白細胞介素-10

白細胞介素-10（亦稱為介白素-10，英文：Interleukin 10，簡稱IL-10），也稱為細胞激素合成抑制因子（cytokine synthesis inhibitory factor，CSIF），是一種抗炎症細胞因子。在人類中，IL-10由「IL10」基因編碼。^[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通過JAK1和Tyk2分別磷酸化IL-10受體1、IL-10受體2的胞質尾端，來誘導STAT3信號傳遞。

白細胞介素-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
別名	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、​潰瘍性結腸炎[1]
基因位置（人類） 染色體 1號染色體[2] 基因座 1q32.1 起始 206,767,602 bp[2] 終止 206,774,541 bp[2]
基因位置（小鼠） 染色體 小鼠1號染色體[3] 基因座 1 E4|1 56.89 cM 起始 130,947,582 bp[3] 終止 130,952,711 bp[3]
RNA表達模式
查閱更多表達數據
基因本體 分子功能 • 血漿蛋白結合 • 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 • 免疫反應 • 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

基因和蛋白質結構

IL-10蛋白是同型二聚體，每個亞基的長度均為178個氨基酸。^[8]

IL-10被歸為2類細胞因子——包括IL-19、IL-20、IL-22、IL-24(Mda-7)、IL-26和I型干擾素（IFN-α,-β,-ε,-κ,-ω），II型（IFN-γ），III型（IFN-λ，^[9]也稱為IL-28A，IL-28B，和IL-29）。^[10]

表達與合成

在人類中，IL-10由「IL10」基因編碼，該基因位於1號染色體上，包含5個外顯子^[6]，主要由單核細胞產生，並在較小程度上由淋巴細胞產生，即II型T輔助細胞（T_H2），肥大細胞，CD4⁺CD25⁺Foxp3⁺調節性T細胞，以及活化的T細胞和B細胞的某些子集。在這些細胞中觸發PD-1後，單核細胞可以產生IL-10^[11]。IL-10上調也由GPCR介導，例如β-2腎上腺素^[12]和2型大麻素^[13]受體。IL-10的表達在未經刺激的組織中極少，似乎需要由共生或病原菌觸發。^[14]IL-10表達在轉錄和轉錄後水平受到嚴格調節。刺激TLR或Fc受體途徑後，在單核細胞中觀察到廣泛的IL-10基因座重塑^[15]。IL-10誘導涉及ERK1/2，p38和NF-κB信號傳導，以及通過轉錄因子NF-κB和AP-1的啟動子結合而引起的轉錄激活。IL-10可能通過負反饋迴路自動調節其表達，該迴路涉及IL-10受體的自分泌刺激和p38信號通路的抑制^[16]。此外，IL-10的表達在轉錄後水平受到廣泛調控，這可能涉及通過富含AU的元件^[17]和諸如let-7^[18]或miR-106的microRNA控制mRNA的穩定性^[19]。

功能

IL-10是一種在免疫調節和炎症中具有多效性的細胞因子。它下調了巨噬細胞上Th1細胞因子、MHC-II類抗原、共刺激分子的表達。它還增強了B細胞的生存、增殖和產生抗體的能力。IL-10可以阻斷NF-kB活動，並參與JAK-STAT信號轉導通路的調節。

IL-10發現與1991年^[20]，最初報道其抑制細胞分泌、抗原呈遞和CD4+細胞活化。^{[21][22][23][24]}進一步的研究表明，IL-10主要抑制脂多糖(LPS)和細菌產物介導的促炎性細胞因子TNFα^[25]、IL-1β^[25]、IL-12^[26]、IFNγ^[27]的分泌，這些細胞因子由Toll樣受體（TLR）觸發的骨髓細胞譜系分泌。

對腫瘤的影響

隨着時間的流逝，IL-10功能的細微差別出現了，因為已證明對荷瘤小鼠的治療可抑制腫瘤轉移^[28]。多個實驗室的進一步研究已經產生了進一步支持IL-10在免疫神經學背景下的免疫刺激能力的數據。從IL-10轉基因小鼠^[29]中轉染的腫瘤細胞系^[30][31]中表達IL-10或用IL-10給藥可控制原發性腫瘤生長並降低轉移負擔。^[32][33]最近，聚乙二醇化重組鼠IL-10（PEG-rMuIL-10）已顯示出誘導IFNγ和CD8⁺T細胞依賴性抗腫瘤免疫力^[34][35]。更具體地，已顯示PEG化的重組人IL-10（PEG-rHuIL-10）增強細胞毒性分子粒酶B和穿孔素的CD8⁺T細胞分泌，並增強T細胞受體依賴性IFNγ的分泌^[36]。

