IL-27對(duì)輔助T細(xì)胞相關(guān)疾病的作用

王利娟綜述王滿俠審校

(蘭州大學(xué)第二附屬醫(yī)院神經(jīng)內(nèi)一科,蘭州730000)

IL-27來源APCs，由P28和EBI3組成。IL-27作用受體gp130和WSX-1復(fù)合體通過激活激酶(JAK)/信號(hào)轉(zhuǎn)導(dǎo)及轉(zhuǎn)錄活化因子(STAT)途徑和促分裂原活化蛋白激酶(MAPK)途徑發(fā)揮生物學(xué)作用。研究發(fā)現(xiàn)IL-27在疾病不同階段、不同細(xì)胞類型發(fā)揮不同效應(yīng)，早期WSX-1缺陷小鼠對(duì)利什曼原蟲感染更加敏感[1]，然而WSX-1 缺陷小鼠感染結(jié)核桿菌晚期產(chǎn)生大量炎癥因子和廣泛的炎癥反應(yīng)，而且更容易死于結(jié)核桿菌感染[2],表現(xiàn)出IL-27早期促進(jìn)Th1細(xì)胞免疫反應(yīng)起到防御作用，而晚期抑制Th1細(xì)胞引起過度炎癥損害。同樣Wsx-1敲除的鼠相比野生鼠，IL-17水平升高且更易患EAE[3]，顯示IL-27對(duì)Th17細(xì)胞免疫反應(yīng)有抑制作用。深入研究發(fā)現(xiàn)IL-27通過誘導(dǎo)初始CD4+T細(xì)胞T-bet、IL-12Rβ2、ICAM-1/LFA-1表達(dá)促進(jìn)向Th1細(xì)胞分化，另一方面IL-27 通過誘導(dǎo)依賴STAT1,STAT3,和誘導(dǎo)共刺激分子ICOS抑制CD4+T細(xì)胞產(chǎn)生IL-17、IL-10?，F(xiàn)已認(rèn)識(shí)到IL-27對(duì)輔助CD4+T細(xì)胞相關(guān)疾病具有多效性，而且作用機(jī)制逐漸被認(rèn)識(shí)。因此，這篇文章主要綜述IL-27對(duì)輔助T細(xì)胞相關(guān)疾病的作用及機(jī)制，為相關(guān)疾病治療提供新思路。

1IL-27

IL-27主要來源抗原提成細(xì)胞(APCs) 的表面 Toll樣受體(TLR)刺激產(chǎn)生，分別通過MyD88依賴性途徑和MyD88非依賴性途徑即TRIF途徑啟動(dòng)下游信號(hào)轉(zhuǎn)導(dǎo)。IL-27是IL-12家族中的異源二聚體細(xì)胞因子[4]，主要表達(dá)于免疫組織，具有多效性，由P28和EBI3組成。EBI3結(jié)構(gòu)上類似為可溶性Ⅰ型細(xì)胞因子受體家族，與IL-12的p40亞基同源；P28為四個(gè)螺旋結(jié)構(gòu)，與 IL-12 的p35具有同源性[4]。IL-27與IL-12家族某些細(xì)胞因子共用亞基，如與IL-35共用亞基EBI3[5]。IL-27亞基之間是以非共價(jià)結(jié)合。早期發(fā)現(xiàn)p28單獨(dú)不能分泌，后研究發(fā)現(xiàn)兩亞基不完全同時(shí)表達(dá)，只有兩亞基同時(shí)表達(dá)才能高效分泌IL-27[4]。小鼠P28蛋白能抑制IL-27介導(dǎo)CD4+T細(xì)胞分泌IFNγ[6],表明p28可單獨(dú)分泌而且抑制IL-27信號(hào)傳導(dǎo)。隨后發(fā)現(xiàn)IL-27p28 可阻斷IL-6,IL-11和 IL-27細(xì)胞因子活性，可能就是通過 gp130亞基阻斷信號(hào)傳導(dǎo)[7,8]。然而最近發(fā)現(xiàn)p28單體可通過gp130受體亞基激活傳導(dǎo)通路[9]，認(rèn)為p28 亞基是一個(gè)獨(dú)立細(xì)胞因子。EBI3單體是否也具有生物活性。

2IL-27受體及信號(hào)傳導(dǎo)

