白血球介素-10

白血球介素-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。

白血球介素-10
已知的結構
PDB直系同源搜尋: PDBe RCSB
識別號
別名IL10;, CSIF, GVHDS, IL-10, IL10A, TGIF, interleukin 10
外部IDOMIM124092 MGI96537 HomoloGene478 GeneCardsIL10
相關疾病
貝賽特氏症、​潰瘍性結腸炎[1]
基因位置(人類
1號染色體
染色體1號染色體[2]
1號染色體
白血球介素-10的基因位置
白血球介素-10的基因位置
基因座1q32.1起始206,767,602 bp[2]
終止206,774,541 bp[2]
RNA表達模式
查閱更多表達數據
直系同源
物種人類小鼠
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]
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],主要由單核白血球產生,並在較小程度上由淋巴細胞產生,即II型T輔助細胞(TH2),肥大細胞,CD4+CD25+Foxp3+調節性T細胞,以及活化的T細胞B細胞的某些子集。在這些細胞中觸發PD-1後,單核白血球可以產生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,在單核白血球中觀察到廣泛的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活化。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-γIL-2IL-3TNFαGM-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活化並導致血栓烷受體活化,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。

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,數千名患有各種自體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,例如程式性死亡配體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!)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。 

參考資料


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