肿瘤抑制因子Rb选择性抑制天然免疫IFN-β产生及其机制研究

发布时间：2018-06-01 04:40

本文选题：成视网膜母细胞瘤蛋白 + 天然免疫　；参考：《浙江大学》2015年博士论文

【摘要】：Ⅰ型干扰素(IFN)作为天然免疫反应中重要的细胞因子,在抗病原体感染过程中发挥重要作用,而其产生的表观调节机制尚不清楚。肿瘤抑制因子在免疫反应和炎症中的作用日益为人们所认识,比如病毒感染会引起机体细胞的应激反应,影响肿瘤抑制因子的功能,从而产生持续的过度炎症反应导致肿瘤的发生。然而肿瘤抑制因子是否在天然免疫中发挥作用,其作用机制如何还亟待深入研究。我们的研究发现Rb作为重要的抑癌分子在免疫器官和细胞中广泛表达并且具有较高的水平。在腹腔巨噬细胞中,TLR配体及病毒触发天然免疫信号活化后,Rb的表达水平上调。髓系特异性敲除Rb (Rb1fl/flLyz2cre+)小鼠的腹腔巨噬细胞经TLR配体、RNA或DNA病毒诱导之后产生IFN-β产生显著增加,而其产生IFN-α, TNF-α, IL-6的水平没有明显变化。由于IFN-γ的产生增多,在致死剂量病毒感染时,Rb1fl/flyz2cre+小鼠与对照组相比生存率明显增高。c-Jun是IFN-γ enhancesome的组分之一,Rb通过与其相互作用选择性结合到Ifnb1的启动子区,而不与Ifna4、Tnf、116的启动子区结合。之后Rb进一步招募HDAC1和HDAC8使Ifnb1启动子区的组蛋白3 (Histone3, H3)和H4去乙酰化,从而选择性抑制Ifnb1的转录活化。综上所述,我们发现了Rb通过促进Ifnb1启动区组蛋白去乙酰化而选择性抑制病原体触发的IFN-β的产生,揭示了经典肿瘤抑制因子Rb在天然免疫中新的非经典调控功能。
[Abstract]:IFN, as an important cytokine in innate immune response, plays an important role in the process of anti-pathogen infection, but the mechanism of its apparent regulation is not clear. The role of tumor suppressor in immune response and inflammation is increasingly recognized. For example, viral infection can cause stress response of body cells and affect the function of tumor suppressor. This leads to a sustained over-inflammatory reaction leading to tumorigenesis. However, whether tumor suppressor plays a role in innate immunity and how to act on it need to be further studied. Our study found that RB, as an important tumor suppressor molecule, is widely expressed in immune organs and cells and has a high level. In peritoneal macrophages, TLR ligand and virus-triggered activation of innate immune signal were up-regulated. Mouse peritoneal macrophages were induced by TLR ligand RNA or DNA virus to produce IFN- 尾, but the levels of IFN- 伪, TNF- 伪 and IL-6 did not change significantly. Due to the increase of IFN- 纬 production, the survival rate of Rb1flr / flyz2cre mice was significantly higher than that of the control group. C-Jun was one of the components of IFN- 纬 enhancesome, and RB was selectively bound to the promoter region of Ifnb1 by interacting with the Rb1fl-flyz2cre mice. It was not associated with the promoter region of Ifna4 (TnfC116). Then RB further recruited HDAC1 and HDAC8 to deacetylation of histone 3 (H3) and H4 in the Ifnb1 promoter, which selectively inhibited the transcriptional activation of Ifnb1. In conclusion, we found that RB selectively inhibits the production of pathogen-triggered IFN- 尾 by promoting deacetylation of histone in the Ifnb1 promoter, which reveals the new nonclassical regulatory function of classical tumor suppressor RB in innate immunity.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R730.3

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