郭 倩，陳緒勇，蘇 茵△

(1. 北京大學(xué)人民醫(yī)院風(fēng)濕免疫科， 北京 100044； 2. 北京大學(xué)國(guó)際醫(yī)院風(fēng)濕免疫科， 北京 102206)

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·綜述·

白細(xì)胞介素2信號(hào)通路相關(guān)分子與系統(tǒng)性紅斑狼瘡

郭 倩1,2，陳緒勇1，蘇 茵1△

(1. 北京大學(xué)人民醫(yī)院風(fēng)濕免疫科， 北京 100044； 2. 北京大學(xué)國(guó)際醫(yī)院風(fēng)濕免疫科， 北京 102206)

白細(xì)胞介素2；紅斑狼瘡，系統(tǒng)性；基因表達(dá)調(diào)控；信號(hào)傳導(dǎo)

系統(tǒng)性紅斑狼瘡(systemic lupus erythematosus，SLE)是一種多因素參與的自身免疫性疾病。研究證實(shí)，B淋巴細(xì)胞、T淋巴細(xì)胞、轉(zhuǎn)錄因子與細(xì)胞因子表達(dá)以及抗原呈遞等異常或缺陷在SLE的發(fā)病中有重要作用，導(dǎo)致包括皮膚、腎、肺、中樞神經(jīng)系統(tǒng)、消化系統(tǒng)及關(guān)節(jié)肌肉等多系統(tǒng)、多器官的損傷[1]。SLE患病率約70/10萬(wàn)，目前我國(guó)至少有100萬(wàn)以上的患者，尤以育齡期女性多見(jiàn)，其病因及發(fā)病機(jī)制尚不完全清楚，遺傳、環(huán)境和病毒感染等因素與其發(fā)病關(guān)系密切[2]。

白細(xì)胞介素2(interleukin-2, IL-2)是一種具有多種生物活性的細(xì)胞因子，由Th1細(xì)胞合成分泌，不僅可以促進(jìn)CD4+及CD8+T細(xì)胞的活化和增殖，還可誘導(dǎo)免疫記憶，對(duì)免疫系統(tǒng)抵抗病原微生物具有重要意義[3-4]。研究證明，SLE患者血清中IL-2水平較正常人明顯減低，并伴隨調(diào)節(jié)性T細(xì)胞(regulatory T cell，Treg)數(shù)目減少、細(xì)胞毒作用減弱等多種免疫功能紊亂[5-6]。

研究提示，SLE患者外周血IL-2的表達(dá)缺陷可能與調(diào)節(jié)IL-2生成的多個(gè)調(diào)控分子的異常有關(guān)，這些分子包括環(huán)磷酸腺苷(cyclic adenosine monophosphate，cAMP)反應(yīng)元件調(diào)節(jié)物(cAMP-responsive element modulator，CREM)、蛋白磷酸酶2A(protein phosphatase 2A，PP2A)、E-74樣因子1(E-74 like factor-1，Elf-1)、B淋巴細(xì)胞誘導(dǎo)成熟蛋白1(B lymphocyte induced maturation protein-1，Blimp-1)及干擾素調(diào)節(jié)因子5(interferon regulator factor 5，IRF-5)等(圖1)，這些分子通過(guò)不同的作用途徑參與IL-2信號(hào)通路的調(diào)節(jié)[7-10]。PP2A一方面通過(guò)激活I(lǐng)L-2轉(zhuǎn)錄抑制因子CREMα來(lái)抑制IL-2的合成；另一方面通過(guò)抑制IL-2的刺激性轉(zhuǎn)錄因子Elf-1來(lái)抑制IL-2的表達(dá)。IRF-5通過(guò)激活I(lǐng)L-2轉(zhuǎn)錄的負(fù)向調(diào)控因子Blimp-1來(lái)抑制IL-2的表達(dá)。

PP2A, protein phosphatase 2A; CREM, cyclic adenosine monophosphate-responsive element modulator; Elf-1, E-74 like factor-1; IRF-5, interferon regulator factor-5; Blimp-1, B lymphocyte induced maturation protein-1; SLE, systemic lupus erythematosus; IL-2, interleukin-2. (+), promote; (-), inhibit.

