修回日期: 2015-12-28
接受日期: 2016-01-06
在线出版日期: 2016-02-08
炎症性肠病是一组反复发生的慢性肠道非特异性炎症, 其发病机制并不十分清楚, 然而免疫调节异常被认为是该病发病的关键因素. 白介素-27(interleukine-27, IL-27)是IL-12家族的新成员, 主要由抗原提呈细胞产生, 能够调节多种T细胞亚型的功能, 并在感染及自身免疫性疾病中发挥重要的免疫调节作用. 近年研究发现IL-27与炎症性肠病的发生、发展关系密切, 本文就IL-27与炎症性肠病的关系作一综述.
核心提示: 白介素-27(interleukine-27, IL-27)属于IL-12家族成员, 主要由抗原提呈细胞, 包括树突状细胞、巨噬细胞等在微生物或其他免疫刺激物刺激下产生, 其受体广泛分布于多种免疫细胞. IL-27可以促进Th1和Tr1分化, 抑制Th2、Th17及Treg应答, 在免疫调节方面具有重要作用.
引文著录: 周力为, 马娜, 李展, 冯百岁. 白介素-27与炎症性肠病关系的研究进展. 世界华人消化杂志 2016; 24(4): 549-557
Revised: December 28, 2015
Accepted: January 6, 2016
Published online: February 8, 2016
Inflammatory bowel disease (IBD), which is characterized by chronic or recurrent relapsing gastrointestinal inflammation, includes ulcerative colitis (UC) and Crohn's disease (CD). The pathogenesis of IBD remains obscure, however, abnormal immune responses are regarded as the major component of IBD pathogenesis. Interleukin-27 (IL-27) is a new member of the IL-12 family, and it is produced by activated antigen-presenting cells and plays an important role in the differentiation and function of different T cell subsets. IL-27 has various immunoregulatory functions and is implicated in the pathogenesis of many infectious and autoimmune diseases. Recent studies have showed that IL-27 is strongly associated with the genesis and development of IBD. Here we provide an overview of the role of IL-27 in the pathogenesis of IBD.
- Citation: Zhou LW, Ma N, Li Z, Feng BS. Role of interleukin-27 in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2016; 24(4): 549-557
- URL: https://www.wjgnet.com/1009-3079/full/v24/i4/549.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i4.549
炎症性肠病(inflammatory bowel disease, IBD)是一组反复发生的慢性炎症性肠道疾病, 临床分型包括溃疡性结肠炎(ulcerative colitis, UC)和克罗恩病(Crohn's disease, CD), 前者主要累及乙状结肠和直肠, 而CD可以累及消化系任何部位[1]. 由于该病易复发, 治疗周期长, 费用高, 给患者带来了很大的经济负担, 但是该病的具体病因至今未明. 目前大多数学者认为该病的发生是由于遗传易感宿主对外界环境和微生物的异常免疫反应, 其中亦可能有精神心理因素的参与. 免疫反应的异常是整个发病过程的核心, 其中包括细胞因子在内的各种免疫效应因子发挥了主要作用. 白介素-27(interleukine-27, IL-27)是新近发现的细胞因子, 属于IL-12家族成员, 主要由抗原提呈细胞(antigen presenting cells, APCs), 包括树突状细胞(dendritic cells, DCs)、单核细胞和巨噬细胞在微生物或其他免疫刺激物刺激下产生, 其受体则广泛分布于多种免疫细胞[2]. 起初IL-27被发现可以促进初始T细胞的增殖与分化, 促进NK及T细胞干扰素-γ(interferon-γ, IFN-γ)的产生, 因此被认作是一种促炎性细胞因子. 然而近十年的研究逐渐证明IL-27可以抑制Th2及Th17应答, 其同样具有限制免疫应答的作用. 目前越来越多的研究表明IL-27在IBD中具有促炎和抗炎双重属性, 其与IBD中的异常免疫调节密切相关, 有望成为疾病治疗的新靶点.