IL-27受體也是異源二聚體，由gp130和WSX-1(IL-27Rα或 TCCR)組成，gp130是信號(hào)傳導(dǎo)亞基、WSX-1是結(jié)合亞基[7]。gp130廣泛分布各種組織的細(xì)胞，而且其它細(xì)胞因子也利用其傳導(dǎo)信號(hào)，如IL-6、IL-11、睫狀神經(jīng)營(yíng)養(yǎng)因子、白血病抑制因子。gp130與IL-12βR2有很高同源性。WSX-1主要表達(dá)于淋巴組織，而且WSX-1是IL-6家族細(xì)胞因子受體的共用β亞基。研究表明IL-27受體兩亞基復(fù)合體是介導(dǎo)IL-27生物效應(yīng)所必要的[8]，后發(fā)現(xiàn)I L- 27的信號(hào)轉(zhuǎn)導(dǎo)并不能用重組可溶性 g p 130- F c 完全阻斷[10]。最近發(fā)現(xiàn)IL-27Rα的可溶性形式是一種天然的IL-27拮抗劑[11]，所以IL-27受體的亞基有待進(jìn)一步研究。

LI-27與受體結(jié)合通過激活激酶(JAK)/信號(hào)轉(zhuǎn)導(dǎo)及轉(zhuǎn)錄活化因子(STAT)途徑和促分裂原活化蛋白激酶(MAPK) 途徑發(fā)揮生物學(xué)作用。IL-27可以激活JAK1、JAK2、TYK2、STAT1、STAT3、STAT4、STAT5蛋白質(zhì)，發(fā)揮主要信號(hào)傳導(dǎo)的是STAT1和STAT3途徑[12-14]。IL-27與受體結(jié)合后使JAK磷酸化激活，隨后JAKs磷酸化STAT轉(zhuǎn)錄因子，在胞質(zhì)內(nèi)形成同源二聚體且進(jìn)入細(xì)胞核，誘導(dǎo)目的基因轉(zhuǎn)錄。IL-27可通過MAPK p38 途徑誘導(dǎo)GADD45γ表達(dá)，促進(jìn)T-bet 表達(dá)[15]。不同細(xì)胞活化狀態(tài)和不同細(xì)胞類型激活JAK/STAT通路類型及活化程度不同。

3IL-27對(duì)輔助T細(xì)胞相關(guān)疾病的作用

3.1IL-27 對(duì)Th1細(xì)胞相關(guān)疾病的作用IL-27起初認(rèn)為具有促炎作用。早期WSX-1缺陷小鼠易感染利什曼原蟲等胞內(nèi)病原體且早期感染IFN-γ減少[16]，同時(shí)WSX-1缺陷的結(jié)腸炎小鼠表現(xiàn)出癥狀明顯減輕且IFN- γ減少[17]，提示IL-27具有促炎作用。深入研究發(fā)現(xiàn)IL-27可以促進(jìn)初始CD4+細(xì)胞增殖和分泌IFNγ[4]，且初始CD4+T細(xì)胞可通過IL-27誘導(dǎo)STAT1激活T-bet表達(dá)促使IL-12Rβ2上調(diào)促進(jìn)向Th1分化[18]。同時(shí)IL-27通過MAPK p38途徑誘導(dǎo)生長(zhǎng)阻滯和DNA損傷基因(GADD45γ)表達(dá)介導(dǎo)T-bet 表達(dá)促進(jìn)向Th1分化[15]。另外IL-27誘導(dǎo)細(xì)胞間粘附分子1(ICAM)-1/淋巴細(xì)胞功能相關(guān)抗原(LFA)-1相互作用通過STAT1依賴途徑促初始CD4+T細(xì)胞向Th1細(xì)胞的分化[13]。

另一方面發(fā)現(xiàn)控制W SX-1 缺陷的小鼠弓形蟲感染后，發(fā)現(xiàn)產(chǎn)生過量 IFN-γ及 T細(xì)胞過度增殖為特征的致死性的炎癥反應(yīng)[3,19]。同時(shí)WSX-1缺陷小鼠結(jié)核感染晚期產(chǎn)生大量的促炎細(xì)胞因子和廣泛的炎癥反應(yīng)而加速了小鼠死亡[20]，表明在炎癥反應(yīng)晚期IL-27抑制過度Th1細(xì)胞免疫反應(yīng)。IL-27增強(qiáng)初始CD4+細(xì)胞反應(yīng)而抑制完全活化的Th1細(xì)胞，發(fā)現(xiàn)初始 T 細(xì)胞表面表達(dá)低水平的 WSX-1,完全活化的 T 細(xì)胞表面表達(dá)高水平的WSX-1[21]，所以表明IL-27對(duì)完全活化CDT+4細(xì)胞有明顯抑制作用。同時(shí)，發(fā)現(xiàn)IL-27通過某些細(xì)胞因子抑制Th1細(xì)胞發(fā)揮生物作用。IL-27可抑制IL-2產(chǎn)生[14]，后發(fā)現(xiàn)IL-27 通過抑制信號(hào)傳導(dǎo)(SOCS) 3途徑抑制IL-2產(chǎn)生抑制Th1免疫反應(yīng)[15]，IL-2具有促進(jìn)T細(xì)胞發(fā)育作用。

