白细胞介素2信号通路相关分子与系统性红斑狼疮

郭 倩，陈绪勇，苏 茵△

(1. 北京大学人民医院风湿免疫科， 北京 100044； 2. 北京大学国际医院风湿免疫科， 北京 102206)



·综述·

白细胞介素2信号通路相关分子与系统性红斑狼疮

郭 倩1,2，陈绪勇1，苏 茵1△

(1. 北京大学人民医院风湿免疫科， 北京 100044； 2. 北京大学国际医院风湿免疫科， 北京 102206)

白细胞介素2；红斑狼疮，系统性；基因表达调控；信号传导

系统性红斑狼疮(systemic lupus erythematosus，SLE)是一种多因素参与的自身免疫性疾病。研究证实，B淋巴细胞、T淋巴细胞、转录因子与细胞因子表达以及抗原呈递等异常或缺陷在SLE的发病中有重要作用，导致包括皮肤、肾、肺、中枢神经系统、消化系统及关节肌肉等多系统、多器官的损伤[1]。SLE患病率约70/10万，目前我国至少有100万以上的患者，尤以育龄期女性多见，其病因及发病机制尚不完全清楚，遗传、环境和病毒感染等因素与其发病关系密切[2]。

白细胞介素2(interleukin-2, IL-2)是一种具有多种生物活性的细胞因子，由Th1细胞合成分泌，不仅可以促进CD4+及CD8+T细胞的活化和增殖，还可诱导免疫记忆，对免疫系统抵抗病原微生物具有重要意义[3-4]。研究证明，SLE患者血清中IL-2水平较正常人明显减低，并伴随调节性T细胞(regulatory T cell，Treg)数目减少、细胞毒作用减弱等多种免疫功能紊乱[5-6]。

研究提示，SLE患者外周血IL-2的表达缺陷可能与调节IL-2生成的多个调控分子的异常有关，这些分子包括环磷酸腺苷(cyclic adenosine monophosphate，cAMP)反应元件调节物(cAMP-responsive element modulator，CREM)、蛋白磷酸酶2A(protein phosphatase 2A，PP2A)、E-74样因子1(E-74 like factor-1，Elf-1)、B淋巴细胞诱导成熟蛋白1(B lymphocyte induced maturation protein-1，Blimp-1)及干扰素调节因子5(interferon regulator factor 5，IRF-5)等(图1)，这些分子通过不同的作用途径参与IL-2信号通路的调节[7-10]。PP2A一方面通过激活IL-2转录抑制因子CREMα来抑制IL-2的合成；另一方面通过抑制IL-2的刺激性转录因子Elf-1来抑制IL-2的表达。IRF-5通过激活IL-2转录的负向调控因子Blimp-1来抑制IL-2的表达。

PP2A, protein phosphatase 2A; CREM, cyclic adenosine monophosphate-responsive element modulator; Elf-1, E-74 like factor-1; IRF-5, interferon regulator factor-5; Blimp-1, B lymphocyte induced maturation protein-1; SLE, systemic lupus erythematosus; IL-2, interleukin-2. (+), promote; (-), inhibit.

图1 系统性红斑狼疮中IL-2缺陷相关通路示意图

Figure1 IL-2 defects signaling pathway in SLE

1 cAMP反应元件调节物抑制IL-2的合成

IL-2的合成调控主要是由IL-2基因的转录完成的[11]，研究提示，CREM与SLE的发病密切相关。CREM是一种转录抑制因子，可通过与IL-2基因的启动子结合限制IL-2基因的转录，SLE患者T细胞可表达高水平的CREM[12]，此外，CREM不仅能与活化T细胞的TCRζ/SYK启动子及原癌基因c-fos近端的启动子结合[13-14]，还可作用于CREM基因的启动子[15]，其中，CREM与c-fos基因启动子的结合可导致c-fos的转录减少，降低Fos蛋白的生成，而Fos蛋白又是IL-2基因转录激活因子激活蛋白1(activator protein-1，AP-1)的组成成分之一，故CREM还可通过抑制c-fos基因的转录间接影响IL-2的生成[14]。

