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. 2021 Feb 28;46(2):169–175. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2021.190678

白细胞介素-33在肿瘤中的双重作用

Dual role of interleukin-33 in tumors

LIU Qianqian 1,2, LU Di 1, HU Jiahua 1, LIANG Junchao 2, CHEN Huoying 1,✉
Editor: 彭 敏宁
PMCID: PMC10929784  PMID: 33678654

Abstract

Interleukin-33 (IL-33) is a new member of the IL-1 cytokine family which plays roles in the nucleus as a nuclear factor and is released by damaged or necrotic cells to act as a cytokine. It can be released via damaged or necrotic cells and functions as a cytokine. The released IL-33 activates the downstream NF-κB and MAPKs signaling pathways through the isomers of the specific receptor ST2 and the interleukin-1 receptor accessory protein (IL-1RAcP), resulting in danger signals and the activated multiple immune responses. IL-33 is abnormally expressed in various tumors and involves in tumorigenesis, development, and metastasis. Moreover, IL-33 can play both pro-tumor and anti-tumor roles in the same type of tumor.

Keywords: interleukin-33, suppression of tumorigenicity 2, tumor, tumor microenvironment

肿瘤的发生、发展与肿瘤微环境密切相关，细胞因子可通过改变肿瘤微环境及特定的信号转导通路影响肿瘤的进程。白细胞介素-33(interleukin-33，IL-33)作为一种诱导2型T辅助细胞(Type 2 T helper cells，Th2)免疫反应的强有力的新型细胞因子[1]，在肿瘤中的作用逐渐成为人们研究的热点。IL-33在多种肿瘤中异常表达，它可能是一柄双刃剑，一方面诱导肿瘤产生免疫耐受从而促进肿瘤的生长及转移，另一方面通过激活抗肿瘤免疫反应从而抑制肿瘤进展，甚至在同一类肿瘤中可通过作用于肿瘤细胞或不同的免疫细胞同时发挥促肿瘤和抗肿瘤的双重作用。

1. IL-33的结构和分布

2005年，Schmitz等[1]发现了IL-1家族的新成员——IL-33，随后证明IL-33即是2003年报道的高内皮静脉核因子。IL-33的分子结构呈三叶草形，由12股IL-1/成纤维生长因子的β链折叠组成[2]。它广泛表达在皮肤、胃、肠、肺等屏障组织和脊髓、脑等中枢神经系统的细胞中[1]，以及巨噬细胞、树突状细胞(dendritic cells，DCs)、肥大细胞等免疫细胞中[3]。

2. IL-33的双面性

对细胞因子生物学活性的深入研究[4-5]发现：一部分细胞因子扮演着双重角色，它们不仅可以通过自分泌或旁分泌的方式释放到细胞外发挥作用，也可以通过核因子的方式发挥作用。这种类型的细胞因子包括IL-1α、高迁移率族蛋白1(high mobility group box-1 protein，HMGB1)等，IL-33也属于其中的一员(图1)。

图1.

图1

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IL-33的蛋白质结构和双重角色

Figure 1 Protein structure and dual role of IL-33

2.1. IL-33作为核转录抑制因子发挥作用

在生理条件下，IL-33作为转录调节因子，其蛋白质经转录翻译后重新进入细胞核，与基因沉默有关的异染色质和有丝分裂的染色质相关联，因此，IL-33被认为具有核转录抑制因子的作用。研究[1, 6] 发现：IL-33氨基末端的1~65位氨基酸残基是DNA结合蛋白同源盒基因家族之一的螺旋-转角-螺旋(HTH)结构域，这个结构决定IL-33与核内异染色质的结合，是IL-33的核定位信号序列(nuclear localization sequence，NLS)，对IL-33的转录抑制活性的发挥很重要[6]。Roussel等[7]通过突变研究进一步发现：IL-33的40~58位氨基酸残基才是IL-33结合到染色质上的关键序列，并被称为IL-33的染色质结合基序(chromatin binding motif，CBM)。IL-33不仅可以促进组蛋白H2A和H2B相互作用导致染色质致密，还能通过CBM与组蛋白H2A-H2B组成的酸性袋状区域相互作用结合到染色体上，从而对基因表达进行负调控。IL-33的羧基末端具有与IL-1细胞因子家族同源的β-三叶草结构，是IL-33与受体结合的部位[1-2]。

目前IL-33在细胞核内的作用仍是IL-33的最大谜团。十多年来，仅有两个课题组对此进行了研究[8-9]，但得不到令人信服的证据证明核内IL-33能够调节基因或蛋白质的表达。核内IL-33是否具有转录调控功能及转录调控的靶基因，需要在更多的细胞种类中研究和证实。