圖1 系統(tǒng)性紅斑狼瘡中IL-2缺陷相關(guān)通路示意圖

Figure1 IL-2 defects signaling pathway in SLE

1 cAMP反應(yīng)元件調(diào)節(jié)物抑制IL-2的合成

IL-2的合成調(diào)控主要是由IL-2基因的轉(zhuǎn)錄完成的[11]，研究提示，CREM與SLE的發(fā)病密切相關(guān)。CREM是一種轉(zhuǎn)錄抑制因子，可通過(guò)與IL-2基因的啟動(dòng)子結(jié)合限制IL-2基因的轉(zhuǎn)錄，SLE患者T細(xì)胞可表達(dá)高水平的CREM[12]，此外，CREM不僅能與活化T細(xì)胞的TCRζ/SYK啟動(dòng)子及原癌基因c-fos近端的啟動(dòng)子結(jié)合[13-14]，還可作用于CREM基因的啟動(dòng)子[15]，其中，CREM與c-fos基因啟動(dòng)子的結(jié)合可導(dǎo)致c-fos的轉(zhuǎn)錄減少，降低Fos蛋白的生成，而Fos蛋白又是IL-2基因轉(zhuǎn)錄激活因子激活蛋白1(activator protein-1，AP-1)的組成成分之一，故CREM還可通過(guò)抑制c-fos基因的轉(zhuǎn)錄間接影響IL-2的生成[14]。

CREM是堿性亮氨酸拉鏈(basic leucine zipper，bZIP)類(lèi)轉(zhuǎn)錄因子，有多種不同啟動(dòng)子和可變剪接調(diào)節(jié)的亞型，其中包括CREMα、CREMβ[16]。Kyttaris等[17]的研究表明，在SLE患者的T細(xì)胞中，CREMα的信使核糖核酸(messenger ribonucleic acid，mRNA)表達(dá)水平明顯升高，雖然這種表達(dá)水平與SLE患者的臨床特征、疾病活動(dòng)度及治療效果之間無(wú)明顯相關(guān)性，但在使用大劑量糖皮質(zhì)激素治療后，CREMα的mRNA表達(dá)可呈下降趨勢(shì)，由此推斷，若能阻斷CREMα的mRNA表達(dá)可能會(huì)使SLE異常的T細(xì)胞功能得到控制。針對(duì)狼瘡小鼠模型的研究證實(shí)，補(bǔ)充IL-2能夠逆轉(zhuǎn)狼瘡小鼠T細(xì)胞中CREMα的過(guò)度表達(dá)[18]。當(dāng)利用17-β雌二醇刺激T細(xì)胞時(shí)，T細(xì)胞的CREMα的mRNA表達(dá)呈劑量依賴(lài)性增加，而抑制雌激素可使IL-2的mRNA表達(dá)及IL-2呈劑量依賴(lài)性減少。由此可見(jiàn)，雌激素可上調(diào)CREMα的mRNA表達(dá)，促使T淋巴細(xì)胞合成和分泌IL-2缺陷[19]。SLE患者T細(xì)胞分泌的細(xì)胞因子呈現(xiàn)明顯的不平衡狀態(tài)，其中CREM不僅可作為轉(zhuǎn)錄抑制因子，還可通過(guò)募集DNA甲基化轉(zhuǎn)移酶3A(DNMT3A)和組蛋白去乙?；?(HDAC1)而介導(dǎo)IL-2的表觀遺傳修飾，使IL-2基因沉默，抑制IL-2的產(chǎn)生[20]。研究顯示，CREM基因本身的轉(zhuǎn)錄調(diào)節(jié)是通過(guò)啟動(dòng)子P1和P2實(shí)現(xiàn)的，并且P1啟動(dòng)子的活性與SLE患者的疾病活動(dòng)度密切相關(guān)[15,21]。