3.2IL-27對(duì)Th2細(xì)胞相關(guān)疾病的作用寄生蟲感染主要引起Th2型體液免疫反應(yīng)，IL-27Rα缺陷小鼠感染寄生蟲表現(xiàn)出加速排除蟲體、IL-4，IL-5，和IL-13細(xì)胞因子表達(dá)增多和杯狀細(xì)胞增生、肥大細(xì)胞增多[22],同時(shí)發(fā)現(xiàn)鼻腔給IL-27可以抑制(OVA)抗原誘發(fā)的氣道高反應(yīng)性和炎癥反應(yīng)[23]，表明IL-27對(duì)Th2細(xì)胞免疫反應(yīng)有抑制作用。進(jìn)一步研究發(fā)現(xiàn)IL-27抑制Th2細(xì)胞分化通過依賴STAT1 介導(dǎo)抑制GATA-3表達(dá)[24,25]，GATA-3是Th2細(xì)胞標(biāo)記性轉(zhuǎn)錄因子。同時(shí)IL-27 可抑制完全分化Th2細(xì)胞的GATA3表達(dá)且對(duì)抑制Th2分泌IL-5、IL-13具有劑量依賴性[23]。所以IL-27可作為新的治療靶點(diǎn)用于Th2細(xì)胞相關(guān)疾病如哮喘或寄生蟲感染。

3.3IL-27對(duì)Th17細(xì)胞相關(guān)疾病的作用Th17細(xì)胞已發(fā)現(xiàn)參與多種疾病而致病，如關(guān)節(jié)炎(CIA) 、 自身免疫性腦脊髓炎(EAE)等。Th17 細(xì)胞主要產(chǎn)生大量 IL- 17參與炎癥反應(yīng)[26]。許多研究顯示IL-27具有抑制Th17細(xì)胞免疫反應(yīng)[27,28]。Wsx-1敲除的鼠相比野生鼠，IL-17水平升高且更易患EAE[3]，同時(shí)發(fā)現(xiàn)外源性給IL-27后表現(xiàn)出Th17細(xì)胞比例減少[29]，表明IL-27可抑制Th17免疫反應(yīng)和減輕致病性。IL-27 通過抑制初始T細(xì)胞RORγt表達(dá)抑制Th17分化[30]，但不能抑制完全分化的Th17細(xì)胞[31,32]。進(jìn)一步分離出記憶細(xì)胞，發(fā)現(xiàn)IL-27可抑制記憶細(xì)胞IL-17的表達(dá)[27]。IL-27抑制CD4+T細(xì)胞產(chǎn)生IL-17,通過SOCS1、STAT1、STAT3依賴途徑[27，31]。最近發(fā)現(xiàn)，IL-27通過STAT1依賴性途徑上調(diào)T細(xì)胞程序性死亡配體(PD-L1)誘導(dǎo)抑制Th17細(xì)胞分化[33]。PD-1-PD-L1的相互作用可抑制T細(xì)胞發(fā)揮生物作用[34,35]。因此IL-27具有保護(hù)性作用對(duì)Th17細(xì)胞介導(dǎo)的疾病。

