张婷娟#, 巫芮#, 方仁东
西南大学动物科技学院, 重庆 400715
收稿日期：2017-08-20；修回日期：2017-11-02；网络出版日期：2017-11-28
基金项目：国家自然科学基金（31400762）；重庆市科委专项（cstc2015jcyjBX0108）；中央高校基本科研业务费专项资金（XDJK2017A003，XDJK2017D033）；重庆高校创新团队建设计划项目（CXTDG201602004）
*通信作者：方仁东, Tel/Fax:+86-23-68251196, E-mail:frend023@hotmail.com
#并列第一作者
摘要：白细胞介素-1α（Interleukin-1α，IL-1α）是IL-1家族中重要的一员。IL-1α是广泛存在于机体中的多功能信号分子，在胞内作为重要的转录因子，调控细胞生长分化；同时可分泌至胞外参与机体炎症应答，在癌症等多种疾病的发生发展中发挥着重要的作用。IL-1α前体和成熟形式都具有生物活性，但成熟形式的IL-1α生物活性大大增强。IL-1α是许多疾病预防治疗的靶标，其成熟与分泌的机制也备受关注。近年的研究表明，病原体感染宿主诱导IL-1α的成熟与分泌受细胞内钙离子浓度及钙蛋白酶活性的调控，部分情况下还有炎症小体信号途径及其他信号途径等。本文将结合本课题组的研究成果对IL-1α的成熟与分泌机制及相关研究进行综合评述。
关键词： IL-1α 钙蛋白酶 炎症小体 成熟与分泌
Research progress in the mechanism of IL-1α maturation and secretion
Tingjuan Zhang#, Rui Wu#, Rendong Fang
College of Animal Science and Technology, Southwest University, Chongqing 400715, China
Received 20 August 2017; Revised 2 November 2017; Published online 28 November 2017
*Corresponding author: Rendong Fang, Tel/Fax: +86-23-68251196; E-mail: frend023@hotmail.com
Supported by the National Natural Science Foundation of China (31400762), by the Chongqing Science and Technology Commission (cstc2015jcyjBX0108), by the Fundamental Research Funds for the Central Universities (XDJK2017A003, XDJK2017D033) and by the Innovation Team Building Program in Chongqing Universities (CXTDG201602004)
#These authors contributed equally to this work
Abstract: Interleukin 1 alpha (IL-1α) is a cytokine of the interleukin 1 family which is existed in many kinds of cells. It is a widespread multiple functional signaling molecule. As an important transcription factor inside the cell, IL-1α can regulate cell growth and differentiation; and secreted extracellular IL-1α can be involved in the host inflammatory responses. Furthermore, IL-1α plays distinct roles in the occurrence and development of cancer and various diseases. Although both the proform and the cleaved form of IL-1α are biologically active, the activity of cleaved form is more enhanced. IL-1α is a potential candidate target for the prevention and treatment of various diseases. Therefore, researchers have paid much attention to the mechanism of IL-1α maturation and secretion. Recent studies have shown that the maturation and secretion of IL-1α are modulated by intracellular calcium concentration and calpain activation. Inflammasome and other signaling pathways might also be involved. In this review, the latest research progresses in the structure and function, the mechanism of maturation and secretion of IL-1α and the relevant diseases are discussed.