IL-27具有异二聚体结构, 其中包含EB病毒诱导基因3(Epstein-Barr virus-induced gene 3, EBi3)和IL-27 p28[3], 两种亚单位通过共价键结合形成IL-27. IL-27类似于其他具有异二聚体结构的细胞因子, 大多由一个结合了相应可溶性受体样蛋白(如IL-6Rα、EBI3)的螺旋束亚基(如IL-12 p35、IL-27 p28)构成, 这些亚基可以相互结合组成多种同源或异二聚体. 例如EBI3同样可与IL-12 p35结合形成IL-35, 参与调控相关调节性T细胞活动[4]. 而IL-27 p28不仅可以以异二聚体形式发挥效应, 亦可独立于EBI3单独发挥生物学作用. 如Stumhofer等[5]发现IL-27 p28可以抑制gp130介导的信号通路, 阻断IL-6、IL-11和IL-27等细胞因子的功能, IL-27 p28发挥了受体拮抗剂的作用.
IL-27受体(IL-27R)是一个由WSX-1/TCCR(IL-27Rα)和gp130组成的异二聚体, 两者都是免疫球蛋白超家族成员[6]. gp130同样是IL-6和IL-35受体的组成部分, 而IL-27Rα为IL-27R独有. 两个亚单位都参与了IL-27信号的传递, 单独存在时均不能有效介导IL-27信号传导[7]. 有研究检测了免疫细胞IL-27Rα的表达情况, 其中NK细胞表达有高水平的IL-27Rα, 但其激活后会出现IL-27Rα的下调. 相反, 初始CD4+ T细胞少量表达IL-27Rα, 而其激活后则表达增加[8]. 或许IL-27对不同状态的免疫细胞会引发不同的信号转导及后续功能效应. IL-27Rα还具有免疫调节作用, 如IL-27Rα可以和gp130及IL-6Rα形成复合体, 进而调节NK细胞和T细胞功能[9]. Dietrich等[10]则发现激活的T细胞、B细胞以及巨噬细胞等多种细胞可以释放可溶性IL-27Rα(sIL-27Rα), 其能抑制IL-27与胞膜受体的结合及下游STAT通路的激活, 此外还检测到了CD患者血清sIL-27Rα水平的升高.
IL-27与其受体结合后激活JAK-STAT及MAPK信号转导通路, 其中IL-27Rα激活JAK1/2进而通过下游的STAT1及STAT3通路参与多种免疫细胞的分化[11-13]. 在Th1细胞方面, STAT1信号可以激活转录因子T-bet和诱导IFN-γ的产生, 亦可通过增加T细胞黏附分子ICAM-1和LFA-1的表达及相互作用进而激活细胞外信号调节激酶(extracellular regulated protein kinases, ERK)信号通路[14], 这均有利于Th1细胞的分化. 在Tr1细胞方面, IL-27信号可以促进Tr1细胞及IL-10的产生, 这是由于STAT3不仅可以诱导转录因子c-Maf[15], 还能上调早期生长反应因子2(early growth response protein 2, Egr-2)的表达, 而后者是B淋巴细胞诱导成熟蛋白1(Blimp-1)的转录调节因子, 其能促进IL-10的产生[2,11]. IL-27虽然可以诱导Tr1细胞, 但会抑制调节性T细胞(regulatory cell, Treg)的分化, 这一作用与STAT3介导的Foxp3抑制密不可分, 而Foxp3是Treg的关键转录因子[16]. 在Th17细胞方面, IL-27通过STAT1上调PD-L1的表达而抑制Th17的分化(详见下文)[17]. 而在NK细胞方面, 激活的STAT1通路会促进IFN-γ分泌并增强NK细胞的功能[18].