3.4IL-27對(duì)Tregs細(xì)胞相關(guān)疾病的作用研究發(fā)現(xiàn)炎癥腸病和胃癌患者的外周血Tregs細(xì)胞數(shù)量減少[36,37]，表明Tregs細(xì)胞減少與致病發(fā)生有關(guān)。Tregs主要通過表達(dá)IL-10發(fā)揮抑制和誘導(dǎo)耐受作用。一系列研究發(fā)現(xiàn)IL-27可促進(jìn)Th1,Th2,Th17，Tregs細(xì)胞亞群產(chǎn)生 IL-10。IL-10 敲除的小鼠易患自發(fā)結(jié)腸炎并且對(duì)癌癥有易感性[38]。心臟移植中發(fā)現(xiàn)IL-27具有移植耐受誘導(dǎo)的作用[39]表明IL-27具有誘導(dǎo)調(diào)節(jié)細(xì)胞的作用。研究發(fā)現(xiàn)IL-10對(duì)Th1及Th17細(xì)胞參與免疫反應(yīng)有抑制作用[29,30,40]。IL-27 促進(jìn)T細(xì)胞產(chǎn)生IL-10是通過依賴性STAT1,STAT3,和誘導(dǎo)共刺激分子ICOS[41,42]。IL-27 可以通過誘導(dǎo) c-Maf 的表達(dá)來促進(jìn)生長(zhǎng)因子 IL-21 的產(chǎn)生和上調(diào)共刺激分子ICOS的表達(dá)，進(jìn)而誘導(dǎo)分泌 IL-10 的 Tr1細(xì)胞的分化和增殖[41,42]，IL-21對(duì)所有Tr1細(xì)胞似乎是自分泌生長(zhǎng)、分化因子[43]。另外發(fā)現(xiàn)IL-27通過MAPK 途徑介導(dǎo)激活蛋白1 (AP-1)誘導(dǎo)IL-21對(duì)IL-10 產(chǎn)生很主要[41,43]。最近，研究表明IL-27誘導(dǎo)CD4+T細(xì)胞Egr-2表達(dá)通過STAT3依賴途徑促進(jìn) IL-10 產(chǎn)生[44]。

另一方面發(fā)現(xiàn)IL-27對(duì)Tregs細(xì)胞免疫反應(yīng)有抑制作用。在IL-27轉(zhuǎn)基因小鼠過度表達(dá)IL-27使Treg細(xì)胞數(shù)量減少而且易患自身免疫性疾病[45]。研究發(fā)現(xiàn)IL-27可通過抑制IL-2產(chǎn)生從而致使Treg細(xì)胞數(shù)量減少，IL-2對(duì)維持Treg細(xì)胞發(fā)育十分重要。發(fā)現(xiàn)IL-27 通過STAT3 途徑抑制Tregs特征性分子標(biāo)志Foxp3、CD25和 CTLA-4的表達(dá)[46]。然而，另發(fā)現(xiàn)IL-27或IL-27Rα缺陷小鼠的 Foxp3+Treg細(xì)胞數(shù)量或比例沒顯著改變[47]。抑制試驗(yàn)中發(fā)現(xiàn)IL-27即不能抑制Foxp3的表達(dá)也不能拮抗Tregs發(fā)揮作用[47,48]。最近發(fā)現(xiàn)IL-27主要促進(jìn)Tregs細(xì)胞的發(fā)育和存活[49]。

3.5IL-27 對(duì) Tfh細(xì)胞相關(guān)疾病的作用近些年發(fā)現(xiàn)濾泡輔助性T細(xì)胞(Tfh)參與多種疾病，在慢性活動(dòng)性乙型肝炎患者外周血中Tfh細(xì)胞的數(shù)量明顯升高并且用阿德福韋酯治療后Tfh細(xì)胞比例明顯減少[50]。同時(shí)，研究發(fā)現(xiàn)類風(fēng)濕關(guān)節(jié)炎患者的外周血中Tfh 細(xì)胞數(shù)量增加[51]并且SLE 患者的血漿中CXCL13 表達(dá)增高[52]，CXCL13是Tfh 細(xì)胞的表面標(biāo)記物CXCR5的配體。IL-21 可誘導(dǎo)CD4+T的 Bcl-6表達(dá)[53],Bcl-6是Tfh細(xì)胞重要性轉(zhuǎn)錄因子。IL-27可促進(jìn)CD4+T細(xì)胞IL-21產(chǎn)生[41,43]。深入研究發(fā)現(xiàn)病原體相關(guān)分子模式(PAMP)激活樹突細(xì)胞特異性黏附分子(DC-SIGN)誘導(dǎo) IL-27 表達(dá)介導(dǎo)(ISGF3)促使T細(xì)胞分化為Tfh 細(xì)胞[54,55]。IL-27對(duì)Tfh 細(xì)胞作用有待進(jìn)一步研究。

3.6IL-27 對(duì)Th22細(xì)胞相關(guān)疾病的作用Th22細(xì)胞是另一類輔助CD4+T細(xì)胞，主要通過分泌IL-22發(fā)揮免疫作用。IL-22作用靶點(diǎn)具有相對(duì)組織特異性，IL-22R高表達(dá)于上皮，如皮膚、 消化道、 呼吸道等。研究發(fā)現(xiàn)銀屑病患者的皮膚組織、 外周血高表達(dá) IL- 22相比對(duì)照組[56],而且用抗 IL- 22 抗體注射銀屑病小鼠后發(fā)現(xiàn)皮膚炎癥反應(yīng)明顯減輕[57]，表明IL-22在皮膚病致病中起到了重要作用。先前研究IL-27 抑制Th17細(xì)胞IL-22 表達(dá)通過介導(dǎo)STAT1 和 SOCS1激活[27],進(jìn)一步研究發(fā)現(xiàn)IL-27可抑制CD4+T表達(dá)IL-22通過上調(diào)SOCS1 介導(dǎo)以劑量依賴型而且不通過誘導(dǎo)IFN-γ 和 IL-10 表達(dá)發(fā)揮作用[58]。