CREM是碱性亮氨酸拉链(basic leucine zipper，bZIP)类转录因子，有多种不同启动子和可变剪接调节的亚型，其中包括CREMα、CREMβ[16]。Kyttaris等[17]的研究表明，在SLE患者的T细胞中，CREMα的信使核糖核酸(messenger ribonucleic acid，mRNA)表达水平明显升高，虽然这种表达水平与SLE患者的临床特征、疾病活动度及治疗效果之间无明显相关性，但在使用大剂量糖皮质激素治疗后，CREMα的mRNA表达可呈下降趋势，由此推断，若能阻断CREMα的mRNA表达可能会使SLE异常的T细胞功能得到控制。针对狼疮小鼠模型的研究证实，补充IL-2能够逆转狼疮小鼠T细胞中CREMα的过度表达[18]。当利用17-β雌二醇刺激T细胞时，T细胞的CREMα的mRNA表达呈剂量依赖性增加，而抑制雌激素可使IL-2的mRNA表达及IL-2呈剂量依赖性减少。由此可见，雌激素可上调CREMα的mRNA表达，促使T淋巴细胞合成和分泌IL-2缺陷[19]。SLE患者T细胞分泌的细胞因子呈现明显的不平衡状态，其中CREM不仅可作为转录抑制因子，还可通过募集DNA甲基化转移酶3A(DNMT3A)和组蛋白去乙酰化酶1(HDAC1)而介导IL-2的表观遗传修饰，使IL-2基因沉默，抑制IL-2的产生[20]。研究显示，CREM基因本身的转录调节是通过启动子P1和P2实现的，并且P1启动子的活性与SLE患者的疾病活动度密切相关[15,21]。

2 PP2A可抑制IL-2的合成

PP2A是一种丝氨酸/苏氨酸磷酸酶，它广泛表达于真核细胞中，由异源三聚体组成，包括一个支架型结构亚基A、一个催化亚基C以及一个调节亚基B。PP2A的催化亚基C(包括α与β两种亚型)和结构亚基A(包括α与β两种亚型)分别由两个高度同源的基因编码：PP2ACα由PPP2CA基因编码，PP2ACβ由PPP2CB基因编码；PP2AAα由PPP2R1A基因编码，PP2AAβ由PPP2R1B基因编码。由于PP2A含有数个不同的调节亚基，使得其可以作用于多种底物，并能够监控多个细胞的生理过程，如细胞周期活动、基因转录和翻译以及细胞凋亡等过程[22]。

研究显示，SLE患者T细胞表达PP2AC的水平可异常升高，异常升高的PP2AC能够促进转录因子和细胞因子间的差异表达，高疾病活动度的SLE患者能够表达更高水平的PP2AC[7]，而PP2AC的作用底物p-CREB是IL-2生成过程中一个非常重要的转录因子[23]，PP2AC可促进p-CREB的脱磷酸[24]，进而抑制p-CREB与IL-2基因启动子相结合，使IL-2分泌减少[7]。此外，SLE患者T细胞中DNA甲基化转移酶1(DNMT1)表达减少，使得PPP2CA基因启动子区域DNA的低甲基化，导致PP2ACα过度表达，促进SLE发病[25]。Tan等[26]的研究证实，在PPP2CA基因内含子的单核苷酸多态性(single nucleotide polymorphism，SNP)位点rs7704116上，携带A等位基因的SLE患者能够诱导PP2AC的mRNA过高表达，进而通过p-CREB去磷酸化过程抑制IL-2产生，该项研究的数据还显示，PPP2CA基因的多态性与欧裔美国人、西班牙裔美国人及亚洲人群中的SLE易感性密切相关。

CREM基因启动子活性与SLE患者的疾病活动度密切相关[21]，转录因子特异性蛋白-1(specificity protein-1，SP-1)可与CREM基因启动子结合，促使后者转录活性增强。在SLE患者T细胞中，PP2A可通过SP-1丝氨酸残基59(Ser59)的去磷酸化使SP-1激活，进而使SP-1能更好地与CREM基因启动子结合，抑制IL-2的合成[21]。T细胞功能失调是SLE患者免疫系统紊乱的核心机制，PP2A→SP-1→CREM的信号通路揭示了SLE患者发生T细胞异常的另一个关键步骤，为我们更好地理解SLE的发病机制打下了理论基础。此外，PP2A还可以通过Elf-1的去磷酸化，促进与非DNA区域结合的相对分子质量为80×103的Elf-1的表达，进而抑制IL-2的生成[10]。

Katsiari等[7]的研究表明，使用适量的PP2AC的小干扰RNA(small interfering RNA，siRNA)能够有效地降低PP2A水平并纠正SLE患者T细胞中IL-2的生成缺陷；此外，在幼年SLE患者中，矫正miRNA-155的表达能够抑制PP2AC的表达水平并增强外周血单个核细胞中IL-2的释放[27]，这些研究均为未来SLE的治疗方案提供了新的治疗靶点。