2 PP2A可抑制IL-2的合成

PP2A是一種絲氨酸/蘇氨酸磷酸酶，它廣泛表達(dá)于真核細(xì)胞中，由異源三聚體組成，包括一個(gè)支架型結(jié)構(gòu)亞基A、一個(gè)催化亞基C以及一個(gè)調(diào)節(jié)亞基B。PP2A的催化亞基C(包括α與β兩種亞型)和結(jié)構(gòu)亞基A(包括α與β兩種亞型)分別由兩個(gè)高度同源的基因編碼：PP2ACα由PPP2CA基因編碼，PP2ACβ由PPP2CB基因編碼；PP2AAα由PPP2R1A基因編碼，PP2AAβ由PPP2R1B基因編碼。由于PP2A含有數(shù)個(gè)不同的調(diào)節(jié)亞基，使得其可以作用于多種底物，并能夠監(jiān)控多個(gè)細(xì)胞的生理過(guò)程，如細(xì)胞周期活動(dòng)、基因轉(zhuǎn)錄和翻譯以及細(xì)胞凋亡等過(guò)程[22]。

研究顯示，SLE患者T細(xì)胞表達(dá)PP2AC的水平可異常升高，異常升高的PP2AC能夠促進(jìn)轉(zhuǎn)錄因子和細(xì)胞因子間的差異表達(dá)，高疾病活動(dòng)度的SLE患者能夠表達(dá)更高水平的PP2AC[7]，而PP2AC的作用底物p-CREB是IL-2生成過(guò)程中一個(gè)非常重要的轉(zhuǎn)錄因子[23]，PP2AC可促進(jìn)p-CREB的脫磷酸[24]，進(jìn)而抑制p-CREB與IL-2基因啟動(dòng)子相結(jié)合，使IL-2分泌減少[7]。此外，SLE患者T細(xì)胞中DNA甲基化轉(zhuǎn)移酶1(DNMT1)表達(dá)減少，使得PPP2CA基因啟動(dòng)子區(qū)域DNA的低甲基化，導(dǎo)致PP2ACα過(guò)度表達(dá)，促進(jìn)SLE發(fā)病[25]。Tan等[26]的研究證實(shí)，在PPP2CA基因內(nèi)含子的單核苷酸多態(tài)性(single nucleotide polymorphism，SNP)位點(diǎn)rs7704116上，攜帶A等位基因的SLE患者能夠誘導(dǎo)PP2AC的mRNA過(guò)高表達(dá)，進(jìn)而通過(guò)p-CREB去磷酸化過(guò)程抑制IL-2產(chǎn)生，該項(xiàng)研究的數(shù)據(jù)還顯示，PPP2CA基因的多態(tài)性與歐裔美國(guó)人、西班牙裔美國(guó)人及亞洲人群中的SLE易感性密切相關(guān)。

CREM基因啟動(dòng)子活性與SLE患者的疾病活動(dòng)度密切相關(guān)[21]，轉(zhuǎn)錄因子特異性蛋白-1(specificity protein-1，SP-1)可與CREM基因啟動(dòng)子結(jié)合，促使后者轉(zhuǎn)錄活性增強(qiáng)。在SLE患者T細(xì)胞中，PP2A可通過(guò)SP-1絲氨酸殘基59(Ser59)的去磷酸化使SP-1激活，進(jìn)而使SP-1能更好地與CREM基因啟動(dòng)子結(jié)合，抑制IL-2的合成[21]。T細(xì)胞功能失調(diào)是SLE患者免疫系統(tǒng)紊亂的核心機(jī)制，PP2A→SP-1→CREM的信號(hào)通路揭示了SLE患者發(fā)生T細(xì)胞異常的另一個(gè)關(guān)鍵步驟，為我們更好地理解SLE的發(fā)病機(jī)制打下了理論基礎(chǔ)。此外，PP2A還可以通過(guò)Elf-1的去磷酸化，促進(jìn)與非DNA區(qū)域結(jié)合的相對(duì)分子質(zhì)量為80×103的Elf-1的表達(dá)，進(jìn)而抑制IL-2的生成[10]。

Katsiari等[7]的研究表明，使用適量的PP2AC的小干擾RNA(small interfering RNA，siRNA)能夠有效地降低PP2A水平并糾正SLE患者T細(xì)胞中IL-2的生成缺陷；此外，在幼年SLE患者中，矯正miRNA-155的表達(dá)能夠抑制PP2AC的表達(dá)水平并增強(qiáng)外周血單個(gè)核細(xì)胞中IL-2的釋放[27]，這些研究均為未來(lái)SLE的治療方案提供了新的治療靶點(diǎn)。