3.7IL-27 對(duì)Th9 細(xì)胞相關(guān)疾病的作用小鼠模型中TGF-β和 IL-4 共同培養(yǎng)的條件下可誘導(dǎo)產(chǎn)生一類以分泌 IL- 9 和 IL- 10 為主的新型 CD4+T 細(xì)胞亞群Th9 細(xì)胞[59]。而人Th9細(xì)胞不分泌IL-10。IL-9依賴所處微環(huán)境表現(xiàn)出促炎和抑制炎癥作用[60]。Elyamana等人研究發(fā)現(xiàn)IL-9R缺陷EAE 小鼠的Th1細(xì)胞和Th17 細(xì)胞比例明顯升高相比野生性小鼠，表現(xiàn)出IL-9具有免疫抑制功能在體內(nèi)和體外。IL-9可通過誘導(dǎo)STAT3 和 STAT5信號(hào)傳導(dǎo)維持Treg細(xì)胞的存活提高調(diào)節(jié) FoxP3 CD4+T 細(xì)胞的抑制作用[61]。然而，另一方面IL-9在過敏性哮喘、寄生蟲感染、實(shí)驗(yàn)性自身免疫性腦脊髓炎參與促炎作用[62-64]。哮喘患者外周血中Th9 、 IL- 9 水平明顯高于健康對(duì)照組[65],表明 IL- 9 參與炎癥反應(yīng)，促進(jìn)病理發(fā)展。在EAE中[66]，IL-27R缺陷小鼠產(chǎn)生IL-9增多相比野生鼠組，同時(shí)發(fā)現(xiàn)加入抗IL-27抗體IL-9產(chǎn)生增多，表明IL-27對(duì)Th9細(xì)胞發(fā)育有抑制作用。IFN-γ 和IL-10對(duì)Th9細(xì)胞發(fā)育具有抑制作用。雖然IL-27 誘導(dǎo)IFN-γ 和IL-10 產(chǎn)生抑制Th9 細(xì)胞發(fā)揮作用,但在IFN-γ和IL-10 缺陷T 細(xì)胞中IL-27可介導(dǎo)抑制Th9 細(xì)胞發(fā)育，表明IL-27即通過IFN-γ和IL-10抑制Th9細(xì)胞發(fā)育也可通過IL-27直接作用[66]。IL-27可抑制Th9細(xì)胞分化通過STAT-1和T-bet 依賴途徑[66]。然而IL-27促進(jìn)Tr1細(xì)胞分泌IL-21增強(qiáng)完全活化Th9細(xì)胞分泌 IL-9[67]。IL-27對(duì)Th9細(xì)胞作用需進(jìn)一步研究。

4結(jié)論

IL-27表現(xiàn)出對(duì)炎癥性疾病和免疫性疾病廣泛抗炎作用，尤其是對(duì)輔助Th1、Th2、Th17、Th22、Th9細(xì)胞相關(guān)疾病的抑制作用。因此，以IL-27中心可作為相關(guān)疾病的靶點(diǎn)，為相關(guān)疾病診斷及治療提供新的方案。但I(xiàn)L-27對(duì)輔助T細(xì)胞相關(guān)疾病的作用、機(jī)制及作為治療靶點(diǎn)有效性還需有待進(jìn)一步研究。

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[收稿2015-06-15修回2015-07-15]

(編輯許四平)

通訊作者及指導(dǎo)教師：王滿俠(1962年-)，女，教授，主任醫(yī)師，碩士生導(dǎo)師，主要從事神經(jīng)感染免疫方面的研究，E-mail:wmx322@aliyun.com。

作者簡(jiǎn)介：王利娟(1987年-)，女，在讀碩士，主要從事神經(jīng)感染免疫疾病方面的研究，E-mail:846434309@qq.com。

中圖分類號(hào)R741.02

文獻(xiàn)標(biāo)志碼A

文章編號(hào)1000-484X(2016)02-0284-05

doi:10.3969/j.issn.1000-484X.2016.02.032