在疾病中的作用

對小鼠的研究表明，肥大細胞也產生IL-10，抵消了這些細胞在變態反應部位的炎症作用^[37]。

IL-10能夠抑制由巨噬細胞和Th1T細胞等細胞產生的促炎細胞因子如IFN-γ、IL-2、IL-3、TNFα和GM-CSF的合成。它也顯示出抑制抗原呈遞細胞的抗原呈遞能力的強大能力。但是，它也對某些T細胞（Th2）和肥大細胞具有刺激性，並刺激B細胞成熟和抗體產生。

IL-10檢查環氧合酶Cyclo-oxygenase-2（COX-2）的可誘導形式。缺乏IL-10已被證明可導致COX激活並導致血栓烷受體激活，從而引起小鼠血管內皮和心臟功能障礙。白介素10基因敲除脆弱的小鼠會隨着年齡的增長而出現心臟和血管功能障礙^[38]。

IL-10與肌動蛋白有關，因為運動會引起IL-1ra，IL-10和sTNF-R的循環水平增加，這表明體育鍛煉可促進抗炎細胞因子的形成。^[39][40]

與健康個體相比，在診斷為多發性硬化症的個體中觀察到較低水平的IL-10^[41]。由於IL-10水平的降低，TNFα水平不能得到有效調節，因為IL-10可以調節TNF-α轉化酶^[42]。結果，TNFα水平升高並導致炎症。^[43]TNFα本身通過TNF受體1誘導少突膠質細胞脫髓鞘，而慢性炎症與神經元脫髓鞘有關。

在黑素瘤細胞系中，IL-10調節NKG2D配體的表面表達。^[44]

臨床使用或試驗

在小鼠中進行的基因敲除研究表明，這種細胞因子在腸道中是必需的免疫調節劑。^[45]的確，克羅恩氏病患者對用重組白介素10產生細菌的治療反應良好，證明了IL-10對抵消人體過度活躍的免疫反應的重要性。^[46]

根據數據，在臨床試驗中，數千名患有各種自身免疫性疾病的患者接受了重組人IL-10（rHuIL-10）的治療。與預期相反，rHuIL-10治療並未對克羅恩病患者的疾病產生重大影響。^[47][48][49]或類風濕關節炎。^[50]rHuIL-10治療最初在牛皮癬中顯示出有希望的臨床數據。^[51]但在一項隨機，雙盲，安慰劑對照的II期臨床試驗中未能達到臨床意義。^[52]對rHuIL-10在人類中作用的進一步研究表明，rHuIL-10除了抑制炎症外，還能夠發揮促炎作用。^[53][54]

聚乙二醇化形式

除這些數據外，目前正在進行一項I期免疫科學臨床試驗，以評估PEG化重組人IL-10（PEG-rHuIL-10，AM0010）的治療能力。^[55]與臨床前免疫免疫學數據一致，研究者報告了實質性的抗腫瘤功效。相反於所報告的在體外和體內產生的IL-10的免疫抑制作用，^{[22][23][24][56][57]}治療癌症患者的PEG-重組人白介-10引發的劑量滴定感應的免疫刺激細胞因子IFNγ，IL-18，IL-7，GM-CSF和IL-4的表達。此外，接受治療的患者的外周CD8+T細胞表達活化標記，例如程序性死亡配體1（PD-L1）+，淋巴細胞活化基因3（LAG3）+和Fas配體（FasL）升高，血清TGFβ降低，其摺疊倍數增加。這些發現與使用PEG-rMuIL-10的已發表的臨床前免疫科學報告^[34][35]以及以前用rHuIL-10治療人類的發現一致。^[53][54]這些數據表明，儘管IL-10可以在細菌產物刺激的髓樣細胞中發揮免疫抑制作用，但對人的rHuIL-10/PEG-rHuIL-10治療主要是免疫刺激。截至2018年 (2018-Missing required parameter 1=month!)^[update]AM0010（又名pegilodecakin）正在進行3期臨床試驗。^[58]

互動

已經證明IL-10與白介素10受體α亞基相互作用。^{[59][60][61][62][63]}

IL-10受體複合物也需要IL10R2鏈來啟動信號傳導。這種配體-受體的組合存在於鳥類和青蛙中，也可能存在於骨魚類中。 

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進一步閱讀

• 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.

外部連結

• 維基共享資源上的相關多媒體資源：白細胞介素-10
• 醫學主題詞表（MeSH）：Interleukin-10