3 Elf-1促進(jìn)IL-2的合成

PP2A可通過(guò)Elf-1的去磷酸化促進(jìn)不能與DNA結(jié)合的相對(duì)分子質(zhì)量為80×103的Elf-1的表達(dá)，從而抑制IL-2的生成[10]，那么Elf-1具體為何物呢？Leiden[28]發(fā)現(xiàn)，Elf-1是由619個(gè)氨基酸序列組成的、屬于Ets(E-twenty six)家族的轉(zhuǎn)錄因子。Elf-1是人類(lèi)IL-2受體α鏈啟動(dòng)子應(yīng)答元件的組成部分之一[29]，其表達(dá)異?？芍苯佑绊慡LE患者中IL-2的作用通路。

Elf-1以相對(duì)分子質(zhì)量為80×103的蛋白質(zhì)形式分布于細(xì)胞質(zhì)中，而在細(xì)胞核中則以相對(duì)分子質(zhì)量為98×103的蛋白質(zhì)形式與DNA結(jié)合。Elf-1基因的翻譯后修飾(如PP2A的磷酸化作用及O-連接的糖基化作用等)可使Elf-1在相對(duì)分子質(zhì)量為80×103和相對(duì)分子質(zhì)量為98×103的形式間相互轉(zhuǎn)換[30]。在SLE患者的T細(xì)胞中，由于磷酸化不足或去磷酸化過(guò)度等原因，導(dǎo)致相對(duì)分子質(zhì)量為98×103形式的Elf-1生成缺陷，進(jìn)而導(dǎo)致TCRζ鏈啟動(dòng)子出現(xiàn)轉(zhuǎn)錄障礙[31]，而正是TCRζ鏈的缺陷以及IL-2轉(zhuǎn)錄調(diào)控中多種異常，在SLE的發(fā)病中起著關(guān)鍵作用[32]。雖然我們了解了Elf-1的成分與結(jié)構(gòu)，并且知道其相對(duì)分子質(zhì)量為80×103的形式能夠抑制IL-2的生成，但目前對(duì)于Elf-1具體通過(guò)何種分子機(jī)制或信號(hào)通路而影響IL-2合成還知之甚少。

4 Blimp-1抑制IL-2的合成

Blimp-1是由PRDM-1基因編碼的，具有SET[Su(var), enhancer of zeste, and trithorax]結(jié)構(gòu)域和鋅指結(jié)構(gòu)的轉(zhuǎn)錄抑制因子，是參與調(diào)控B淋巴細(xì)胞終末分化環(huán)節(jié)的關(guān)鍵轉(zhuǎn)錄因子之一[33]。

近10年來(lái)，多項(xiàng)研究已經(jīng)證實(shí)了Blimp-1在T細(xì)胞分化中有重要作用[34-35]，Martins等[34]的研究數(shù)據(jù)顯示，Blimp-1缺陷的CD4+T細(xì)胞受體經(jīng)體外刺激后，可表現(xiàn)出較強(qiáng)的高增殖反應(yīng)，并伴有IL-2的合成量明顯增加，因此認(rèn)為Blimp-1可負(fù)性調(diào)節(jié)IL-2的產(chǎn)生。隨后，Gong等[36]的研究發(fā)現(xiàn)，增強(qiáng)Blimp-1表達(dá)可抑制由TCR刺激所誘導(dǎo)的IL-2產(chǎn)生，這一結(jié)果與Martins等[34]的研究相互映照。有研究證實(shí)，狼瘡小鼠的外周血單個(gè)核細(xì)胞(peripheral blood mononuclear cell, PMBC)表達(dá)的Blimp-1水平明顯上調(diào)[37]，而B(niǎo)limp-1的siRNA能夠抑制狼瘡小鼠的B淋巴細(xì)胞分化并阻止狼瘡病情的進(jìn)展[38]，這些研究進(jìn)一步證實(shí)了Blimp-1與狼瘡小鼠的發(fā)病相關(guān)。