Key words: IL-1α calpain inflammasome maturation and secretion
白细胞介素-1α (IL-1α)是一种广泛表达于多种细胞中的组成型蛋白，与IL-1β同属IL-1家族，二者具有一定的相似性，均可与细胞表面受体IL-1R1结合[1]。与IL-1β不同，IL-1α以分泌形式或膜结合形式存在，其前体(pro-IL-1α)和成熟形式都具有生物活性。IL-1α是一种多功能分子，在胞内可作为转录因子，促进相关基因表达；在胞外参与机体炎症反应，在抗微生物感染中发挥着重要的作用，同时参与自发炎症及肿瘤等疾病的发生发展。因此，IL-1α是预防治疗相关疾病的重要靶标。近年来，关于IL-1α的诱导表达，特别是其成熟与分泌机制的研究有了较大进展。本课题组前期也研究并报道了肺炎链球菌、结核分枝杆菌等感染宿主诱导IL-1α的成熟与分泌的详细机制[2-3]。本文将结合课题组的最新研究成果对IL-1α的结构与功能、成熟与分泌机制等进行总结评述和展望。
1 IL-1α的结构与功能 1.1 IL-1α的结构 IL-1α在大多数休眠非造血干细胞中组成性表达，例如位于胃肠道、肝脏、肾脏和表皮等上皮细胞[4-5]。IL-1α在核内首先经转录翻译为由271个氨基酸组成、分子量为31 kDa的前体蛋白(pro-IL-1α)。与IL-1β相似，IL-1α缺乏一个信号肽序列，其前体蛋白可以被切割为17 kDa的C端成熟形式和16 kDa的N末端前体肽段(NTP)[6]。IL-1α前体N末端有一功能性的核定位信号序列(nuclear localization signal，NLS) LKKRRL，被特定的酶切割后仍存在于NTP上[7]，而C端则分泌至胞外发挥作用(图 1)。与IL-1β不同，IL-1α前体和成熟形式都具有生物活性，经切割后IL-1α与IL-1R1亲和力增强，生物活性大大增强[8]。目前有研究显示，在不同的氨基酸位点对IL-1α前体进行切割后所得IL-1α成熟形式生物活性存在差异，但是其确切原因仍需进一步研究[9]。
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| 图 1 IL-1α的成熟与分泌机制 Figure 1 The mechanism of IL-1α maturation and secretion. |
| 图选项 |
1.2 IL-1α的功能 IL-1α可在细胞内和细胞外发挥多重作用。在细胞内，IL-1α以前体形式存在并发挥作用。pro-IL-1α作为细胞核内转录因子促进基因表达，调控细胞生长分化，其功能依赖于N端的核定位信号[10]。IL-1α还与一些促炎细胞因子的表达具有紧密联系。有报道指出，在牛的颗粒细胞中IL-1α能够通过MAPK和NF-κB通路上调IL-6的表达[11]。在细胞凋亡过程中，IL-1α也发挥着重要的作用。染色体结合性的IL-1α存在于巨噬细胞及黑色素瘤细胞中，IL-1α从坏死细胞中释放，但是仍保留在凋亡细胞核中，保持免疫耐受，阻止炎症发生，其释放方式的差别是区分坏死性细胞死亡和凋亡性细胞死亡的重要依据[12-13]。尽管多项研究表明IL-1α能够结合DNA，但是在不同的细胞类型中细胞核IL-1α的生理学功能仍不清楚，IL-1α与染色体结合后如何影响转录过程仍需进一步研究。
除了在细胞内的上述功能，IL-1α还可分泌至胞外参与机体炎症反应及免疫应答。胞外的IL-1α包括可溶性的成熟形式的IL-1α或是膜结合性的pro-IL-1α。IL-1α一旦释放到胞外，可溶性或是膜结合性IL-1α通过特定的精氨酸残基及蛋白质拓扑结构与细胞表面的IL-1R相结合，触发IL-1R3的招募，形成信号转导复合物，募集MyD88，激活NF-kB和JNK，MAPK目的基因转录[14]。
2 IL-1α的成熟与分泌机制 IL-1α前体和成熟形式都具有生物活性，但经切割后成熟的IL-1α与IL-1R1亲和力增强，其生物活性也大大增强。近年来相关研究表明，IL-1α的成熟与分泌是一个复杂的多因素参与的过程，包括细胞内钙离子浓度及钙蛋白酶(calpain)活性的调控、部分情况下还有炎症小体信号途径及其他途径的参与(图 1)。