3 Elf-1促进IL-2的合成

PP2A可通过Elf-1的去磷酸化促进不能与DNA结合的相对分子质量为80×103的Elf-1的表达，从而抑制IL-2的生成[10]，那么Elf-1具体为何物呢？Leiden[28]发现，Elf-1是由619个氨基酸序列组成的、属于Ets(E-twenty six)家族的转录因子。Elf-1是人类IL-2受体α链启动子应答元件的组成部分之一[29]，其表达异常可直接影响SLE患者中IL-2的作用通路。

Elf-1以相对分子质量为80×103的蛋白质形式分布于细胞质中，而在细胞核中则以相对分子质量为98×103的蛋白质形式与DNA结合。Elf-1基因的翻译后修饰(如PP2A的磷酸化作用及O-连接的糖基化作用等)可使Elf-1在相对分子质量为80×103和相对分子质量为98×103的形式间相互转换[30]。在SLE患者的T细胞中，由于磷酸化不足或去磷酸化过度等原因，导致相对分子质量为98×103形式的Elf-1生成缺陷，进而导致TCRζ链启动子出现转录障碍[31]，而正是TCRζ链的缺陷以及IL-2转录调控中多种异常，在SLE的发病中起着关键作用[32]。虽然我们了解了Elf-1的成分与结构，并且知道其相对分子质量为80×103的形式能够抑制IL-2的生成，但目前对于Elf-1具体通过何种分子机制或信号通路而影响IL-2合成还知之甚少。

4 Blimp-1抑制IL-2的合成

Blimp-1是由PRDM-1基因编码的，具有SET[Su(var), enhancer of zeste, and trithorax]结构域和锌指结构的转录抑制因子，是参与调控B淋巴细胞终末分化环节的关键转录因子之一[33]。

近10年来，多项研究已经证实了Blimp-1在T细胞分化中有重要作用[34-35]，Martins等[34]的研究数据显示，Blimp-1缺陷的CD4+T细胞受体经体外刺激后，可表现出较强的高增殖反应，并伴有IL-2的合成量明显增加，因此认为Blimp-1可负性调节IL-2的产生。随后，Gong等[36]的研究发现，增强Blimp-1表达可抑制由TCR刺激所诱导的IL-2产生，这一结果与Martins等[34]的研究相互映照。有研究证实，狼疮小鼠的外周血单个核细胞(peripheral blood mononuclear cell, PMBC)表达的Blimp-1水平明显上调[37]，而Blimp-1的siRNA能够抑制狼疮小鼠的B淋巴细胞分化并阻止狼疮病情的进展[38]，这些研究进一步证实了Blimp-1与狼疮小鼠的发病相关。

Blimp-1在T细胞中的主要作用之一是通过直接抑制IL-2及c-fos基因的转录而实现的[8]。Fos是AP-1的主要成分之一，而AP-1是IL-2的转录激活因子，故抑制Fos蛋白的生成亦会影响IL-2的合成[14]。IL-2可通过诱导PRDM-1基因表达生成Blimp-1，并通过Blimp-1抑制IL-2自身的表达，控制免疫应答在适当状态，Blimp-1的这一功能，对由细胞因子缺乏诱导的T细胞凋亡及减弱T细胞抗原特异性的增殖反应非常重要[8]。

IL-2是T细胞中Blimp-1表达的强效诱导剂[36]，Blimp-1对IL-2基因转录的抑制作用主要包括以下几点：(1)表达Blimp-1的细胞不分泌或少分泌IL-2；(2)Blimp-1的mRNA表达水平与IL-2的mRNA表达呈负相关；(3)在Blimp-1缺乏的CD4+T细胞中，IL-2的水平及IL-2的mRNA表达可持续增高；(4)在活化的CD4+T细胞中，内源性Blimp-1可通过特异性结合IL-2基因调节区域发挥作用[8]。因此认为，IL-2可诱导Blimp-1生成，而Blimp-1可抑制IL-2的合成与分泌，两者形成了一个调节IL-2水平的负反馈调节环路。

5 IRF-5抑制IL-2的合成

干扰素调节因子(interferon regulatory factor，IRF)是Ⅰ型干扰素最具特征性的转录调节因子，在调节固有免疫和适应免疫反应等诸多方面起关键作用[39]。IRF-5是属于IRFs家族成员之一，近年来的多项研究显示，由IRF-5缺乏所导致的自身抗体和炎性细胞因子的生成与SLE发病密切相关，功能实验也验证了IRF-5与SLE在遗传学上的关联。