Blimp-1在T細(xì)胞中的主要作用之一是通過(guò)直接抑制IL-2及c-fos基因的轉(zhuǎn)錄而實(shí)現(xiàn)的[8]。Fos是AP-1的主要成分之一，而AP-1是IL-2的轉(zhuǎn)錄激活因子，故抑制Fos蛋白的生成亦會(huì)影響IL-2的合成[14]。IL-2可通過(guò)誘導(dǎo)PRDM-1基因表達(dá)生成Blimp-1，并通過(guò)Blimp-1抑制IL-2自身的表達(dá)，控制免疫應(yīng)答在適當(dāng)狀態(tài)，Blimp-1的這一功能，對(duì)由細(xì)胞因子缺乏誘導(dǎo)的T細(xì)胞凋亡及減弱T細(xì)胞抗原特異性的增殖反應(yīng)非常重要[8]。

IL-2是T細(xì)胞中Blimp-1表達(dá)的強(qiáng)效誘導(dǎo)劑[36]，Blimp-1對(duì)IL-2基因轉(zhuǎn)錄的抑制作用主要包括以下幾點(diǎn)：(1)表達(dá)Blimp-1的細(xì)胞不分泌或少分泌IL-2；(2)Blimp-1的mRNA表達(dá)水平與IL-2的mRNA表達(dá)呈負(fù)相關(guān)；(3)在Blimp-1缺乏的CD4+T細(xì)胞中，IL-2的水平及IL-2的mRNA表達(dá)可持續(xù)增高；(4)在活化的CD4+T細(xì)胞中，內(nèi)源性Blimp-1可通過(guò)特異性結(jié)合IL-2基因調(diào)節(jié)區(qū)域發(fā)揮作用[8]。因此認(rèn)為，IL-2可誘導(dǎo)Blimp-1生成，而B(niǎo)limp-1可抑制IL-2的合成與分泌，兩者形成了一個(gè)調(diào)節(jié)IL-2水平的負(fù)反饋調(diào)節(jié)環(huán)路。

5 IRF-5抑制IL-2的合成

干擾素調(diào)節(jié)因子(interferon regulatory factor，IRF)是Ⅰ型干擾素最具特征性的轉(zhuǎn)錄調(diào)節(jié)因子，在調(diào)節(jié)固有免疫和適應(yīng)免疫反應(yīng)等諸多方面起關(guān)鍵作用[39]。IRF-5是屬于IRFs家族成員之一，近年來(lái)的多項(xiàng)研究顯示，由IRF-5缺乏所導(dǎo)致的自身抗體和炎性細(xì)胞因子的生成與SLE發(fā)病密切相關(guān)，功能實(shí)驗(yàn)也驗(yàn)證了IRF-5與SLE在遺傳學(xué)上的關(guān)聯(lián)。

SLE患者血清IRF-5的水平明顯增高[40]，活化的IRF-5可誘導(dǎo)Ⅰ型干擾素基因和PRDM-1基因的轉(zhuǎn)錄[41-42]。PRDM-1基因編碼的Blimp-1蛋白是IL-2生成過(guò)程中的負(fù)性調(diào)節(jié)因子[34]，故IRF-5可通過(guò)促進(jìn)Blimp-1的表達(dá)間接抑制IL-2的產(chǎn)生。有關(guān)狼瘡小鼠的研究表明，雌性小鼠表達(dá)的IRF-5的mRNA水平較雄性小鼠更高，同時(shí)該研究結(jié)果還顯示，雌激素可上調(diào)小鼠IRF-5基因的表達(dá)[43]。

IL-2是維持免疫系統(tǒng)各項(xiàng)功能正常運(yùn)行所必需的細(xì)胞因子，在SLE患者及狼瘡小鼠模型中，IL-2的合成及功能障礙已被廣泛證實(shí)。近年來(lái)的多項(xiàng)研究逐一揭示了影響IL-2生成的多個(gè)環(huán)節(jié)及多種因素，這些影響因素或通過(guò)改變基因所在染色質(zhì)，或通過(guò)直接影響IL-2基因的轉(zhuǎn)錄，或通過(guò)基因轉(zhuǎn)錄后的蛋白修飾而達(dá)到調(diào)控IL-2的目的。如本文所闡述的SLE中IL-2缺陷相關(guān)通路的分子中，PP2A一方面通過(guò)激活I(lǐng)L-2轉(zhuǎn)錄抑制因子CREMα來(lái)抑制IL-2的合成，另一方面通過(guò)抑制IL-2的刺激性轉(zhuǎn)錄因子Elf-1來(lái)抑制IL-2的表達(dá)，而IRF-5則通過(guò)激活I(lǐng)L-2轉(zhuǎn)錄的負(fù)向調(diào)控因子Blimp-1來(lái)抑制IL-2的表達(dá)。

