劉善輝，張世超，吉尚戎

(蘭州大學(xué) 生命科學(xué)學(xué)院, 蘭州 730000)

IL-33活性調(diào)節(jié)及在疾病中的調(diào)控作用

劉善輝，張世超，吉尚戎

(蘭州大學(xué) 生命科學(xué)學(xué)院, 蘭州 730000)

IL-33是近期發(fā)現(xiàn)的IL-1家族新成員，與傳統(tǒng)的細(xì)胞因子有所不同，其N端結(jié)構(gòu)域具有核定位信號(hào)，具有轉(zhuǎn)錄調(diào)節(jié)活性。IL-33可通過(guò)IL-33/ST2L信號(hào)途徑促進(jìn)2型免疫反應(yīng)參與心血管疾病、阿爾茨海默癥、癌癥、肥胖等多種重大疾病的調(diào)節(jié)。綜述近年IL-33研究進(jìn)展，闡釋不同剪切形式和二硫鍵分子“開(kāi)關(guān)”對(duì)IL-33活性的影響，介紹IL-33/ST2L在一些重大疾病中的調(diào)控作用，為后續(xù)IL-33在疾病診斷治療中的應(yīng)用提供參考。

IL-1家族；IL-33/ST2L信號(hào)；2型免疫反應(yīng)；二硫鍵

白細(xì)胞介素是一類介導(dǎo)白細(xì)胞同其他細(xì)胞間相互作用的細(xì)胞因子[1]，具有活化機(jī)體免疫細(xì)胞而促進(jìn)機(jī)體抵抗外界病原菌入侵、消除自身免疫抗原等作用。IL-33是2005年發(fā)現(xiàn)的IL-1家族最新成員(IL-1F11)，在內(nèi)皮細(xì)胞中高表達(dá)[2-3]。通常IL-33表達(dá)并儲(chǔ)存于細(xì)胞核內(nèi)，當(dāng)細(xì)胞受到損傷或壞死時(shí)，可作為預(yù)警素被大量釋放至胞外。釋放到胞外后IL-33的活性受到多種因素的調(diào)節(jié)，如IL-33可以被Caspase-3/7、cathepsin G、elastase等酶剪切[4-8]，不同的剪切形式可以導(dǎo)致IL-33活性喪失或增強(qiáng)；近期發(fā)現(xiàn)IL-33分子內(nèi)的二硫鍵也可作為“分子開(kāi)關(guān)”調(diào)節(jié)其活性[9]。IL-33可通過(guò)IL-33/ST2信號(hào)途徑誘導(dǎo)Th2細(xì)胞分化[3, 10]，還可通過(guò)活化調(diào)節(jié)性T細(xì)胞、巨噬細(xì)胞、固有淋巴樣型細(xì)胞(ILC2s)[11]等免疫細(xì)胞發(fā)揮調(diào)節(jié)作用，促進(jìn)2型細(xì)胞因子產(chǎn)生。IL-33通過(guò)活化免疫細(xì)胞產(chǎn)生2型免疫應(yīng)答對(duì)多種疾病有重要的調(diào)節(jié)作用，主要可以分為3類：自身免疫疾病、過(guò)敏性反應(yīng)疾病和心血管疾病。近期發(fā)現(xiàn)IL-33可緩解阿爾茨海默病(Alzheimer’s disease，AD)。本文將重點(diǎn)介紹IL-33的結(jié)構(gòu)特點(diǎn)和作用機(jī)理，為后續(xù)IL-33在疾病的診斷治療中的開(kāi)發(fā)應(yīng)用提供參考。

1 IL-33結(jié)構(gòu)

IL-33是IL-1家族第11號(hào)新成員(IL-1F11)。人源IL-33定位于9號(hào)染色體(9p24.1)，包含的7個(gè)外顯子編碼270個(gè)氨基酸多肽，1～3號(hào)外顯子編碼N端核定位結(jié)構(gòu)域，4～7號(hào)外顯子編碼C端細(xì)胞因子結(jié)構(gòu)域。C端細(xì)胞因子結(jié)構(gòu)域折疊成由12個(gè)β鏈組成IL-1家族蛋白典型的β-三葉草結(jié)構(gòu)[12-13]。IL-33 C端具有典型的細(xì)胞因子活性(細(xì)胞因子結(jié)構(gòu)域)，即IL-33的C端結(jié)構(gòu)域能與IL-33受體ST2結(jié)合。通過(guò)對(duì)IL-33 N端截短突變體研究，發(fā)現(xiàn)N端40～58位氨基酸為染色質(zhì)結(jié)合基序(chromatin-binding motif，CBM)(圖1),其中的M45、L47、R48、 S49、 G50和I53是結(jié)合的重要位點(diǎn)。對(duì)比人、小鼠、狗的IL-33序列發(fā)現(xiàn)，M45、L47、R48、S49、G50高度保守[14]。CBM可通過(guò)識(shí)別H2A-H2B酸性口袋從而結(jié)合染色質(zhì)并調(diào)節(jié)染色質(zhì)固縮[10]。IL-33的CBM是否能同IL-1家族其他成員一樣，結(jié)合到某些靶基因上[15]，調(diào)節(jié)靶基因轉(zhuǎn)錄，尚未見(jiàn)報(bào)道。

