Th17、IL-17在幽门螺杆菌相关性胃癌中的研究进展

摘要

辅助性T细胞17(T helper cell 17, Th17)是一种新发现的CD4⁺ T细胞亚型, 他以分泌白介素17(interleukin 17, IL-17)和表达转录因子RORγ为特征, 在机体各种肿瘤和感染性疾病中起着重要作用. 胃癌是一种与慢性幽门螺杆菌(Helicobacter pylori, H. pylori)感染密切相关的恶性肿瘤, 死亡率极高. 研究发现, Th17及其分泌的IL-17在H. pylori感染所致的慢性萎缩性胃炎、胃溃疡、不典型增生、肠上皮化生及胃癌的发生、发展中起着不可忽视的作用, 相关研究为胃癌的早期诊断、个性化防治、瘤苗开发和预后评价提供了新思路.

关键词: 辅助性T细胞17; 白介素17; 幽门螺杆菌; 胃癌; 癌前病变

Role of Th17 and IL-17 in Helicobacter pylori-related gastric carcinogenesis

Wei Li, Zhen Yang, De-Qiang Huang, Nong-Hua Lv

Wei Li, Zhen Yang, De-Qiang Huang, Nong-Hua Lv, Department of Gastroenterology, the First Affiliated Hospital of Nanchang University; Gastroenterology Institute of Jiangxi Province; Jiangxi Provincial Key Laboratory for Digestive Diseases, Nanchang 330006, Jiangxi Province, China

Correspondence to: Nong-Hua Lv, Professor, Chief Physician, Department of Gastroenterology, the First Affiliated Hospital of Nanchang University; Gastroenterology Institute of Jiangxi Province; Key Laboratory of Digestive Diseases of Jiangxi Province, 17 Yongwaizheng Avenue, Nanchang 330006, Jiangxi Province, China. lunonghua@163.com

Received: January 20, 2012
Revised: February 18, 2012
Accepted: March 6, 2012
Published online: April 18, 2012

Abstract

T helper 17 (Th17) cells are a newly defined subset of CD4⁺ effecter T cells characterized by the secretion of interleukin 17 (IL-17) and transcription factor RORγ. They play significant roles in the pathogenesis of various tumors and bacterial infectious diseases. Gastric carcinoma is closely related to Helicobacter pylori (H. pylori) infection and has a very high mortality. Evidence shows that both Th17 and IL-17 play critical roles in the pathogenesis of H. pylori-associated gastric carcinoma and precancerous lesions. Elucidation of the roles of Th17 and IL-17 in H. pylori-related gastric carcinogenesis will provide new clues to the early diagnosis, personalized prevention and immunotherapy, vaccination and prognostic evaluation of gastric carcinoma.

Key Words: T helper cell 17; Interleukin 17; Helicobacter pylori; Gastric carcinoma; Precancerous lesions

0 引言

胃癌是一种最常见的消化系恶性肿瘤, 死亡率高居全球癌症第2位, 其发生是一个多因素、多步骤的过程. 幽门螺杆菌(Helicobacter pylori, H. pylori)作为体内最常见的一种慢性感染, 与胃癌及癌前病变的关系密切[1]. 目前, H. pylori致癌的确切机制尚不明晰, 加之早期胃癌的诊断困难、临床治疗的效果不佳, 使得H. pylori相关性胃癌的防治工作任重道远[2]. 辅助性T细胞17(T helper cell 17, Th17)是一种新发现的CD4⁺ T细胞亚型, 与其分泌的白介素17(interleukin 17, IL-17)共同参与了H. pylori感染的胃黏膜炎症反应[3]. 研究发现, H. pylori感染患者体内IL-17 mRNA表达水平显著升高[4], IL-17A、IL-17F基因多态性与H. pylori感染性胃癌密切相关[5]. 此外, 胃腺癌患者肿瘤内IL-17低表达还可提示预后不良[6]. 近年来, Th17及IL-17在H. pylori相关性胃癌中所发挥的作用越发受到关注, 本文就相关研究报道作一综述.