2.1 Calpain依赖途径 IL-1α分泌至胞外可分为主动和被动途径，两种途径中calpain都参与了IL-1α的成熟与分泌。England等[15]研究表明细胞坏死性凋亡通过Ca2+和calpain调控IL-1α的加工和释放。在主动分泌过程中，IL-1α也可经calpain加工为成熟形式，分泌至胞外[16-17]。体外试验表明calpainⅠ和calpainⅡ都能够对重组的小鼠睾丸中的IL-1α前体进行切割[18]。另有研究指出含有膜渗透性calpain抑制剂的细胞培养环境可能会通过抑制内源性IL-1α的成熟和分泌而促进上皮细胞的生长[19]。Sorrentino等[20]研究表明肺脏肿瘤关联性的浆液型树突状细胞(plasmacytoid dendritic cells，pDCs)能够激活AIM2炎症小体，促进Ca2+外流、线粒体产生活性氧，引起calpain活化及IL-1α分泌水平升高。我们课题组利用肺炎链球菌野生型菌株D39和ply基因缺失菌株(?ply)感染巨噬细胞，通过检测胞内的钙离子浓度以及calpain的底物α-fodrin活性，结合使用钙离子螯合剂和多种calpain抑制剂的实验验证了calpain在肺炎链球菌感染诱导IL-1α的成熟与分泌中的关键作用。肺炎链球菌溶血素(pneumolysin，PLY)诱导钙离子内流引起calpain的活化，IL-1α被活化的calpain切割为成熟形式并分泌至胞外[2]。此外，在单核细胞增生性李斯特菌[21]和结核分枝杆菌[3]感染巨噬细胞模型中发现类似的IL-1α成熟与分泌的机制。因此，胞内钙离子浓度升高，引起calpain活化可能是多数病原菌感染宿主诱导IL-1α成熟与分泌的通用机理。但是在其他病原菌感染及无菌炎症中，不排除该信号通路以外的其他信号通路的存在，有待于进一步的研究。
2.2 炎症小体信号途径 有研究报道指出，炎症小体与IL-1α的分泌具有密切的联系。IL-1α虽然不是半胱天冬酶-1 (caspase-1)的底物，但是IL-1α可与caspase-1结合，促进非传统蛋白分泌[22]。另有研究证明，胞内的IL-1R2会通过结合IL-1α前体而阻止calpain对IL-1α的加工以及分泌，而活化的caspase-1则能够切割IL-1R2，从而使得IL-1α前体被calpain加工并进一步释放[23]。Michela等[24]报道在肺肿瘤病灶中巨噬细胞聚集，且其促肿瘤活性受NLRP3炎症小体调节，并引起caspase-11依赖性的IL-1α释放。NLRP3炎症小体激动剂，如尿酸盐结晶或尼日利亚菌素可诱导IL-1α的成熟，引起IL-1β和IL-1α的共分泌[25]。Gro?等研究还发现NLRP1、NLRP3、NLRC4以及AIM2这四种炎症小体的所有激动剂都能够诱导IL-1α分泌，在ATP、尼日利亚菌素以及有活性的白色念珠菌刺激下IL-1α的分泌完全依赖于caspase-1、ASC和NLRP3。NLRP1、AIM2以及NLRC4炎症小体活化也可引起caspase-1依赖性的IL-1α和IL-1β的共同分泌。但是IL-1α的分泌并不完全依靠炎症小体，部分NLRP3炎症小体的激动剂能够以一种炎症小体非依赖性的途径诱导IL-1α分泌[26]。本课题组用肺炎链球菌感染ASC-/-及caspase1-/-小鼠巨噬细胞，发现IL-1α的成熟与分泌不依赖于caspase-1、ASC，表明炎症小体在肺炎链球菌感染巨噬细胞诱导IL-1α成熟与分泌过程中无显著影响[2]。同样地，Dewamitta等[21]研究表明小鼠巨噬细胞感染单增李斯特菌后，caspase-1和ASC不参与IL-1α的成熟与分泌。综上所述，IL-1α的成熟与分泌有炎症小体依赖途径、部分依赖途径和非依赖途径。不同的感染及炎症情况下炎症小体在IL-1α的成熟与分泌中的作用差异较大，有待进一步研究。