2 IL-33活性影響因素

2.1 酶切對(duì)IL-33活性的影響

當(dāng)細(xì)胞受損或壞死時(shí)，IL-33可以作為預(yù)警素被大量釋放。通常認(rèn)為IL-33同IL-1家族成員IL-1β、IL-18類似，需要caspase-1的剪切加工成熟[8]。點(diǎn)突變(D178A)IL-33發(fā)現(xiàn)，caspase-1剪切IL-33的位點(diǎn)位于IL-1樣結(jié)構(gòu)域的ASP178位置。對(duì)應(yīng)的酶切產(chǎn)物IL-331-178與 IL-33179-270喪失活化ST2下游信號(hào)的能力，而未經(jīng)剪切的IL-331-270具有激活ST2下游信號(hào)的活性[16]，除了caspase1外，caspase-3、caspase-7也能在ASP178位置剪切IL-33(圖1)[4]。此外，中性粒細(xì)胞產(chǎn)生的彈性蛋白酶(Elastase)和組織蛋白酶G(cathepsin G)也可參與IL-33活性的調(diào)節(jié)。cathepsin G 可在F94、L108處酶解IL-33，Elastase可在 I98處酶解IL-33。3種酶切產(chǎn)物IL-3395-270、IL-33109-270和IL-3399-270相比于IL-331-270活性增強(qiáng)10倍左右[7]。此外，中性粒細(xì)胞表達(dá)的PR3(Neutrophil proteinase 3)也可酶切IL-33，酶切產(chǎn)物IL-33117-270擁有很強(qiáng)促炎活性，刺激HMC-1、Raw264.7細(xì)胞后將促進(jìn)IL-8、TNF-α、IL-6等大量產(chǎn)生[6]。

圖1 1L-33結(jié)構(gòu)及不同形式剪切

2.2 二硫鍵“分子開(kāi)關(guān)”對(duì)IL-33活性影響

二硫鍵的形成與否對(duì)蛋白質(zhì)的結(jié)構(gòu)穩(wěn)定性、功能活性具有重要影響[17]。二硫鍵對(duì)IL-33活性同樣有重要調(diào)節(jié)作用。IL-33分子中含有4個(gè)半胱氨酸(C208、C227、C232、C259)，4個(gè)半胱氨酸可以形成兩個(gè)分子內(nèi)二硫鍵(C208-C259、C227-C232)。近期研究發(fā)現(xiàn)，當(dāng)IL-33的兩個(gè)二硫鍵形成時(shí)，IL-33同ST2L結(jié)合位點(diǎn)處的構(gòu)象發(fā)生變化，將導(dǎo)致IL-33喪失同其受體ST2L的結(jié)合能力。即氧化還原驅(qū)動(dòng)IL-33二硫鍵的形成可以作為一個(gè)分子開(kāi)關(guān)，通過(guò)調(diào)節(jié)其與配體ST2L的結(jié)合，以精確調(diào)控其活性[9]。

3 IL-33/ST2L信號(hào)途徑

ST2屬于IL-1R超家族成員，其基因通過(guò)可變剪切產(chǎn)生多種產(chǎn)物，目前研究較多的是分泌型sST2蛋白和跨膜型ST2L蛋白這兩種蛋白[18]。相對(duì)于ST2L，sST2缺乏跨膜區(qū)和胞內(nèi)結(jié)構(gòu)域。炎癥條件下，sST2血清濃度升高，并參與炎癥應(yīng)答調(diào)控，故sST2也被作為心力衰竭(congestive heart failure，HF)、心血管死亡(cardiovascular mortality)等的風(fēng)險(xiǎn)指標(biāo)。IL-33作用于ST2L，首先IL-33同細(xì)胞表面的ST2L結(jié)合，隨后IL-33/ST2L二聚物招募IL-1RacP，IL-1RacP結(jié)合到該二聚物后可穩(wěn)定IL-33/ST2L的結(jié)合[19]。該復(fù)合物的形成將招募MyD88、IRAK1、IRAK4、TRAF6等信號(hào)分子，最終通過(guò)活化NF-κB和MAPK信號(hào)通路促進(jìn)炎癥相關(guān)因子轉(zhuǎn)錄表達(dá)[20]；而sST2分子也可與IL-33結(jié)合，通過(guò)捕獲游離的IL-33，抑制IL-33/ST2L信號(hào)通路[21](圖2)。