1 Th17细胞及其细胞因子IL-17概述

Th17细胞是一类新发现的辅助性CD4⁺ T细胞亚型, 活化后可分泌IL-17A、IL-6、TNF-α等细胞因子, 并且表达转录因子RORγ, 在机体多种肿瘤和慢性感染性疾病中起着关键性作用[7,8]. IL-17家族包括IL-17A(即通常所说的IL-17)、IL-17B、IL-17C、IL-17D、IL-17E(IL-25)和IL-17F, IL-17可以上调IL-6、转化生长因子β(transforming growth factor β, TGF-β)、肿瘤坏死因子α(tumor necrosis factor α, TNF-α)的表达, 启动炎症级联反应. 此外, IL-17还可以参与中性粒细胞的增殖、成熟和趋化, 激活T细胞防御功能, 在肿瘤防御方面起着重要作用[9]. 研究发现, IL-17在H. pylori感染导致的胃黏膜恶性病变中起着不可忽视的作用[10].

2 Th17及IL-17表达的上游调控因子

2.1 TGF-β和IL-6是Th17细胞分化的必需因子

Veldhoen等[11]提出, TGF-β在诱导初始T细胞分化为Th17细胞过程中起着关键作用. IL-6是信号转导及转录激活因子3(signal transducers and activators of transcription 3, STAT3)的激活物, 而STAT3的激活能够诱导IL-17的高表达, TGF-β和IL-6能够取代活化的树突状细胞(dentritic cell, DC)培养液, 诱导初始T细胞分化为Th17[12].

2.2 IL-23是Th17细胞分化的诱导因子

IL-23由DC等分泌, 参与介导STAT3磷酸化, 刺激Th17细胞分泌IL-17[13]. 但IL-23只能促进记忆性Th17细胞增殖并维持其活性, 却不能诱导初始T细胞分化为Th17细胞[14,15].

2.3 IFN-γ、IL-4和IL-27是Th17细胞分化的抑制因子

干扰素γ(interferon γ, IFN-γ)和IL-4可以通过抑制TGF-β1下游Smad3的磷酸化作用, 从而抑制TGF-β1对Th17分化的诱导作用[16]. IL-27通过与IL-27受体链和gp130受体链组成的复合物结合, 对Th17进行负反馈调节[17].

2.4 ROR-γt是促进Th17分化的主要转录因子

研究发现, ROR-γt可以通过染色体重塑开放IL-17基因座位, 并促进其他因子与IL-17启动子相结合, 由此上调IL-17的表达水平[18]. 此外, ROR-γt还可以通过调节IL-23/IL-23R轴来诱导Th17的分化[19].

此外, IL-1β、IL-21对Th17、IL-17表达水平的上调作用和IL-2、IL-10对Th17分化的负调节作用, 均有所报道[8-14].

3 Th17及IL-17在H. pylori致癌过程中的作用

胃癌的发病是由H. pylori、环境、宿主等多种因素共同决定的, 且H. pylori与宿主之间的相互作用在H. pylori致癌过程中起着关键性作用[20]. 近年来, 大量论著证实了以Th17/IL-17为中心的免疫反应与H. pylori感染相关的胃黏膜恶性病变关系密切.

3.1 H. pylori感染与胃黏膜组织病理损伤

目前, H. pylori致癌的确切机制仍疑云重重. 现有研究主要围绕着宿主免疫介导的黏膜损伤、H. pylori毒力因子(尿素酶、黏附素、CagA、VacA、iceA等)、p53基因突变、ROS致DNA损伤、环氧合酶-2(COX-2)高表达等方面展开[21,22]. 就宿主抗感染的免疫损伤方面来说, H. pylori诱发胃癌的可能机制包括慢性炎症、免疫逃避和免疫抑制3部分[23]. Müller等[24]指出, H. pylori能够破坏并操纵Th细胞的信号转导通路从而抑制免疫应答, 利于持续感染, 导致不同程度的胃黏膜损伤.

3.2 H. pylori免疫逃逸

近年来, 不少学者针对H. pylori能够在免疫功能完好的宿主胃黏膜长期定植的机制进行了研究. Lewis等[25]发现, H. pylori可以通过诱导精氨酸酶-Ⅱ的表达来下调巨噬细胞一氧化氮合酶(NOS)的翻译水平, 从而进行免疫逃逸. Solnick等[26]认为, H. pylori能够积极地改变胞壁表面抗原, 以逃避宿主T细胞介导的免疫反应. 此外, Kao等[27]指出, H. pylori能够促进调节性T细胞(Treg)的分化, 从而使Th17所驱动的免疫反应受抑制, 利于持续感染.

