IL-6和TGF-β信号的协同作用促进FOXP3蛋白的降解
发布时间：2018-08-26 13:44
【摘要】：获得性免疫系统中,CD4辅助性T细胞(CD4+T helper)根据它所接受的外界刺激和环境的不同能够分化为Th1,Th2, Th17口iTreg。其中Th17细胞是一种重要的促炎性免疫细胞,能够产生IL-17、IL-6和肿瘤坏死因子(TNF)等炎症性细胞因子,不仅能介导机体的防御机制,同时在诱导自体免疫组织损伤,产生自身免疫性疾病方面也发挥重要的作用；相反,iTreg是一类具有负调节作用的免疫细胞,表达特异性转录因子FOXP3,能够维持机体的免疫耐受性,减少免疫损伤。细胞因子TGF-β在CD4+T细胞分化成iTreg细胞的过程中发挥关键性的作用,它可以与T细胞受体信号通路协同作用,诱导Treg细胞的特异性蛋白FOXP3的表达；相反,当TGF-p与IL-6协同作用时,可以诱导CD4+T细胞分化成TH17细胞。目前已经证明,IL-6可以下调FOXP3蛋白的表达,从而使CD4+T细胞分化成Th17,但是其中的机制仍不清楚。 在来源于人的Treg中,IL-6的刺激会降低FOXP3mRNA的表达水平,为了研究IL-6对FOXP3蛋白表达的影响,我们构建了稳定表达FOXP3蛋白的Jurkat-T细胞系。我们注意到,当用IL-6单独刺激Jurkat-T细胞时,FOXP3的蛋白表达水平并没有发生改变,而当IL-6和TGF-p协同刺激时,FOXP3的蛋白表达水平在12h时开始减少。我们假设FOXP3蛋白表达水平的下降是由于蛋白酶体介导的降解,我们用蛋白酶抑制剂MG132处理细胞发现,IL-6和TGF-p不能再使FOXP3蛋白的表达水平发生变化。我们的实验数据证明,IL-6和TGF-p的协同刺激能够激活某种泛素化酶,从而诱导FOXP3的泛素化降解,说明FOXP3的翻译后修饰对于FOXP3蛋白的稳定性、功能和T细胞的分化起到重要的调节功能。
[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.
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R392
本文编号：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.
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R392
【参考文献】
相关期刊论文 前1条
1 ;IL-10-Producing Type 1 Regulatory T Cells and Allergy[J];Cellular & Molecular Immunology;2007年04期
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