圖2 1L-33/ST2L信號(hào)途徑

4 IL-33可通過(guò)IL-33/ST2L信號(hào)途徑調(diào)控多種疾病

過(guò)去大量研究闡明了IL-33可通過(guò)IL-33/ST2L信號(hào)途徑影響體內(nèi)先天、后天免疫細(xì)胞(圖3)[11, 22-24]，促進(jìn)機(jī)體2型炎癥反應(yīng)的發(fā)生和發(fā)展，進(jìn)而導(dǎo)致多種疾病。本文將重點(diǎn)介紹近些年IL-33通過(guò)IL-33/ST2L信號(hào)途徑調(diào)節(jié)2型細(xì)胞因子表達(dá)，并進(jìn)一步調(diào)節(jié)動(dòng)脈粥樣硬化、肥胖、類風(fēng)濕性關(guān)節(jié)炎等疾病的研究進(jìn)展，同時(shí)介紹IL-33在阿爾茨海默病的發(fā)生中的作用。

4.1 IL-33同動(dòng)脈粥樣硬化

動(dòng)脈血管壁的慢性炎癥反應(yīng)被認(rèn)為在動(dòng)脈粥樣硬化斑的形成中起到關(guān)鍵性的作用[25-26]。除內(nèi)皮細(xì)胞、平滑肌細(xì)胞外，動(dòng)脈血管壁還被巨噬細(xì)胞、T/B淋巴細(xì)胞、DC細(xì)胞和中性白細(xì)胞等免疫細(xì)胞浸潤(rùn)。細(xì)胞免疫、體液免疫及機(jī)體非特異性免疫反應(yīng)均參與動(dòng)脈粥樣硬化的調(diào)控[20, 27]。

圖3 1L-33可活化多種免疫細(xì)胞調(diào)控2型免疫反應(yīng)

IL-33可通過(guò)IL-33/ST2L信號(hào)途徑抑制動(dòng)脈粥樣硬化的發(fā)展。對(duì)動(dòng)脈粥樣硬化模型ApoE-/-小鼠連續(xù)6周腹腔注射IL-33，小鼠主動(dòng)脈竇處的動(dòng)脈粥樣硬化斑明顯減小。該模型中，IL-33促進(jìn)Th1/Th2平衡向后者偏移；且動(dòng)脈粥樣硬化斑塊處的F4/80+巨噬細(xì)胞和CD3+T細(xì)胞明顯減少，小鼠體內(nèi)的oxLDL抗體IgM表達(dá)水平升高[28]。小鼠腹腔注射IL-33受體sST2發(fā)現(xiàn)，IL-33抑制動(dòng)脈粥樣硬化的作用受到抑制，暗示sST2可通過(guò)抑制IL-33/ST2信號(hào)通路抑制IL-33在動(dòng)脈粥樣硬化疾病中的作用(圖2)[29]。

此外，IL-33還可影響巨噬細(xì)胞形成泡沫細(xì)胞而抑制動(dòng)脈粥樣硬化的發(fā)展[4]。IL-33可降低泡沫細(xì)胞對(duì)乙酰低密度脂蛋白和ox-LDL的攝取，并增加膽固醇外流。近期的研究表明ILC2細(xì)胞在IL-33的刺激下(圖3)，通過(guò)分泌IL-4、IL-9和IL-13，促進(jìn)嗜酸性粒細(xì)胞、巨噬細(xì)胞活化，從而抑制動(dòng)脈粥樣硬化發(fā)展[30]。

4.2 IL-33同肥胖

脂肪組織可分為白色脂肪組織和褐色脂肪組織[30]。白色脂肪組織是能量貯存場(chǎng)所；褐色脂肪組織為脂肪分解消耗場(chǎng)所，褐色脂肪細(xì)胞可通過(guò)線粒體解偶聯(lián)蛋白1(UCP-1)促進(jìn)脂肪燃燒產(chǎn)生熱量及能量。除此外，另外的一種中間態(tài)脂肪細(xì)胞米色脂肪細(xì)胞也能表達(dá)UCP-1蛋白，促進(jìn)脂肪分解。