IBD是一种自身免疫相关疾病, 研究发现IBD患者结肠组织中IL-27表达明显增高[19], 且已有韩国学者发现IL-27在CD和UC患者的基因多态性分析中与正常人明显不同, 其多态性基因位于IBD1易感位点上, 可能与IBD易感性相关[20]. 越来越多的研究报道IL-27可以促进Th1和Tr1细胞的分化, 抑制Th2、Th17细胞及Treg的应答, 其在免疫调节方面具有重要作用, 因此认为IL-27与IBD密切相关.
Thl/Th2失衡一直被认为是IBD的发病机制之一, 其中CD主要是Thl型反应介导的疾病, 而对于UC, 近来研究认为其是Thl和Th2共同作用的结果, 在早期Thl型反应较强, 而晚期则以Th2型反应占优势. 在Th1细胞方面, IL-27具有促进Th1型免疫反应的作用, Villarino等[21]利用IL-10及IL-27Rα缺陷小鼠证明了在缺少IL-10的情况下, IL-27可以促进肠道Th1并抑制Th2型免疫反应. 相比于单纯IL-10缺陷小鼠, IL-10和IL-27双重缺陷小鼠出现了推迟的肠道炎症反应且Th1特征性细胞因子IFN-γ水平明显下降, 尽管多有文献报道IL-27的抗炎属性, 但其对Th1型反应在肠道炎症起始期的启动作用可能和IBD的发病有关. Th2细胞方面, IL-27可以抑制Th2型免疫反应, Shimizu等[22]发现IL-27Rα缺陷的狼疮模型小鼠会出现Th1/Th2平衡向Th2型免疫的偏移, 进而导致Th2介导的类似于人膜性肾小球肾炎的免疫病理过程. IL-27抑制GATA-3的表达是其抑制Th2细胞分化的分子基础, 这一作用依赖于STAT1[23,24]. 另有研究报道肥大细胞亦表达IL-27受体[6], IL-27可以通过调节肥大细胞功能而影响Th2型免疫反应[23]. 因此IL-27可能通过影响Th1/Th2平衡而参与IBD的发病.
Th17细胞是最近发现的一种与Th1和Th2细胞亚群无关的新的辅助性T细胞亚群, 其作为慢性炎症的关键介质, 在IBD免疫调节中发挥重要作用[25]. Th17细胞产生促炎细胞因子IL-17、IL-22及粒细胞集落刺激因子(granulocyte macrophage-colony stimulating factor, GM-CSF)[26,27], 参与多种自身免疫疾病发病过程. 虽然IL-27和IL-23同为IL-12家族, 但二者作用相反[28], IL-27在试验中多展现出其负调节Th17细胞应答的功能. 如Anderson等[29]利用WSX-1-/-小鼠证明了在利什曼原虫感染模型中, IL-27信号的缺失会导致T细胞源性IL-10及IFN-γ水平的下降, IL-17+CD4+ T细胞数量明显增多以及病理学损伤的加重. 在IBD相关研究中, IL-27同样发挥了抑制Th17细胞的作用, Troy等[30]利用DSS结肠炎模型证实IL-27Rα-/-小鼠在高剂量DSS模型中出现更加严重的结肠炎, 并且Th17细胞明显活跃. 在另一项以TNBS灌肠作为结肠炎模型的研究中, Sasaoka等[31]给予小鼠持续皮下注射重组单链IL-27显著改善了结肠的长度、坏死范围及病理学评分, 且呈剂量依赖关系, IL-27显著抑制了包括IL-17在内的多种炎性细胞因子, 通过分析肠系膜淋巴结细胞证实了Th17细胞数量的减少. 这些研究结果和在其他几种自身免疫疾病模型[如实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis, EAE)、CIA]中所得出的结果一致[32,33], IL-27均发挥了免疫抑制作用.