2.2. IL-33作为细胞因子发挥作用

当细胞发生损伤或坏死时，IL-33作为警报素被释放到细胞外，通过IL-1受体家族的肿瘤发生抑制子2(suppression of tumorigenicity 2，ST2，也被称为IL-1RL1)和IL-1受体辅助蛋白(interleukin 1 receptor auxiliary protein，IL-1RAcP)构成的异构体激活下游的核因子κB(nuclear factor-kappa B，NF-κB)和丝裂原活化蛋白激酶(mitogen activated protein kinases，MAPKs)通路来启动多种免疫反应[10-12]。IL-33以旁分泌或自分泌的方式作用于附近表达ST2受体的免疫细胞。ST2包括sST2，ST2L，ST2V和ST2LV[13] 4种亚型，其中sST2不具有跨膜序列，为可溶型ST2，可分泌到细胞外诱捕IL-33，仅表达于肥大细胞和成纤维细胞中。ST2L具有跨膜序列，为跨膜型ST2，不能分泌到细胞外，表达于成纤维细胞、肥大细胞、嗜酸性粒细胞、Th2细胞、DCs、自然杀伤细胞(natural killer cells，NKs)、自然杀伤T细胞(natural killer T cells，NKT细胞)等，并可在Th1、Th17、调节性T细胞(regulatory T cells，Tregs)、CD8+ T细胞、巨噬细胞和髓系来源的抑制性细胞(myeloid-derived suppressor cells，MDSCs)中诱导产生[12,14-17]。IL-33可通过ST2L直接调控以上免疫细胞的数量和功能，也可通过促进趋化因子和细胞因子的产生间接调控这些免疫细胞的功能。因此，IL-33被认为是一个多功能的细胞因子。

3. IL-33在肿瘤中的双重作用

近年来，IL-33在肿瘤免疫中的作用及其机制备受关注。大量研究[18-21]表明：IL-33参与胃癌、结肠癌、肺癌、胰腺癌、乳腺癌、肝癌、卵巢癌、巨细胞癌等多种肿瘤的发生和发展，与胃癌、肺癌、胰腺癌等的诊断、治疗或预后相关。研究[19,22-24]显示：IL-33在肿瘤免疫中发挥双重作用。一方面它与肿瘤的发生、增殖及转移有关，另一方面它又能激活机体免疫效应机制从而抑制肿瘤的生长。

3.1. IL-33与肺癌

3.1.1. 在肺癌中的促肿瘤作用

IL-33可促进肺癌尤其是非小细胞肺癌(non-small cell lung cancer，NSCLC)的生长和转移。Wang 等[25]发现：IL-33及其受体ST2在NSCLC的肿瘤细胞而非浸润淋巴细胞中高表达，且IL-33和ST2的表达均与疾病进展密切相关。过表达IL-33可促进NSCLC的生长和转移，反之则抑制。同时，NSCLC患者血清中IL-33含量显著高于健康对照者，IL-33可作为评估疾病恶性分型、分期与病情进展的潜在指标，为其应用于临床治疗提供了一定的理论依据[26]。在临床前模型中可通过直接和间接途径抑制IL-33的表达进而抑制肺癌的生长，这也验证了IL-33在肺癌中的促肿瘤作用[27]。

IL-33/ST2信号作用于肿瘤细胞时，可发挥促肺癌生长和转移的作用，如：1)IL-33/ST2信号可通过上调NSCLC肿瘤细胞膜上葡萄糖转运蛋白1的表达，增加肿瘤细胞的葡萄糖摄取和糖酵解，进而促进NSCLC的生长和转移[25]。2)IL-33/ST2信号可激活蛋白激酶B(protein kinase B，PKB/AKT)-MMP-2/9通路，从而促进A549肺癌细胞的迁移和侵袭[28]。3)Akimoto等[29]发现：Lewis肺癌中的低转移性细胞而非高转移性细胞表达功能性ST2L。IL-33诱导ST2L+的低转移细胞死亡，使ST2L-的高转移细胞存活下来，从而促进肺癌生长和转移。

