負(fù)性影響，其中會(huì)出現(xiàn)免疫細(xì)胞凋亡增加、免疫器官萎縮和免疫功能下降等[4]。有研究發(fā)現(xiàn)，大鼠力竭游泳后胸腺、脾和外周血淋巴細(xì)胞凋亡率都明顯高于對(duì)照組[43]。Concordet J-P等發(fā)現(xiàn)胸腺細(xì)胞凋亡受糖皮質(zhì)激素受體的介導(dǎo)，讓W(xué)istar大鼠進(jìn)行力竭訓(xùn)練，發(fā)現(xiàn)胸腺細(xì)胞DNA都表現(xiàn)出凋亡特征[44]。另一研究發(fā)現(xiàn)小鼠在6%坡度跑臺(tái)上以35m/min跑90min后能觀察到小鼠胸腺細(xì)胞凋亡的早期信號(hào)[45]。Lin等以13.8m/min×60-90 min/d的運(yùn)動(dòng)強(qiáng)度，讓大鼠連續(xù)運(yùn)動(dòng)兩天，發(fā)現(xiàn)大鼠胸腺細(xì)胞出現(xiàn)凋亡特征，但是服用抗氧化劑后能改善細(xì)胞的凋亡特征，說(shuō)明運(yùn)動(dòng)誘發(fā)的胸腺細(xì)胞凋亡的因素之一活性氧[46]。另有研究發(fā)現(xiàn)，在運(yùn)動(dòng)前30min給小鼠服用抗氧化劑N-乙酰-L-半胱氨酸(NAC)或生理鹽水(SAL)，跑臺(tái)運(yùn)動(dòng)90min，2°斜坡(EX,22m/min,25m/min,28m/min各30min)，分別于運(yùn)動(dòng)后立即處死(IMM)和運(yùn)動(dòng)后24h處死。發(fā)現(xiàn)EX + SAL +1MM組小鼠分離的胸腺細(xì)胞顯示一個(gè)早期凋亡跡象[47][48]。以上研究顯示，運(yùn)動(dòng)對(duì)胸腺細(xì)胞凋亡影響的機(jī)制研究甚少。

5　結(jié)論

5.1死亡信號(hào)通路參與了大鼠胸腺細(xì)胞的分化、發(fā)育和成熟過(guò)程。大鼠胸腺細(xì)胞內(nèi)檢測(cè)到了死亡信號(hào)通路的各種成分。力竭運(yùn)動(dòng)會(huì)導(dǎo)致胸腺細(xì)胞凋亡增加，但是否由Fas/FasL信號(hào)途徑介導(dǎo)還需新的實(shí)驗(yàn)證實(shí)。

5.2線粒體信號(hào)通路與胸腺細(xì)胞凋亡有關(guān)已有研究證實(shí)，且抗氧化劑的服用能減緩胸腺細(xì)胞凋亡的發(fā)生。但運(yùn)動(dòng)狀態(tài)下胸腺細(xì)胞凋亡的線粒體機(jī)制還有待于進(jìn)一步證實(shí)。

5.3內(nèi)質(zhì)網(wǎng)凋亡信號(hào)途徑與胸腺細(xì)胞凋亡的研究，內(nèi)質(zhì)網(wǎng)凋亡信號(hào)途徑與運(yùn)動(dòng)狀態(tài)下胸腺細(xì)胞凋亡的研究等都非常少，這將是今后胸腺細(xì)胞凋亡機(jī)制研究中重點(diǎn)關(guān)注的問(wèn)題。

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Mechanisms of the thymocyte apoptosis induced by exercise

(1.Nanfang College of Sun Yai-sen University,Guangzhou 510000,China；2.Linyi University,Linyi 276005,China)

YANG Gui-ming2,WANG Xue-qin2

Intense exercise leads to post-exercise lymphocytopenia and immunosuppression, possibly by triggering thymocyte apoptosis. This article reviews the death receptor, mitochondria and endoplasmic reticulum apoptosis mechanism, and tries to find the main mechanism of thymocyte apoptosis. Results: 1) The thymocyte apoptosis are mediated by death receptor and mitochondrial mechanisms; 2) The endoplasmic reticulum adjustment mechanism study is very little in thymus. These results suggest that exercise-induced thymocyte apoptosis relates to mitochondrial apoptotic mechanisms closely, and the other need to be confirmed by further studies.

exercise; thymus; apoptosis; death receptor; mitochondria; endoplasmic reticulum

2016-06-18

楊貴明(1984-)，男，茂名市人，碩士，講師

研究方向：體育教學(xué)與訓(xùn)練

G804.2

A

1007-323X(2016)04-0097-04