白细胞介素-10

白细胞介素-10（亦稱為介白素-10，英文：Interleukin 10，簡稱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的訊號需要藉由細胞膜上的介白素-10受體（IL-10受體）傳遞到細胞內。IL-10受體在作用時構型為含四個次單元的蛋白質複合體，其中包含兩個IL-10受體1（IL-10R1）單元以及兩個IL-10受體2（IL-10R2）單元。在接收到IL-10訊號時，IL-10R1會先直接與IL-10結合，之後呼叫（recruit）IL-10R2形成完整複合體，以進行後續的訊號傳遞，IL-10R2並不直接與IL-10結合。^[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
已知的結構 PDB 直系同源搜索: PDBe RCSB PDBID列表 1ILK、​1INR、​1J7V、​1LK3、​1Y6K、​2ILK、​2H24
識別號
别名	IL10；, CSIF, GVHDS, IL-10, IL10A, TGIF, interleukin 10
外部ID	OMIM：124092 MGI：96537 HomoloGene：478 GeneCards：IL10
相關疾病
貝賽特氏症、​溃疡性结肠炎^[1]
基因位置（人类） 染色体 1號染色體^[2] 基因座 1q32.1 起始 206,767,602 bp^[2] 终止 206,774,541 bp^[2]
基因位置（小鼠） 染色体 小鼠1号染色体^[3] 基因座 1 E4|1 56.89 cM 起始 130,947,582 bp^[3] 终止 130,952,711 bp^[3]
RNA表达模式
查阅更多表达数据
基因本體 分子功能 • 血浆蛋白结合 • 生長因子活性 • 細胞因子活性 • interleukin-10 receptor binding • protein dimerization activity 細胞組分 • 細胞外區域 • 細胞外空間 生物學過程 • negative regulation of chronic inflammatory response to antigenic stimulus • positive regulation of MHC class II biosynthetic process • 內皮細胞凋亡過程的負調控 • 造血作用 • negative regulation of interferon-gamma production • regulation of sensory perception of pain • positive regulation of B cell apoptotic process • negative regulation of chemokine (C-C motif) ligand 5 production • response to inactivity • negative regulation of cytokine activity • negative regulation of interleukin-1 production • cellular response to hepatocyte growth factor stimulus • cellular response to estradiol stimulus • negative regulation of interleukin-6 production • 老化 • positive regulation of DNA-binding transcription factor activity • negative regulation of apoptotic process • negative regulation of cytokine production involved in immune response • response to glucocorticoid • cytoplasmic sequestering of NF-kappaB • negative regulation of interleukin-18 production • negative regulation of MHC class II biosynthetic process • response to activity • response to organic substance • response to carbon monoxide • leukocyte chemotaxis • type 2 immune response • negative regulation of myeloid dendritic cell activation • response to insulin • negative regulation of interleukin-8 production • response to lipopolysaccharide • B cell proliferation • negative regulation of T cell proliferation • negative regulation of nitric oxide biosynthetic process • branching involved in labyrinthine layer morphogenesis • defense response to bacterium • regulation of complement-dependent cytotoxicity • 免疫反应 • 基因調節 • B cell differentiation • regulation of isotype switching • 腫瘤壞死因子產生的負調控 • negative regulation of membrane protein ectodomain proteolysis • inflammatory response • cellular response to lipopolysaccharide • negative regulation of B cell proliferation • negative regulation of inflammatory response • negative regulation of cytokine production • positive regulation of transcription by RNA polymerase II • negative regulation of interleukin-12 production • defense response to protozoan • negative regulation of sensory perception of pain • positive regulation of macrophage activation • liver regeneration • regulation of synapse organization • positive regulation of endothelial cell proliferation • negative regulation of cell population proliferation • negative regulation of heterotypic cell-cell adhesion • positive regulation of heterotypic cell-cell adhesion • positive regulation of cell cycle • negative regulation of mitotic cell cycle • endothelial cell apoptotic process • regulation of response to wounding • negative regulation of vascular associated smooth muscle cell proliferation • positive regulation of vascular associated smooth muscle cell proliferation • interleukin-12-mediated signaling pathway • positive regulation of transcription, DNA-templated • negative regulation of autophagy • cytokine-mediated signaling pathway • positive regulation of receptor signaling pathway via JAK-STAT • positive regulation of pri-miRNA transcription by RNA polymerase II • negative regulation of hydrogen peroxide-induced neuron death • positive regulation of sprouting angiogenesis Sources:Amigo / QuickGO
直系同源
物種	人類	小鼠
Entrez	3586	16153
Ensembl	ENSG00000136634	ENSMUSG00000016529
UniProt	P22301	P18893
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 Mb	Chr 1: 130.95 – 130.95 Mb
PubMed​查找	^[4]	^[5]
維基數據
檢視/編輯人類 檢視/編輯小鼠