SLE患者血清IRF-5的水平明显增高[40]，活化的IRF-5可诱导Ⅰ型干扰素基因和PRDM-1基因的转录[41-42]。PRDM-1基因编码的Blimp-1蛋白是IL-2生成过程中的负性调节因子[34]，故IRF-5可通过促进Blimp-1的表达间接抑制IL-2的产生。有关狼疮小鼠的研究表明，雌性小鼠表达的IRF-5的mRNA水平较雄性小鼠更高，同时该研究结果还显示，雌激素可上调小鼠IRF-5基因的表达[43]。

IL-2是维持免疫系统各项功能正常运行所必需的细胞因子，在SLE患者及狼疮小鼠模型中，IL-2的合成及功能障碍已被广泛证实。近年来的多项研究逐一揭示了影响IL-2生成的多个环节及多种因素，这些影响因素或通过改变基因所在染色质，或通过直接影响IL-2基因的转录，或通过基因转录后的蛋白修饰而达到调控IL-2的目的。如本文所阐述的SLE中IL-2缺陷相关通路的分子中，PP2A一方面通过激活IL-2转录抑制因子CREMα来抑制IL-2的合成，另一方面通过抑制IL-2的刺激性转录因子Elf-1来抑制IL-2的表达，而IRF-5则通过激活IL-2转录的负向调控因子Blimp-1来抑制IL-2的表达。

深刻认识各种因素的生理角色及其在疾病状态下的作用，了解IL-2生成过程中的调控机制，将使我们能更好地理解SLE这一系统性疾病的病理生理过程，为今后制定新的治疗策略、开发新的治疗靶点提供理论依据。

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(2016-07-28收稿)

(本文编辑：任英慧)

SUMMARY Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease, which characterized by complex immunological abnormalities and multiple tissue and organ damages. The etiology and pathogenesis of SLE have not been entirely recognized. Genetic, environmental and viral infections and other factors might be related to the pathogenetic mechanisms of SLE. Interleukin-2 (IL-2) is a critical cytokine produced by T cells upon activation and is important for the generation of T regulatory cells and activation-induced cell death. In SLE patients, T cells display decreased capacity to produce IL-2. Impaired IL-2 expression resulted in decreased generation of regulatory T lymphocytes, and defect of activation-induced cell death. Former researches indicated that IL-2 deficiency in SLE is important for the pathogenesis and treatment of SLE. Several regulating molecules can affect the transcription of IL-2 gene and had an important role in the pathogenesis of SLE. These molecules include cyclic AMP-responsive element modulator (CREM), protein phosphatase 2A (PP2A), E-74 like factor 1 (Elf-1), B lymphocyte induced maturation protein-1 (Blimp-1) and interferon regulator factor 5 (IRF-5). CREM is a transcriptional inhibitor that can repress the transcription of the IL-2 gene by binding to the promoter of the IL-2 gene. PP2A is a Ser/Thr phosphatase that expressed in eukaryotic cells ubiquitously, it represents a negative regulator of the IL-2 gene promoter activity. Elf-1 belongs to the Ets family of transcription factors and can promote the expression of IL-2. Blimp-1 is a crucial transcription factors for regulating B lymphocyte terminal differentiation, an important function of Blimp-1 in T cells is to repress IL-2 gene transcription directly. Interferon regulatory factors (IRFs) are distinctive transcriptional regulators of type Ⅰ interferons (IFNs) and IFN inducible genes, IRF-5 is a member of the IRFs family. IRF-5 is found to be increased in SLE and can regulate the production of IL-2 negatively. PP2A can inhibit the synthesis of IL-2 in two ways: on the one hand, activating the IL-2 transcription inhibitory factor CREMα, on the other hand, inhibiting IL-2 stimulating transcription factor Elf-1. While IRF-5 can activate the IL-2 transcription negative regulator Blimp-1 as to inhibit IL-2 expression. These molecules participate in the regulation of IL-2 through different pathways. This paper reviews the current knowledge of IL-2 signaling pathway regulating molecules in SLE.

Interleukin-2 signaling pathway regulating molecules in systemic lupus erythematosusGUO Qian1,2, CHEN Xu-yong1, SU Yin1△

(1. Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing 100044, China; 2. Department of Rheumatology and Immunology, Peking University International Hospital, Beijing 102206, China)

Interleukin-2; Lupus erythematosus, systemic; Gene expression regulation; Signal transduction

国家自然科学基金(81471600，81172844)资助 Supported by the National Natural Science Foundation of China (81471600, 81172844)

R593.24

A

1671-167X(2016)06-1100-05

10.3969/j.issn.1671-167X.2016.06.032

时间：2016-10-31 16：33：02

http://www.cnki.net/kcms/detail/11.4691.R.20161031.1633.032.html

△ Corresponding author’s e-mail, suyin0921@163.com