此外，IL-33/ST2信号还可作用于免疫细胞，发挥促肿瘤的免疫调节作用，如：1)IL-33通过增加巨噬细胞中抗菌肽LL-37的表达来加重肺癌的炎症，从而促进肺癌细胞的体外增殖[30]。2)IL-33依赖的2型先天淋巴细胞(Type 2 innate lymphoid cells，ILC2)被激活后通过抑制肺部NKs介导的先天性抗肿瘤免疫力来促进Lewis肺癌的转移，IL-33的靶向治疗可逆转NKs抑制并减轻癌症负担[31]。3)阻断IL-33/ST2信号可抑制M2型肿瘤相关巨噬细胞(M2 tumor-associated macrophages，TAMs)的极化，减少Tregs在NSCLC肿瘤微环境中的积累，从而形成功能性免疫监视[27]，从反面证明IL-33/ST2通过诱导免疫抑制，使肺癌细胞逃避免疫杀伤。

3.1.2. 在肺癌中的抗肿瘤作用

IL-33也能发挥抑制肺癌进展的作用。Akimoto 等[29]和Yang 等[32]分别报道：与正常肺组织和细胞相比，IL-33与ST2在肺腺癌、肺鳞状细胞癌等多种肺癌组织及肺癌细胞系中表达下降，且与肺癌的进展呈负相关。肺癌患者血清IL-33含量低于健康对照者，亦与肺癌的进展呈负相关[33]。IL-33主要通过激活抗肿瘤免疫来抑制肺癌的进展，如：1)IL-33激活NF-κB信号通路，促进CD8+ T细胞和NKs的增殖、活化和浸润，从而减少Lewis肺癌小鼠模型中肿瘤的肺转移[34]。2)IL-33通过MyD88途径促进DCs的分化和成熟，增加CD8+ T细胞和NKs的抗肿瘤免疫力，并抑制肺癌细胞的增殖和生长[35]。3)IL-33还可通过上调圆柱瘤蛋白(CYLD)的表达来促进DCs诱导的T细胞增殖和IL-17分泌，从而介导肺腺癌的免疫调节，明显抑制肿瘤的生长[36]。

3.2. IL-33与乳腺癌

3.2.1. 在乳腺癌中的促肿瘤作用

IL-33/ST2信号通路与乳腺癌的进展密切相关。Liu 等[37]研究发现：乳腺癌患者癌组织中IL-33的表达水平高于同一患者的正常乳腺组织，并与分化良好的表型、人表皮生长因子受体2(human epidemal growth factor receptor 2，HER2)过表达、更多淋巴结受累、恶性肿瘤家族史有关。Hu等[38]研究发现：在乳腺癌患者中，较高的血清IL-33水平预示着晚期临床分期、分化差的癌细胞和肿瘤复发。

同样，IL-33/ST2信号作用于肿瘤细胞时，可发挥促乳腺癌进展的作用，如：1)IL-33通过与正常上皮和乳腺癌细胞中的ST2-大阪甲状腺癌激酶(cancer Osaka thyroid，COT)相互作用促进COT的磷酸化，IL-33/ST2/COT级联信号诱导肿瘤微环境中癌症相关炎症，促进乳腺上皮细胞增殖和肿瘤发生[39]。2)IL-33可通过诱导肿瘤干细胞，促进乳腺癌的内分泌抵抗[38]。3)IL-33/ST2信号通路还可促进肿瘤细胞表达VEGF，减少肿瘤细胞坏死[40]。

另一方面，IL-33/ST2信号可影响肿瘤微环境中免疫细胞的浸润和应答，促进乳腺癌的进展和转移。IL-33/ST2信号通路通过增加免疫抑制细胞MDSCs的瘤内积累，减少NKs的浸润，减弱机体的先天抗肿瘤免疫力，进而促进乳腺癌的生长和转移[41]。癌症相关的成纤维细胞来源的IL-33可以上调Th2型炎症，诱导促转移的肿瘤微环境的形成，促进乳腺癌的肺转移[42]。在ST2-/-小鼠中乳腺癌的进展和转移被抑制，这主要与NKs的细胞毒性增强和全身Th1/Th17细胞因子的增加有关，反向证明IL-33/ST2的促乳腺癌作用[43]。更有研究[44]使用重组病毒样颗粒(VLP)递送IL-33蛋白对乳腺癌小鼠进行抗IL-33主动免疫，有效重塑了肿瘤微环境并增强了抗肿瘤免疫反应，显著抑制原位肿瘤的生长，也反向证明了IL-33的致瘤作用。

3.2.2. 在乳腺癌中的抗肿瘤作用

有关IL-33抗乳腺癌的报道不多。在研究IL-33是否具有抗肿瘤活性时，Gao等[45]发现：肿瘤细胞来源的IL-33可通过促进NKs和CD8+ T细胞产生干扰素-γ(interferon-γ，IFN-γ)，抑制小鼠乳腺癌的生长和转移。Qi等[46]也报道：IL-33可以诱导NKs的局部募集和全身活化，有效抑制小鼠乳腺癌的肺转移，进一步表明IL-33/ST2信号主要通过激活抗肿瘤免疫反应发挥抑制肿瘤的作用。