肥胖表現(xiàn)為白色脂肪組織處的脂肪細(xì)胞脂肪含量增加，脂肪細(xì)胞體積增大。并伴隨著較低水平的炎癥反應(yīng)。IL-33可以通過(guò)IL-33/ST2信號(hào)通路調(diào)節(jié)ILC2和Treg分化(圖3)，進(jìn)而調(diào)控白色脂肪組織代謝，此代謝過(guò)程發(fā)生紊亂時(shí)，將發(fā)展為慢性炎癥，最終導(dǎo)致肥胖、胰島素耐受等。近期研究顯示， Rnase ω1能誘導(dǎo)肥胖患者的脂肪細(xì)胞釋放IL-33，除此之外，脂肪組織內(nèi)皮細(xì)胞也表達(dá)大量的IL-33，釋放出的IL-33通過(guò)識(shí)別受體ST2在脂肪組織處誘導(dǎo)2型免疫反應(yīng)，即IL-33活化ILC2，活化后的ILC2分泌甲硫氨酸腦啡肽誘導(dǎo)脂肪細(xì)胞產(chǎn)生Ucp1，促進(jìn)米色脂肪向褐色脂肪分化[31]。

4.3 IL-33同關(guān)節(jié)炎

類風(fēng)濕性關(guān)節(jié)炎(Rheumatoid arthritis，RA)是一種常見(jiàn)的慢性自身免疫疾病。主要表現(xiàn)為關(guān)節(jié)滑膜處持續(xù)的炎癥反應(yīng)。即關(guān)節(jié)滑液中滲出的炎癥細(xì)胞釋放的炎癥性細(xì)胞因子和蛋白酶侵蝕關(guān)節(jié)組織，造成關(guān)節(jié)滑膜增生、骨和軟骨破壞。在RA病人關(guān)節(jié)滑膜組織、成纖維母細(xì)胞以及CIA模型小鼠的關(guān)節(jié)中能檢測(cè)到IL-33大量存在。這些大量表達(dá)的IL-33可以通過(guò)IL-33/ST2信號(hào)通路活化肥大細(xì)胞(圖3)，促進(jìn)肥大細(xì)胞分泌炎癥性細(xì)胞因子IL-6、IL-1、TNF-α。這些炎癥因子又可通過(guò)Th17等放大炎癥效應(yīng)。對(duì)CIA小鼠注射IL-33，可加劇小鼠的病情[32]，而當(dāng)沉默IL-33或使用IL-33受體ST2的中和抗體阻斷IL-33/ST2信號(hào)通路時(shí)，都能抑制病情的發(fā)展[33]。對(duì)CIA模型小鼠短期注射sST2-Fc融合蛋白即能抑制炎癥因子IFN-gamma、TNF-α、IL-6、IL-12等的表達(dá)，逆轉(zhuǎn)病情[34]。因此在RA中，IL-33被作為一個(gè)潛在的藥物靶標(biāo)[34-36]。

4.4 IL-33參與調(diào)控阿爾茨海默病

阿爾茨海默病(Alzheimer’s disease，AD)是一種慢性神經(jīng)退行性疾病，患者主要表現(xiàn)為記憶能力降低，認(rèn)知能力減弱，AD的具體發(fā)病機(jī)理尚不清楚，目前尚無(wú)有效治療手段。越來(lái)越多的證據(jù)暗示IL-33也參與了AD的調(diào)控。首先，在AD病人的腦內(nèi)IL-33表達(dá)降低。IL-33轉(zhuǎn)染人成神經(jīng)母細(xì)胞瘤(SY5Y-APP695WT)后，Aβ1-40分泌量下降30%[37]；其次，MCI(Mild cognitive impairment)病人血液中sST2含量顯著高于正常人群，這些結(jié)果暗示IL-33參與AD的調(diào)控，目前的研究結(jié)果顯示IL-33可能通過(guò)兩條途徑作用于AD。不依賴于IL-33/ST2信號(hào)途徑的調(diào)控[37]；依賴于IL-33/ST2信號(hào)途徑的調(diào)控[38]。進(jìn)一步研究發(fā)現(xiàn)，IL-33可通過(guò)動(dòng)員神經(jīng)膠質(zhì)細(xì)胞(CD11b+CD45hi)吞噬并清除Aβ，減少淀粉樣蛋白斑塊；還可誘導(dǎo)腦啡肽酶表達(dá)，促進(jìn)可溶性Aβ降解[38]。