深刻認(rèn)識(shí)各種因素的生理角色及其在疾病狀態(tài)下的作用，了解IL-2生成過(guò)程中的調(diào)控機(jī)制，將使我們能更好地理解SLE這一系統(tǒng)性疾病的病理生理過(guò)程，為今后制定新的治療策略、開(kāi)發(fā)新的治療靶點(diǎn)提供理論依據(jù)。

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(2016-07-28收稿)

(本文編輯：任英慧)

SUMMARY Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease, which characterized by complex immunological abnormalities and multiple tissue and organ damages. The etiology and pathogenesis of SLE have not been entirely recognized. Genetic, environmental and viral infections and other factors might be related to the pathogenetic mechanisms of SLE. Interleukin-2 (IL-2) is a critical cytokine produced by T cells upon activation and is important for the generation of T regulatory cells and activation-induced cell death. In SLE patients, T cells display decreased capacity to produce IL-2. Impaired IL-2 expression resulted in decreased generation of regulatory T lymphocytes, and defect of activation-induced cell death. Former researches indicated that IL-2 deficiency in SLE is important for the pathogenesis and treatment of SLE. Several regulating molecules can affect the transcription of IL-2 gene and had an important role in the pathogenesis of SLE. These molecules include cyclic AMP-responsive element modulator (CREM), protein phosphatase 2A (PP2A), E-74 like factor 1 (Elf-1), B lymphocyte induced maturation protein-1 (Blimp-1) and interferon regulator factor 5 (IRF-5). CREM is a transcriptional inhibitor that can repress the transcription of the IL-2 gene by binding to the promoter of the IL-2 gene. PP2A is a Ser/Thr phosphatase that expressed in eukaryotic cells ubiquitously, it represents a negative regulator of the IL-2 gene promoter activity. Elf-1 belongs to the Ets family of transcription factors and can promote the expression of IL-2. Blimp-1 is a crucial transcription factors for regulating B lymphocyte terminal differentiation, an important function of Blimp-1 in T cells is to repress IL-2 gene transcription directly. Interferon regulatory factors (IRFs) are distinctive transcriptional regulators of type Ⅰ interferons (IFNs) and IFN inducible genes, IRF-5 is a member of the IRFs family. IRF-5 is found to be increased in SLE and can regulate the production of IL-2 negatively. PP2A can inhibit the synthesis of IL-2 in two ways: on the one hand, activating the IL-2 transcription inhibitory factor CREMα, on the other hand, inhibiting IL-2 stimulating transcription factor Elf-1. While IRF-5 can activate the IL-2 transcription negative regulator Blimp-1 as to inhibit IL-2 expression. These molecules participate in the regulation of IL-2 through different pathways. This paper reviews the current knowledge of IL-2 signaling pathway regulating molecules in SLE.

Interleukin-2 signaling pathway regulating molecules in systemic lupus erythematosusGUO Qian1,2, CHEN Xu-yong1, SU Yin1△

(1. Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing 100044, China; 2. Department of Rheumatology and Immunology, Peking University International Hospital, Beijing 102206, China)

Interleukin-2; Lupus erythematosus, systemic; Gene expression regulation; Signal transduction

國(guó)家自然科學(xué)基金(81471600，81172844)資助 Supported by the National Natural Science Foundation of China (81471600, 81172844)

R593.24

A

1671-167X(2016)06-1100-05

10.3969/j.issn.1671-167X.2016.06.032

時(shí)間：2016-10-31 16：33：02

http://www.cnki.net/kcms/detail/11.4691.R.20161031.1633.032.html

△ Corresponding author’s e-mail, suyin0921@163.com