3.3. IL-33与结直肠癌

3.3.1. 在结直肠癌中的促肿瘤作用

IL-33/ST2信号通路参与结直肠癌的生长和转移。IL-33及其受体ST2在腺瘤和结直肠癌基质细胞和癌细胞中均表达增加[47-48]，且在人较低级别和早期结直肠癌中表达更高[49]。在结直肠癌小鼠模型和发生肠道肿瘤的ApcMin/+转基因小鼠模型中，增强IL-33/ST2的信号转导可促进结直肠癌的生长和转移，反之则抑制[48-50]。

IL-33/ST2在结直肠癌中的作用取决于IL-33的来源和其作用的细胞。Maywald等[48]在ApcMin/+转基因小鼠模型中发现来源于肠上皮的IL-33通过协调激活基质细胞和促肿瘤微环境的形成来促进肿瘤的发展。Zhang等[51]也发现：肿瘤来源而不是宿主来源的IL-33通过动员细胞因子的表达和促进CD11b+GR1+及CD11b+F4/80+骨髓细胞的募集来重塑肿瘤微环境，并激活内皮细胞，促进肿瘤血管生成，从而促进小鼠结直肠癌的生长和肝转移。在腺瘤和结直肠癌的基质中也发现IL-33+和ST2+微血管的密度增加[47]，表明调节肿瘤血管生成也是IL-33/ST2促进结直肠癌恶性转化的一个重要方式。IL-33作用于人结直肠癌细胞并促进其表达IL-6、趋化因子受体(CXCR)4、MMP-2和MMP-9[52]，这些因子具有促肿瘤转移作用。IL-33还可作用于肿瘤微环境中的免疫细胞，如促进ST2+ Treg的增殖和浸润，诱导Th2细胞因子的生成，以及调控肠道巨噬细胞的M1和M2极化，从而有利于结直肠癌细胞的生长[50, 53]。

此外，在肠道这个特殊屏障中，IL-33还可通过调控肠道屏障和微生物菌群影响结直肠癌的进展，如IL-33/ST2信号通路的激活破坏了肠道屏障的完整性，并诱导免疫细胞分泌促肿瘤发生的IL-6[49]。IL-33还可调节肠道抗微生物肽的表达，从而促进结肠肿瘤的进展[50]。

3.3.2. 在结直肠癌中的抗肿瘤作用

IL-33抗结直肠癌的方式也与IL-33的来源和其作用的细胞有关。IL-33可诱导结肠癌细胞表达趋化因子CCL2，从而募集巨噬细胞。在结肠癌小鼠模型中，ST2敲除使肿瘤局部的巨噬细胞浸润减少，导致肿瘤生长增强[54]。在过表达IL-33的小鼠结直肠癌细胞CT26形成的移植瘤中，IL-33的局部分泌产生了大量具有强效抗肿瘤活性的ILC2。IL-33促进ILC2分泌大量CXCR2配体，诱导表达CXCR2的肿瘤细胞特异性凋亡[55]，表明肿瘤细胞分泌的IL-33也可作用于肿瘤微环境中具有抗肿瘤免疫效应的免疫细胞进而发挥抑制肿瘤的作用。还有研究[56]报道敲除IL-33后，CD8+ T细胞和Treg比例失衡，CD8+ T细胞的活化及抗肿瘤免疫力被损害，使小鼠结肠癌细胞C26形成的移植瘤生长加速[56]。IL-33治疗可减慢结直肠癌的生长以及向肺和肝的转移，机制包括IL-33诱导嗜酸性粒细胞的募集、活化和脱颗粒[57]，促进淋巴细胞上CD40L的信号转导及CD4+ T细胞的活化[58]。同样，IL-33还可能通过调控肠道微生物稳态抑制结直肠癌的进展，如Malik等[59]发现：IL-33可促进B细胞产生IgA以维持肠道微生物稳态，并抑制IL-1α依赖性结肠炎和结肠炎相关癌症的进展。

