IL-6和TGF-β信號的協(xié)同作用促進FOXP3蛋白的降解
發(fā)布時間：2018-08-26 13:44
【摘要】：獲得性免疫系統(tǒng)中,CD4輔助性T細胞(CD4+T helper)根據(jù)它所接受的外界刺激和環(huán)境的不同能夠分化為Th1,Th2, Th17口iTreg。其中Th17細胞是一種重要的促炎性免疫細胞,能夠產(chǎn)生IL-17、IL-6和腫瘤壞死因子(TNF)等炎癥性細胞因子,不僅能介導(dǎo)機體的防御機制,同時在誘導(dǎo)自體免疫組織損傷,產(chǎn)生自身免疫性疾病方面也發(fā)揮重要的作用；相反,iTreg是一類具有負調(diào)節(jié)作用的免疫細胞,表達特異性轉(zhuǎn)錄因子FOXP3,能夠維持機體的免疫耐受性,減少免疫損傷。細胞因子TGF-β在CD4+T細胞分化成iTreg細胞的過程中發(fā)揮關(guān)鍵性的作用,它可以與T細胞受體信號通路協(xié)同作用,誘導(dǎo)Treg細胞的特異性蛋白FOXP3的表達；相反,當(dāng)TGF-p與IL-6協(xié)同作用時,可以誘導(dǎo)CD4+T細胞分化成TH17細胞。目前已經(jīng)證明,IL-6可以下調(diào)FOXP3蛋白的表達,從而使CD4+T細胞分化成Th17,但是其中的機制仍不清楚。 在來源于人的Treg中,IL-6的刺激會降低FOXP3mRNA的表達水平,為了研究IL-6對FOXP3蛋白表達的影響,我們構(gòu)建了穩(wěn)定表達FOXP3蛋白的Jurkat-T細胞系。我們注意到,當(dāng)用IL-6單獨刺激Jurkat-T細胞時,FOXP3的蛋白表達水平并沒有發(fā)生改變,而當(dāng)IL-6和TGF-p協(xié)同刺激時,FOXP3的蛋白表達水平在12h時開始減少。我們假設(shè)FOXP3蛋白表達水平的下降是由于蛋白酶體介導(dǎo)的降解,我們用蛋白酶抑制劑MG132處理細胞發(fā)現(xiàn),IL-6和TGF-p不能再使FOXP3蛋白的表達水平發(fā)生變化。我們的實驗數(shù)據(jù)證明,IL-6和TGF-p的協(xié)同刺激能夠激活某種泛素化酶,從而誘導(dǎo)FOXP3的泛素化降解,說明FOXP3的翻譯后修飾對于FOXP3蛋白的穩(wěn)定性、功能和T細胞的分化起到重要的調(diào)節(jié)功能。
[Abstract]:CD4 helper T cells in the acquired immune system (CD4 T helper) can differentiate into Th1,Th2, Th17 mouth iTreg. according to the external stimuli and the environment it receives. Among them, Th17 cells are important pro-inflammatory immune cells, which can produce inflammatory cytokines such as IL-17,IL-6 and tumor necrosis factor (TNF), which not only mediate the defense mechanism of the body, but also induce autoimmune tissue damage. On the contrary, ITreg is a kind of immune cells with negative regulatory effect. The expression of specific transcription factor FOXP3, can maintain immune tolerance and reduce immune damage. The cytokine TGF- 尾 plays a key role in the differentiation of CD4 T cells into iTreg cells. It can act synergistically with T cell receptor signaling pathway to induce the expression of specific protein FOXP3 in Treg cells. CD4 T cells can be induced to differentiate into TH17 cells. It has been proved that IL-6 can down-regulate the expression of FOXP3 protein, which makes CD4 T cells differentiate into Th17, but the mechanism is still unclear. In order to study the effect of IL-6 on the expression of FOXP3 protein, we constructed a Jurkat-T cell line with stable expression of FOXP3 protein. We observed that the protein expression level of FOXP3 did not change when Jurkat-T cells were stimulated by IL-6 alone, but the protein expression level of FXP3 began to decrease at 12h after co-stimulation of IL-6 and TGF-p. We hypothesized that the decrease of FOXP3 protein expression was due to proteasome mediated degradation. We treated cells with protease inhibitor MG132 and found that IL-6 and TGF-p could no longer change the expression level of FOXP3 protein. Our experimental data show that the co-stimulation of IL-6 and TGF-p can activate a Ubiquitin enzyme and induce the degradation of Ubiquitin of FOXP3, which indicates that the post-translational modification of FOXP3 is stable to the FOXP3 protein. Function and T cell differentiation play an important regulatory role.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2011
【分類號】：R392
本文編號：2205042
[Abstract]:CD4 helper T cells in the acquired immune system (CD4 T helper) can differentiate into Th1,Th2, Th17 mouth iTreg. according to the external stimuli and the environment it receives. Among them, Th17 cells are important pro-inflammatory immune cells, which can produce inflammatory cytokines such as IL-17,IL-6 and tumor necrosis factor (TNF), which not only mediate the defense mechanism of the body, but also induce autoimmune tissue damage. On the contrary, ITreg is a kind of immune cells with negative regulatory effect. The expression of specific transcription factor FOXP3, can maintain immune tolerance and reduce immune damage. The cytokine TGF- 尾 plays a key role in the differentiation of CD4 T cells into iTreg cells. It can act synergistically with T cell receptor signaling pathway to induce the expression of specific protein FOXP3 in Treg cells. CD4 T cells can be induced to differentiate into TH17 cells. It has been proved that IL-6 can down-regulate the expression of FOXP3 protein, which makes CD4 T cells differentiate into Th17, but the mechanism is still unclear. In order to study the effect of IL-6 on the expression of FOXP3 protein, we constructed a Jurkat-T cell line with stable expression of FOXP3 protein. We observed that the protein expression level of FOXP3 did not change when Jurkat-T cells were stimulated by IL-6 alone, but the protein expression level of FXP3 began to decrease at 12h after co-stimulation of IL-6 and TGF-p. We hypothesized that the decrease of FOXP3 protein expression was due to proteasome mediated degradation. We treated cells with protease inhibitor MG132 and found that IL-6 and TGF-p could no longer change the expression level of FOXP3 protein. Our experimental data show that the co-stimulation of IL-6 and TGF-p can activate a Ubiquitin enzyme and induce the degradation of Ubiquitin of FOXP3, which indicates that the post-translational modification of FOXP3 is stable to the FOXP3 protein. Function and T cell differentiation play an important regulatory role.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2011
【分類號】：R392
【參考文獻】
相關(guān)期刊論文 前1條
1 ;IL-10-Producing Type 1 Regulatory T Cells and Allergy[J];Cellular & Molecular Immunology;2007年04期
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