5 展望

正常情況下，機(jī)體IL-33作為“預(yù)警素”被大量?jī)?chǔ)存于細(xì)胞內(nèi)，當(dāng)細(xì)胞凋亡或壞死時(shí)才被大量釋放出體外。IL-33具有轉(zhuǎn)錄調(diào)節(jié)活性和細(xì)胞因子活性，自發(fā)現(xiàn)以來(lái)，大量研究仍舊停留于IL-33的C端細(xì)胞因子活性上。即IL-33可通過(guò)IL-33/ST2L信號(hào)途徑募集MyD88、IRAK1、IRAK4、TRAF6等信號(hào)分子，活化NF-κB和MAPK(圖2)，促進(jìn)炎癥相關(guān)基因應(yīng)答，目前這條途徑研究較為清楚。而IL-33 N端具有轉(zhuǎn)錄調(diào)節(jié)活性，其是否參與某些靶基因的表達(dá)調(diào)控[33]？這些靶基因在炎癥相關(guān)疾病中扮演什么角色？還有待進(jìn)一步研究。凋亡細(xì)胞、粒細(xì)胞等產(chǎn)生的Caspase-1/3/7、Elastase、Cathepsin G等酶對(duì)IL-33剪切(圖1)，使其與ST2L結(jié)合能力喪失或增強(qiáng)。這種作用避免了機(jī)體因?yàn)樽陨砑?xì)胞正常凋亡引起過(guò)度的免疫反應(yīng)，也促進(jìn)了機(jī)體在炎癥狀態(tài)下炎癥反應(yīng)的放大，有利于機(jī)體對(duì)外來(lái)抗原等的清除，體現(xiàn)了機(jī)體在不同逆境條件下的一種自我保護(hù)機(jī)制。IL-33受體ST2表達(dá)于多種免疫相關(guān)細(xì)胞表面(圖3)，因此IL-33在自身免疫炎癥、代謝相關(guān)疾病中都可通過(guò)“免疫開(kāi)關(guān)”的作用誘導(dǎo)2型細(xì)胞因子表達(dá)，調(diào)節(jié)疾病的發(fā)生與發(fā)展。IL-33的這種作用，對(duì)于治療由于免疫失衡引起的疾病指明了一個(gè)新的方向；此外，新發(fā)現(xiàn)IL-33在治療AD中的作用，為AD研究與治療提供了新的方向。

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IL-33:activation, regulation and function

LIU Shan-hui, ZHANG Shi-chao, JI Shang-rong

(School of Life Sciences, Lanzhou University， Lanzhou 730000, China)

IL-33, a novel member of the IL-1 family, mediates its biological effects via the ST2 receptor (also known as IL-1RL1), and initiates a type 2 immune response during cardiovascular disease, Alzheimer′s disease, cancer and obesity. IL-33 is a dual-function protein that act both as a cytokine and as an intracellular nuclear factor. Here, we review the recent advances on how IL-33 activity is regulated by proteolysis and oxidation-driven conformational change of two disulphide bonds formation, and the newly discovered roles of IL-33 in atherosclerosis, obesity, rheumatoid arthritis, and Alzheimer′s disease. IL-33 mobilizes innate immunity and acquires immunity to initiate type-2 immune response by the IL-33/ST2L pathway. Therapeutic strategy targeting IL-33 may be an effective strategy to ameliorate these diseases.

IL-1 family； IL-33/ST2L signal； type 2 immune response； two disulphide bonds

2016-09-04；

2016-09-29

中央高?；究蒲袠I(yè)務(wù)費(fèi)專項(xiàng)資金(lzujbky-2016-k11)

劉善輝，博士研究生, 研究方向?yàn)榈鞍踪|(zhì)結(jié)構(gòu)功能與自身免疫疾病，E-mail: liushh2014@lzu.edu.cn;張世超，博士研究生，研究方向?yàn)榈鞍踪|(zhì)的功能及表達(dá)調(diào)控，E-mail：zhangshch08@lzu.edu.cn

吉尚戎，教授,博士,研究方向?yàn)榈鞍踪|(zhì)結(jié)構(gòu)功能及重要蛋白質(zhì)參與慢性炎癥疾病調(diào)控的分子機(jī)制，E-mail: jsr@lzu.edu.cn

R392

A

2095-1736(2017)03-0078-04

doi∶10.3969/j.issn.2095-1736.2017.03.078