3.4. IL-33与黑色素瘤

3.4.1. 在黑色素瘤中的促肿瘤作用

近年来，黑色素瘤成为发病率增长最快的恶性肿瘤之一。IL-33能促进黑色素瘤的生长与转移。Gao等[45]在研究IL-33的抗肿瘤活性时发现：在小鼠移植瘤模型中，尽管肿瘤表达的IL-33可诱导强烈的I型免疫应答和抑制肿瘤生长，但同时也促进脾脏中ST2+ Treg的增殖和肿瘤中ST2+ Treg的浸润，这是有利于黑色素瘤生长的。IL-33/ST2轴还可通过激活黑素瘤细胞中的ERK1/2-MMP-2/9通路调节血管生成拟态，进而促进黑色素瘤的发展[60]。可见，重塑肿瘤微环境和诱导血管生成是IL-33/ST2促进黑色素瘤生长的重要方式。在III期黑色素瘤患者中，血清IL-33水平明显升高，证明了IL-33与黑色素瘤转移的相关性[61]。IL-33预处理可通过降低CD8+ T细胞的细胞毒性和增强Treg的免疫抑制作用来促进小鼠黑色素瘤的转移[61]。

3.4.2. 在黑色素瘤中的抗肿瘤作用

IL-33对黑色素瘤具有较好的抗肿瘤活性，这主要是通过调节多种免疫细胞的增殖、活化和浸润来实现的。IL-33可激活NF-κB信号通路，促进NKs和CD8+ T细胞的增殖、活化和浸润[34]，肿瘤细胞分泌的IL-33还可促进NKs和CD8+ T细胞产生IFN-γ[45, 62]，从而抑制小鼠黑色素瘤的生长和转移。在小鼠黑色素瘤移植瘤模型中，Dominguez等[62]揭示了一种新的IL-33-ST2-MyD88-STAT1轴，它可以在已长成的肿瘤中恢复髓样树突状细胞(marrow-derived dendritic cells，mDC)的激活和成熟，从而恢复抗肿瘤免疫反应的强度。IL-33能够募集和激活ST2+的嗜酸性粒细胞[63-64]和ILC2[55]，从而有效杀死黑色素瘤细胞，抑制其生长和转移。IL-33还可诱导肿瘤局部浸润的MDSCs表达主要组织相容性复合体(major histocompatibility complex，MHC)II类分子，从而提高肿瘤微环境的免疫原性[45]，并抑制MDSC的分化和免疫抑制活性，进一步抑制小鼠黑色素瘤移植瘤的生长[65]。

4. 结 语

IL-33的异常表达与肺癌、乳腺癌、结直肠癌、黑色素瘤等肿瘤的恶性程度密切相关，提示IL-33可能是肿瘤诊断和预后的重要生物学标志及治疗靶点。IL-33可通过多种作用方式影响肿瘤的进展。一方面，IL-33可作用于表达ST2的肿瘤细胞，直接影响肿瘤细胞的发生、存活、增殖和转移；另一方面，IL-33/ST2信号还可作用于肿瘤微环境中的多种免疫细胞，调控它们的增殖、活化、浸润及细胞因子的产生等，进而影响肿瘤的进展[22]。IL-33来源的复杂性也是影响其作用的一个重要方面。一般而言，肿瘤细胞来源的IL-33可通过促进NKs和CD8+ T细胞介导的I型免疫应答、促进ILC2和嗜酸性粒细胞在肿瘤局部的聚集，从而发挥抗肿瘤作用；而肿瘤基质细胞和血清(或宿主)来源的IL-33则可诱导M2型巨噬细胞极化，促进Tregs和MDSCs聚集到肿瘤局部，并增加促肿瘤细胞因子的产生，重塑肿瘤微环境，从而促肿瘤进展。因此，影响IL-33在肿瘤中作用的因素是多方面的。IL-33是发挥抗肿瘤还是促肿瘤作用，与IL-33的来源、IL-33作用的细胞种类及肿瘤微环境中浸润免疫细胞和细胞因子的类型密切相关。

然而，现有研究大多关注IL-33作为细胞因子的功能，而其作为核因子，在核内的作用及定位的变化对肿瘤发生、发展的影响远未阐明。核内IL-33功能的阐明对于进一步理解IL-33在肿瘤进展中作用的复杂性具有重要意义。

利益冲突声明

作者声称无任何利益冲突。

Funding Statement

国家自然科学基金(81860474)；广西自然科学基金(2018GXNSFBA281036)；广西高校中青年教师基础能力提升项目(2018KY0411)。

This work was supported by the National Natural Science Foundation (81860474), the Natural Science Foundation of Guangxi Zhuang Autonomous Region (2018GXNSFBA281036), and the Basic Professional Ability Improvement Project for Young and Middle-aged Teachers of Colleges and Universities of Guangxi Zhuang Autonomous Region (2018KY0411), China.

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202102169.pdf

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