基因和蛋白质结构

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

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（T_H2），肥大细胞，CD4⁺CD25⁺Foxp3⁺调节性T细胞，以及活化的T细胞和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

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+细胞活化。^{[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

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

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-γ、IL-2、IL-3、TNFα和GM-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。

在黑素瘤细胞系中，IL-10调节NKG2D配体的表面表达。^[44]

临床使用或试验

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

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细胞表达活化标记，例如程序性死亡配體1（PD-L1）+，淋巴细胞活化基因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!)^[update]AM0010（又名pegilodecakin）正在进行3期临床试验。^[58]

互动

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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进一步阅读

• Bortesi L, Rossato M, Schuster F, Raven N, Stadlmann J, Avesani L, Falorni A, Bazzoni F, Bock R, Schillberg S, Pezzotti M. Viral and murine interleukin-10 are correctly processed and retain their biological activity when produced in tobacco. BMC Biotechnology. March 2009, 9 (1): 22. PMC 2667500  . PMID 19298643. doi:10.1186/1472-6750-9-22. 
• Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annual Review of Immunology. 2001, 19 (1): 683–765. PMID 11244051. doi:10.1146/annurev.immunol.19.1.683. 
• Girndt M. Humoral immune responses in uremia and the role of IL-10. Blood Purification. 2003, 20 (5): 485–8. PMID 12207099. doi:10.1159/000063553. 
• Beebe AM, Cua DJ, de Waal Malefyt R. The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Cytokine & Growth Factor Reviews. 2003, 13 (4–5): 403–12. PMID 12220553. doi:10.1016/S1359-6101(02)00025-4. 
• Mocellin S, Panelli MC, Wang E, Nagorsen D, Marincola FM. The dual role of IL-10. Trends in Immunology. January 2003, 24 (1): 36–43. PMID 12495723. doi:10.1016/S1471-4906(02)00009-1. 
• Roncarolo MG, Battaglia M, Gregori S. The role of interleukin 10 in the control of autoimmunity. Journal of Autoimmunity. June 2003, 20 (4): 269–72. PMID 12791310. doi:10.1016/S0896-8411(03)00047-7. 
• Groux H, Cottrez F. The complex role of interleukin-10 in autoimmunity. Journal of Autoimmunity. June 2003, 20 (4): 281–5. PMID 12791313. doi:10.1016/S0896-8411(03)00044-1. 
• Llorente L, Richaud-Patin Y. The role of interleukin-10 in systemic lupus erythematosus. Journal of Autoimmunity. June 2003, 20 (4): 287–9. PMID 12791314. doi:10.1016/S0896-8411(03)00043-X. 
• Asadullah K, Sabat R, Friedrich M, Volk HD, Sterry W. Interleukin-10: an important immunoregulatory cytokine with major impact on psoriasis. Current Drug Targets. Inflammation and Allergy. June 2004, 3 (2): 185–92. PMID 15180472. doi:10.2174/1568010043343886. 
• Stenvinkel P, Ketteler M, Johnson RJ, Lindholm B, Pecoits-Filho R, Riella M, Heimbürger O, Cederholm T, Girndt M. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly. Kidney International. April 2005, 67 (4): 1216–33. PMID 15780075. doi:10.1111/j.1523-1755.2005.00200.x. 
• Chang CF, Wan J, Li Q, Renfroe SC, Heller NM, Wang J. Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage. Neurobiol. Dis. July 2017, 103: 54–69. PMC 5540140  . PMID 28365213. doi:10.1016/j.nbd.2017.03.016. 
• Copeland KF. Modulation of HIV-1 transcription by cytokines and chemokines. Mini Reviews in Medicinal Chemistry. December 2005, 5 (12): 1093–101. PMID 16375755. doi:10.2174/138955705774933383. 

外部链接

•   维基共享资源上的相關多媒體資源：白细胞介素-10
• 醫學主題詞表（MeSH）：Interleukin-10