白细胞介素-10

白细胞介素-10(亦称为介白素-10,英文:Interleukin 10,简称IL-10),也称为细胞激素合成抑制因子(cytokine synthesis inhibitory factor,CSIF),是一种抗炎症细胞因子。在人类中,IL-10由“IL10”基因编码。[6]IL-10的讯号需要借由细胞膜上的介白素-10受体(IL-10受体)传递到细胞内。IL-10受体在作用时构型为含四个次单元的蛋白质复合体,其中包含两个IL-10受体1(IL-10R1)单元以及两个IL-10受体2(IL-10R2)单元。在接收到IL-10讯号时,IL-10R1会先直接与IL-10结合,之后呼叫(recruit)IL-10R2形成完整复合体,以进行后续的讯号传递,IL-10R2并不直接与IL-10结合。[7]IL-10通过JAK1和Tyk2分别磷酸化IL-10受体1、IL-10受体2的胞质尾端,来诱导STAT3信号传递。

白细胞介素-10
已知的结构
PDB直系同源搜索: PDBe RCSB
识别号
别名IL10;, CSIF, GVHDS, IL-10, IL10A, TGIF, interleukin 10
外部IDOMIM124092 MGI96537 HomoloGene478 GeneCardsIL10
相关疾病
贝赛特氏症、​溃疡性结肠炎[1]
基因位置(人类
1号染色体
染色体1号染色体[2]
1号染色体
白细胞介素-10的基因位置
白细胞介素-10的基因位置
基因座1q32.1起始206,767,602 bp[2]
终止206,774,541 bp[2]
RNA表达模式
查阅更多表达数据
直系同源
物种人类小鼠
Entrez
Ensembl
UniProt
mRNA​序列

NM_000572

NM_010548

蛋白序列

NP_000563

NP_034678

基因位置​(UCSC)Chr 1: 206.77 – 206.77 MbChr 1: 130.95 – 130.95 Mb
PubMed​查找[4][5]
维基数据
查看/编辑人类查看/编辑小鼠

基因和蛋白质结构

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IL-10蛋白是同型二聚体,每个亚基的长度均为178个氨基酸[8]

IL-10被归为2类细胞因子——包括IL-19、IL-20、IL-22、IL-24(Mda-7)、IL-26和I型干扰素(IFN-α,-β,-ε,-κ,-ω),II型(IFN-γ),III型(IFN-λ,[9]也称为IL-28A,IL-28B,和IL-29)。[10]

表达与合成

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在人类中,IL-10由“IL10”基因编码,该基因位于1号染色体上,包含5个外显子[6],主要由单核细胞产生,并在较小程度上由淋巴细胞产生,即II型T辅助细胞(TH2),肥大细胞,CD4+CD25+Foxp3+调节性T细胞,以及激活的T细胞B细胞的某些子集。在这些细胞中触发PD-1后,单核细胞可以产生IL-10[11]。IL-10上调也由GPCR介导,例如β-2肾上腺素[12]和2型大麻素[13]受体。IL-10的表达在未经刺激的组织中极少,似乎需要由共生或病原菌触发。[14]IL-10表达在转录和转录后水平受到严格调节。刺激TLR或Fc受体途径后,在单核细胞中观察到广泛的IL-10基因座重塑[15]。IL-10诱导涉及ERK1/2,p38和NF-κB信号传导,以及通过转录因子NF-κB和AP-1的启动子结合而引起的转录激活。IL-10可能通过负反馈回路自动调节其表达,该回路涉及IL-10受体的自分泌刺激和p38信号通路的抑制[16]。此外,IL-10的表达在转录后水平受到广泛调控,这可能涉及通过富含AU的元件[17]和诸如let-7[18]或miR-106的microRNA控制mRNA的稳定性[19]

功能

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IL-10是一种在免疫调节和炎症中具有多效性的细胞因子。它下调了巨噬细胞上Th1细胞因子、MHC-II类抗原、共刺激分子的表达。它还增强了B细胞的生存、增殖和产生抗体的能力。IL-10可以阻断NF-kB活动,并参与JAK-STAT信号转导通路的调节。

IL-10发现与1991年[20],最初报道其抑制细胞分泌、抗原呈递和CD4+细胞激活。[21][22][23][24]进一步的研究表明,IL-10主要抑制脂多糖(LPS)和细菌产物介导的促炎性细胞因子TNFα[25]、IL-1β[25]、IL-12[26]、IFNγ[27]的分泌,这些细胞因子由Toll样受体(TLR)触发的骨髓细胞谱系分泌。