3.3 Th17、IL-17对H. pylori感染的免疫应答

近年来, 大量研究关注于Th17细胞针对H. pylori所产生的特异性保护作用, 认为这主要是通过诱导中性粒细胞活化来发挥作用的. Akhiani等[28]提出, 细菌抗原刺激巨噬细胞和DC产生大量的IL-6与TGF-β, 共同诱导初始T细胞分化、成熟. 另外, H. pylori尿素酶B(UreB)也能诱导IL-17因子的表达[29]. 此外, IL-1β和TNF-α能促进TGF-β和IL-6对Th17细胞的诱导作用, 但不能取代TGF-β和IL-6[30]. 活化后的Th17细胞分泌IL-17、IL-6、TNF-α、IL-22等细胞因子发挥抗感染免疫应答.

3.3.1 IL-17(IL-17A): Sebkova等[31]采用IL-17分别刺激胃癌细胞MKN28和H. pylori感染的正常胃上皮细胞, 均发现细胞外信号调节蛋白激酶1/2(ERK1/2)、激活蛋白-1(AP-1)、核因子κβ(NF-κβ)被激活, 启动了炎症瀑布反应. IL-17还可以诱导细胞间粘附因子的表达, 促进T细胞反应[32]. 此外, IL-17可以刺激成纤维细胞过度表达MMPs, 引起黏膜损伤[33].

3.3.2 IL-6: IL-6能够促进B细胞增殖分化, 诱导抗体分泌[34], 还可以促进造血干细胞增殖, 诱导中性粒细胞活化, 参与炎症反应[35].

3.3.3 TNF-α: TNF-α能够促进IL-2α、IFN-γ的表达, 并激活CTL, 诱导肿瘤细胞凋亡. Mosaffa等[36]发现广谱抗肿瘤物ABCG2短期(72 h)作用于胃癌细胞后可以导致TNF-α、IL-6、IL-1β的表达水平下降.

3.3.4 IL-22: IL-22可以促进C-反应蛋白(CRP)和抗菌肽的生成, 参与宿主上皮屏障的防御作用[37].

3.4 Th17与IL-17在H. pylori致癌过程中的作用

大量动物实验发现, 在H. pylori感染早期, 小鼠体内IL-17A和IL-22的mRNA水平显著升高, 此外, TNF-α、IL-17的外周血水平也有所升高[38,39]. Oertli等[40]指出, 小鼠体内Th17细胞介导的免疫应答水平与H. pylori感染所致的慢性萎缩性胃炎、异型增生和肠上皮化生有所关联. Allen等[41]在H. pylori慢性感染致胃炎的小鼠模型中发现, IL-17能够通过激活Ras/MAPK信号通路, 参与调节H. pylori感染所激活的单核巨噬系统应答水平. Flach等[42]发现, 小鼠胃黏膜的H. pylori感染水平和TNF、IL-12p40、IL-17、IFN-γ表达之间呈现明显的负相关. 还有研究采用多种细胞因子抑制剂腹腔注射的方法来比较各因子在H. pylori感染中发挥的作用, 发现尽管Th1活性有所增强, 但只有Th17分泌的IL-17所起的中和作用与H. pylori定植有关, 表明以IFN-γ为基础的IL-17免疫应答在抗H. pylori方面比TNF更为重要[43]. 然而, DeLyria等[44]在早期采用H. pylori主动免疫小鼠后, 检测到Th17细胞大量生成并发挥重要的免疫保护作用. 可进一步的实验结果却出人意料, 小鼠体内IL-17表达水平的上升反而伴随着H. pylori定植数量的增多. Olivares等[45]发现, 实验小鼠在中和IL-17和IL-17A受体基因靶位的控制下, 胃炎、胃溃疡、胃癌等检出率更高. Rolig等[46]采用免疫荧光法检测到, 具有诱导细胞凋亡作用的H. pylori趋化性突变体che(-)细胞内Th17 mRNA呈低表达, 且Th17针对H. pylori感染的免疫反应是由伴随着细菌感染的细胞凋亡信号所驱动的.