IL-27对Th17细胞的抑制作用依赖于STAT1/STAT3和T-bet, 这两条信号通路将引起RORα和RORγt表达减少, 而后两者是Th17分化的关键转录因子[21,34-36]. 然而已成熟的Th17细胞虽然有IL-27R的表达, 但其对IL-27信号几乎没有响应, 未能检测到成熟Th17细胞RORα、RORγt表达水平的变化[37]. 为了进一步揭示IL-27与Th17细胞的作用关系, Hirahara等[17]将初始CD4+ T细胞和IL-27预处理的T细胞共培养, 观察到了增强的PD-1/PD-L1相互作用并且其通过反式激活作用抑制了Th17细胞的分化, 在相关动物实验中, 经IL-27预处理的T细胞高表达PD-L1, 小鼠实验性过敏性脑脊髓炎明显缓解亦伴有Th17细胞分化受限. PD-1/PD-L1是一类T细胞表面抑制性分子, 能够引起癌症与慢性病毒感染过程中T细胞的衰竭, 是目前研究最多的免疫治疗的靶点之一[38-40], 而这项研究将其与IL-27这两种限制T细胞活动的机制联系在了一起.
Treg是免疫系统中维持免疫耐受的主力军, 其表面表达有功能的IL-27R[41]. 一些早期研究[16,42,43]提示IL-27可以抑制Foxp3的上调并通过STAT3抑制Treg. 例如Cox等[44]报道了IL-27在结肠炎模型中对Treg的抑制作用, 将IL-27Rα-/- CD45+Rbhi T细胞植入免疫缺陷小鼠, 和对照组WT CD45+Rbhi T细胞小鼠相比, 观察到了Foxp3+Treg数量的减少及减轻的肠道炎症. 另外, IL-27还可以抑制维持Treg分化的重要细胞因子IL-2的产生, 这是其抑制Treg分化的另一机制[42,45].
然而Ebi3、IL-27 p28或IL-27Rα缺陷小鼠拥有正常的Treg数量, 随着相关研究的进展, 亦有多项研究报道了IL-27具有促进Treg生长和存活的作用[44,46,47]. 如Moon等[48]应用外源性IL-27引起小鼠Foxp3+ Treg数量上升并观察到胶原诱导性关节炎的缓解, 同时发现IL-27能上调Treg抑制性受体PD-1和CTLA-4的表达, 这从另一方面提示了IL-27具有促进Treg功能的作用. 在基于结肠炎模型的研究中, 同样有研究报道[47]Treg的增殖需要IL-27的参与. 此外, Do等[49]还发现IL-27可以诱导Treg免疫负调控分子淋巴细胞激活基因3(Lag3)的表达, 而后者对Treg的免疫抑制功能至关重要, 在此结肠炎模型中IL-27R-/- Treg无法像对照组Treg那样抑制致肠炎性T细胞的增殖和炎性细胞因子的表达.
总之, IL-27对Treg具有双重调节作用. 如果体内Treg与Th17失衡或者Treg缺乏, 则正常菌群和食物性抗原的刺激可引起结肠黏膜的炎性反应, 甚至导致肠黏膜损伤及IBD的发生. IBD患者外周血和结肠黏膜中的Treg数量明显减少, 但是其功能并无异常, IL-27是否通过对Treg的调节作用而参与IBD的发病, 值得进一步研究.