对肿瘤的影响

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随着时间的流逝,IL-10功能的细微差别出现了,因为已证明对荷瘤小鼠的治疗可抑制肿瘤转移[28]。多个实验室的进一步研究已经产生了进一步支持IL-10在免疫神经学背景下的免疫刺激能力的数据。从IL-10转基因小鼠[29]中转染的肿瘤细胞系[30][31]中表达IL-10或用IL-10给药可控制原发性肿瘤生长并降低转移负担。[32][33]最近,聚乙二醇化重组鼠IL-10(PEG-rMuIL-10)已显示出诱导IFNγ和CD8+T细胞依赖性抗肿瘤免疫力[34][35]。更具体地,已显示PEG化的重组人IL-10(PEG-rHuIL-10)增强细胞毒性分子粒酶B和穿孔素的CD8+T细胞分泌,并增强T细胞受体依赖性IFNγ的分泌[36]

在疾病中的作用

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对小鼠的研究表明,肥大细胞也产生IL-10,抵消了这些细胞在变态反应部位的炎症作用[37]

IL-10能够抑制由巨噬细胞和Th1T细胞等细胞产生的促炎细胞因子如IFN-γIL-2IL-3TNFαGM-CSF的合成。它也显示出抑制抗原呈递细胞的抗原呈递能力的强大能力。但是,它也对某些T细胞(Th2)和肥大细胞具有刺激性,并刺激B细胞成熟和抗体产生。

IL-10检查环氧合酶Cyclo-oxygenase-2(COX-2)的可诱导形式。缺乏IL-10已被证明可导致COX激活并导致血栓烷受体激活,从而引起小鼠血管内皮和心脏功能障碍。白介素10基因敲除脆弱的小鼠会随着年龄的增长而出现心脏和血管功能障碍[38]

IL-10与肌动蛋白有关,因为运动会引起IL-1ra,IL-10和sTNF-R的循环水平增加,这表明体育锻炼可促进抗炎细胞因子的形成。[39][40]

与健康个体相比,在诊断为多发性硬化症的个体中观察到较低水平的IL-10[41]。由于IL-10水平的降低,TNFα水平不能得到有效调节,因为IL-10可以调节TNF-α转化酶[42]。结果,TNFα水平升高并导致炎症。[43]TNFα本身通过TNF受体1诱导少突胶质细胞脱髓鞘,而慢性炎症与神经元脱髓鞘有关。

黑素瘤细胞系中,IL-10调节NKG2D配体的表面表达。[44]

临床使用或试验

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在小鼠中进行的基因敲除研究表明,这种细胞因子在肠道中是必需的免疫调节剂。[45]的确,克罗恩氏病患者对用重组白介素10产生细菌的治疗反应良好,证明了IL-10对抵消人体过度活跃的免疫反应的重要性。[46]

根据数据,在临床试验中,数千名患有各种自身免疫性疾病的患者接受了重组人IL-10(rHuIL-10)的治疗。与预期相反,rHuIL-10治疗并未对克罗恩病患者的疾病产生重大影响。[47][48][49]或类风湿关节炎。[50]rHuIL-10治疗最初在牛皮癣中显示出有希望的临床数据。[51]但在一项随机,双盲,安慰剂对照的II期临床试验中未能达到临床意义。[52]对rHuIL-10在人类中作用的进一步研究表明,rHuIL-10除了抑制炎症外,还能够发挥促炎作用。[53][54]

聚乙二醇化形式

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除这些数据外,目前正在进行一项I期免疫科学临床试验,以评估PEG化重组人IL-10(PEG-rHuIL-10,AM0010)的治疗能力。[55]与临床前免疫免疫学数据一致,研究者报告了实质性的抗肿瘤功效。相反于所报告的在体外和体内产生的IL-10的免疫抑制作用,[22][23][24][56][57]治疗癌症患者的PEG-重组人白介-10引发的剂量滴定感应的免疫刺激细胞因子IFNγ,IL-18,IL-7,GM-CSF和IL-4的表达。此外,接受治疗的患者的外周CD8+T细胞表达激活标记,例如程序性死亡配体1(PD-L1)+,淋巴细胞激活基因3(LAG3)+和Fas配体(FasL)升高,血清TGFβ降低,其折叠倍数增加。这些发现与使用PEG-rMuIL-10的已发表的临床前免疫科学报告[34][35]以及以前用rHuIL-10治疗人类的发现一致。[53][54]这些数据表明,尽管IL-10可以在细菌产物刺激的髓样细胞中发挥免疫抑制作用,但对人的rHuIL-10/PEG-rHuIL-10治疗主要是免疫刺激。截至2018年 (2018-Missing required parameter 1=month!)AM0010(又名pegilodecakin)正在进行3期临床试验。[58]

互动

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已经证明IL-10与白介素10受体α亚基相互作用[59][60][61][62][63]

IL-10受体复合物也需要IL10R2链来启动信号传导。这种配体-受体的组合存在于鸟类和青蛙中,也可能存在于骨鱼类中。 

参考资料

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