在临床方面, Jafarzadeh等[47]发现H. pylori感染阳性患者的IL-17、IL-23血清水平比阴性组明显升高, 并且IL-17的表达受cagA影响. Harris[48]和Freire[49]等研究组均发现H. pylori感染阳性的胃炎患者体内IL-17A、IL-23的水平以及Foxp3(+)细胞数量均大幅升高, 在儿童中尤为显著. Zhang等[50]发现胃癌患者比健康志愿者的外周血Th17检出水平更高, 且与晚期胃MALT淋巴瘤的关系尤为密切. 此外, 胃癌进展期患者接受治疗后, IL-17、IL-23p19、RORγ在肿瘤组织和外周血的浓度均显著增加. Mizuno等[51]对36例伴溃疡(GU)和29例非溃疡(NU)的H. pylori感染患者及H. pylori阴性对照者进行研究发现, IL-17和IL-8的表达水平: GU组>NU组>空白组; GU患者每个活检部位(溃疡: R = 0.62, P<0.0001; 胃窦: R = 0.61, P<0.0001). Zhou等[52]对人胃腺癌细胞AGS中IL-17A介导的细胞内信号通路进行了研究, 发现IL-17A能够激活3条MAPK通路(ERK, P38和JNK)和下游转录因子AP-1和P65 NF-κB并且可以诱导IL-8的表达, 提示IL-17与下游IL-17R的结合可以激活介导胃黏膜炎症和癌变发生的关键信号通路. Chen等[53]对192例胃腺癌手术切除标本进行研究发现, 肿瘤内IL-17高表达的胃腺癌切除患者5年存活率明显高于IL-17低表达者, COX多元风险分析提示, 肿瘤内IL-17表达水平是一个影响5年总体存活率的独立因子, 肿瘤内IL-17的低表达可能提示预后不良. Shibata等[54]对811例(胃癌287例, 非胃癌524例)H. pylori感染患者进行检测发现, IL-17A(rs2275913 G-197A)等位基因与胃癌病变进程显著相关, 且胃癌组的IL-17A/197A纯合子频率高于非癌组.

4 结论

一直以来, 早期胃癌的诊断较为困难, 临床就诊的胃癌患者多属中晚期, 加之治疗手段局限、H. pylori根除治疗后再感染现象普遍, 这大大加重了胃癌的危险性[55]. Th17细胞亚群的发现, 弥补了H. pylori相关性胃黏膜恶性病变过程中, 宿主Th1/Th2细胞介导免疫反应机制的不足, 相关研究对胃癌的早期检测、个性化防治、瘤苗开发和预后判断究竟具有怎样的实际意义呢? 让我们拭目以待.

评论

背景资料

近年来, 人们对幽门螺杆菌(Helicobacter pylori, H. pylori)与宿主之间的相互作用关系进行了大量研究, 而辅助性T细胞17(T helper cell 17, Th17)在H. pylori致癌过程中所扮演的角色显得日益重要.

同行评议者

陈卫昌, 教授, 苏州大学附属第一医院消化内科

研发前沿

目前, H. pylori致胃癌的确切机制仍不清楚, Th17细胞及其分泌的细胞因子IL-17在机体抗感染免疫反应中发挥了重要作用, 明确Th17、IL-17与H. pylori相关性胃癌之间的关系, 有助于进一步理解H. pylori致胃癌的机制, 为胃癌的防治提供有效的指导.

相关报道

大量研究发现, H. pylori感染的患者体内IL-17 mRNA表达水平显著升高, 且与胃黏膜病理损伤的严重程度高度相关. 此外, IL-17A和IL-17F基因多态性与H. pylori相关性胃癌的关联性, 也得到了证实.

应用要点

进一步明确Th17细胞介导的宿主抗H. pylori慢性感染的免疫应答机制及其在胃黏膜癌变进程中所起的调控作用, 对胃癌及癌前病变的早期监测、个性化防治、肿瘤疫苗开发和预后判断均具有重要意义.

同行评价

本文就Th17和IL-17在H. pylori相关性胃癌的研究方面进行综述, 资料较新颖, 文献量大, 有一定的可读性和科学性, 并有一定的研究参考价值.

备注

编辑: 张姗姗 电编: 鲁亚静

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