IL-10是机体内重要的免疫调节因子, 能抑制抗原递呈反应及多种炎症因子的合成和生物活性, 是一种重要的抗炎因子, 其在IBD的发病中可能发挥着重要的作用[50]. 近十年来多项研究[51-54]表明IL-27在感染及自身免疫模型中可以促进Th1、Th2、Th17及Treg等多种T淋巴细胞产生IL-10. Hanson等[55]给予小鼠口服能分泌重组IL-27的乳酸乳球菌(LL-IL-27), 观察到IL-10水平的上升及结肠炎症的减轻, 而改将IL-10-/-CD4+CD45Rbhi T细胞过继移植到Rag-/-小鼠体内则未能发挥乳酸乳球菌的上述治疗效应, 可见IL-10是IL-27发挥效应的必要条件. 然而以相同的方式给予小鼠口服LL-IL-10却未能改善肠道炎症, 进一步分析发现通过给予LL-IL-27所诱导的肠道IL-10水平是直接给予LL-IL-10的20倍之多, 这或许是LL-IL-27虽然通过IL-10发挥抗炎效应, 但却比LL-IL-10具有更好治疗效果的原因. IL-27促进IL-10的分子机制较为复杂, 其中不仅有STAT1和STAT3信号的参与[43], 共刺激受体ICOS等分子提供的共刺激信号同样不可或缺[56]. 另有研究[57]表明IL-27可以激活MAPK信号通过激活转录因子AP-1而诱导IL-21的产生, 而后者是维持IL-10表达的重要辅助因子. 虽然在肠道炎症中, IL-27常被认为是通过诱导CD4+ T细胞产生IL-10而发挥免疫抑制作用, 但Dann等[58]发现柠檬酸杆菌可以引起IL-10缺陷小鼠的肠黏膜炎症, 而IL-27可以减轻这一作用, 若中和IL-27则出现严重的结肠炎, 提示除了诱导IL-10, IL-27还有其他途径发挥抑制性作用且是不依赖IL-10的. 虽然IL-27和IL-10都具有抑炎作用, 但IL-27-/-小鼠并不像IL-10-/-小鼠那样会出现自发性结肠炎[59-61], IL-10在维持免疫应答自我平衡中扮有不可或缺的角色. 此外, IL-10主要通过作用于巨噬细胞和DCs来发挥免疫抑制作用, 而IL-27或许可以直接抑制T细胞的活动, 二者具有不同的细胞靶点. 总之, IL-27可能通过影响淋巴细胞IL-10的产生而作为一种炎症负反馈调节机制参与IBD的发病.
固有免疫细胞是连接特异性免疫应答和非特异性免疫应答的桥梁, 控制着效应和调节性T细胞平衡, 在维持机体免疫系统的稳态中发挥重要作用. IL-27也可以调节多种固有免疫细胞的功能[62-64], 有研究[65]报道IL-27可以减少嗜酸性粒细胞的凋亡, 促进其黏附作用及细胞因子和趋化因子的释放. 亦有研究表明IL-27可以增强肥大细胞IL-1和肿瘤坏死因子(tumor necrosis factor, TNF)的产生, 但Kido等[66]做出了相反报道, 研究发现IL-27Rα-/-MRL/lpr小鼠(系统性红斑狼疮模型小鼠)在出现皮肤损害的同时真皮层肥大细胞数量增多, IL-27限制了肥大细胞的活性. NKT细胞方面, IL-27R-/-小鼠体内iNKT细胞减少并表现出对依赖于iNKT细胞的噁唑酮结肠炎模型的抵抗, 而TNBS结肠炎模型未受影响[67], 提示IL-27可以促进NKT细胞的分化及功能. APC方面, 虽然巨噬细胞和DC都可以分泌IL-27, 但IL-27对其调节作用尚待进一步研究. 有研究[68]报道IL-27可以抑制DCs的功能, 在敲除IL-27Rα后, DCs展现出更强的T细胞激活能力, 这或许是IL-27免疫抑制作用的机制之一. Mascanfroni等[69]做出了类似的报道, 鼠DCs的IL-27信号抑制了Th1、Th17细胞应答并减轻了EAE的发生发展, 同时还观察到IL-27能诱导免疫调节分子CD39的表达, 通过降低胞外ATP浓度, 下调NLRP3炎性小体的激活. 另外, IL-27还能促进DCs免疫抑制分子PD-L1的表达, 这可能是其抑制T细胞活化的另一种机制[70]. 然而作用于APCs的IL-27信号似乎不仅仅只有免疫抑制功能, 如Visperas等[71]报道IL-27可作用于APCs并在T细胞转染性结肠炎模型中发挥促炎作用, IL-27Rα−/− TCRβ−/−小鼠肠道组织结构完好, 而IL-27Rα+/+ TCRβ−/−小鼠很快出现了体质量下降及结肠组织炎性细胞浸润, 进一步分析发现, IL-27促进了APCs细胞因子IL-1β和IL-6的产生, 而这有利于Th17细胞的分化及肠道炎症的发生. 由此可推测, IL-27或通过在固有免疫中发挥重要的调节作用而参与IBD的发病.