2.3 其他途径 有研究表明IL-1α前体除了以calpain和caspase-1依赖性的方式被加工外，颗粒酶B、中性粒细胞弹性蛋白酶以及糜蛋白酶等均可切割IL-1α前体，增强其促炎活性[27]。在胞内及无细胞环境(cell-free)中，IL-1α前体的切割由calpain完成，而在胞外空间，颗粒酶B在天冬氨酸103对IL-1α前体进行切割[9]。此外，有研究发现在钙结合蛋白A13依赖性的IL-1α分泌机制中Cu2+水平的升高也会促进IL-1α分泌[28]。Fettelschoss等[29]发现在缺失IL-1β基因细胞中不能分泌IL-1α，提示IL-1β的存在对IL-1α的分泌具有重要作用。另有报道指出在角化细胞中，由紫外诱导的DNA损伤可提高IL-1α的转录与分泌水平[30]。Castillo等[31]研究发现自噬作用也能抑制IL-1α的成熟与分泌，结核分枝杆菌感染和依赖自噬蛋白5 (autophagy protein 5，ATG-5)的自噬过程阻断IL-1α的活化与分泌，减轻肺部炎症和组织损伤。此外，调控坏死性凋亡的其他关键信号分子，例如混合谱系激酶结构区域样蛋白、线粒体磷酸酶PGAM5也可能参与IL-1α的加工释放[32-33]。因此，在不同条件下，机体可选择不同方式对IL-1α进行切割加工，calpain、炎症小体及多种酶、蛋白都参与了IL-1α的成熟与分泌过程。
3 IL-1α与相关疾病 IL-1α作为一种重要的促炎因子，参与机体抗微生物感染、无菌炎症、肿瘤相关疾病以及一些自发炎症的调节。有研究发现腺病毒能够通过活化IL-1α诱导机体免疫应答，IL-1α与IL-1R1通路参与抗病毒反应[34]。Dewamitta等[21]研究报道重组的IL-1α能够提高小鼠对单增李斯特菌感染的耐受性。Vonk等[35]研究表明IL-1α在抗白色念珠菌感染的固有免疫中发挥着重要的作用。小鼠感染嗜肺军团菌后，IL-1α促使中性粒细胞募集，诱导炎症产生[36]。猪感染蓝耳病毒不同毒株后，其肺部细胞因子应答进行对照研究后表明在高致病性的菌株中，IL-1α表达水平更高，这可能对临床症状起始阶段和间质性肺炎的发生有重要意义[37]。David等[38]指出调控IL-1α加工和分泌的抑制机制将为严重的急性脑损伤提供新的治疗靶标。Mauro等[39]通过构建小鼠心肌梗塞模型发现，阻塞IL-1α能够降低炎症小体的激活，因此阻断IL-1α将会是一种新颖的治疗缺血再灌注损伤(I/R)的药物靶标。一些证据显示IL-1α在慢性炎症疾病中有重要作用。在吸烟引起的肺部炎症模型中，IL-1α对调节肺部炎症反应以及慢性阻塞性肺病(chronic obstructive pulmonary disease，COPD)中具有重要作用[40]。早期IL-1α释放是诱发炎症发生的重要步骤，因此被认为是治疗风湿疾病的潜在靶标之一[41]。IL-1α也参与了肿瘤的发生发展过程。林丹丹等[42]利用小鼠急性肝损伤模型证明分泌型和膜型IL-1α在急性肝损伤和肝癌中发挥着不同的作用。患有头部及颈部鳞状细胞癌的病人，IL-1α的表达水平常被作为远处转移的预后指标[43]。据调查在15604个癌症病例中，卵巢癌遗传危险因素分析显示在IL-1α单核苷酸多态性rs17561和亮细胞癌症类型易感性降低之间有紧密联系[44]。临床试验中表明以IL-1α驱动的前馈信号放大回路为靶标的IL-1α封闭多克隆抗体对治疗癌症具有重要意义[45-46]。另外，Cloeman等[47]在临床试验中使用IL-1α的目标多克隆抗体(MABp1)治疗银屑癣。
4 展望 IL-1α作为无菌炎症反应的关键驱动因子，在机体抗多种微生物感染中发挥着重要的作用，同时在2型糖尿病、银屑癣以及多种癌症等疾病中备受重视，现已成为多种疾病治疗的潜在靶标。因此，深入研究IL-1α的成熟与分泌机制，将为拓展炎症及感染性疾病的新干预途径提供理论依据，为临床试验中预防治疗多种疾病提供坚实的理论基础。
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