目前普遍认为, 肠黏膜屏障功能异常是IBD发病的分子基础. IBD发病时肠黏膜屏障功能异常, 肠腔内抗原物质向肠黏膜固有层移位, 进一步激活固有层免疫细胞, 导致肠黏膜异常炎症反应. 肠上皮细胞表达有完整的IL-27受体, 并且可以激活下游多个信号通路, 在肠道炎症发生时, 可以检测到IL-27受体的高表达. 除了对T细胞的作用, IL-27还可以激活肠上皮细胞STAT3及STAT6通路, 促进上皮增殖和黏膜屏障的重建[72]. IL-27还可以诱导肠上皮细胞清道夫受体DMBT1及吲哚胺2,3-双加氧酶1(indoleamine 2,3-dioxygenase 1, IDO1)基因的表达, 促进抗菌蛋白的分泌并抑制肠道微生物的生长[72]. IL-27的上述功能有利于肠屏障功能的维持, 减少黏膜层微生物对固有免疫细胞的刺激, 因此是肠黏膜屏障的保护因子之一.
IL-27作为免疫调节因子可以诱导Th1、Tr1, 但抑制Th2、Th17和Treg的分化和功能. 然而在某些情况下, IL-27对特定T细胞亚型可能具有相反作用, 例如抑制Th1或促进Treg的产生和激活. 因此IL-27并不是单纯的抗炎或促炎细胞因子, 在免疫反应的不同阶段及不同微环境下不同通路的激活很可能是导致IL-27发挥免疫促进或者抑制作用的决定性因素. IL-27作为一种新型的细胞免疫调节因子参与了IBD的发病过程, 有望为IBD的临床治疗提供新靶向.
炎症性肠病(inflammatory bowel disease, IBD)是一组反复发生的慢性肠道非特异性炎症, 其发病机制并不十分清楚, 然而免疫调节异常被认为是该病发病的关键因素. 白介素-27(interleukine-27, IL-27)是IL-12家族的新成员, 能够调节多种T细胞亚型的功能, 在自身免疫性疾病中具有重要的免疫调节作用. 近年研究发现白介素-27与IBD的发生、发展关系密切.
崔梅花, 主任医师, 航天中心医院消化科, 北京大学航天临床医学院; 缪应雷, 主任医师, 昆明医科大学第一附属医院消化内科
IL-27在IBD中具有促炎和抗炎双重属性, 其与IBD中的异常免疫调节密切相关, 有望成为疾病治疗的新靶点.
2014年Hanson等创新性地给予小鼠口服能分泌重组IL-27的乳酸乳球菌, 并观察到IL-10水平的上升及结肠炎症的减轻. 进一步揭示了IL-27与IL-10在炎症反应中的异同之处.
在介绍IL-27基本概念、结构及其生物学功能的基础上, 重点阐述了其与IBD中的免疫异常在不同方面的关系, 同时指出目前研究的不完善之处.
IL-27在多种自身免疫性疾病的发病机制中扮有重要角色, 是潜在的治疗靶点. 目前主要通过各种相关疾病模型开展对IL-27的研究, 总结这些结论益于指导IL-27在人自身免疫性疾病中的相关研究.
肠黏膜屏障: 是指将肠腔内细菌、食物抗原等物质与肠黏膜固有层免疫细胞隔离以避免固有层内免疫细胞激活的肠黏膜结构, 主要由肠黏膜表面的黏液层、上皮细胞层、黏膜基底层构成.
本文从IL-27与各类致炎因子之间的作用机制进行叙述, 资料丰富, 选题新颖, 构思良好, 具有一定学术价值.
编辑: 郭鹏 电编: 闫晋利
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