本文選題：成視網(wǎng)膜母細(xì)胞瘤蛋白 + 天然免疫��； 參考：《浙江大學(xué)》2015年博士論文

【摘要】：Ⅰ型干擾素(IFN)作為天然免疫反應(yīng)中重要的細(xì)胞因子,在抗病原體感染過程中發(fā)揮重要作用,而其產(chǎn)生的表觀調(diào)節(jié)機(jī)制尚不清楚。腫瘤抑制因子在免疫反應(yīng)和炎癥中的作用日益為人們所認(rèn)識,比如病毒感染會引起機(jī)體細(xì)胞的應(yīng)激反應(yīng),影響腫瘤抑制因子的功能,從而產(chǎn)生持續(xù)的過度炎癥反應(yīng)導(dǎo)致腫瘤的發(fā)生。然而腫瘤抑制因子是否在天然免疫中發(fā)揮作用,其作用機(jī)制如何還亟待深入研究。我們的研究發(fā)現(xiàn)Rb作為重要的抑癌分子在免疫器官和細(xì)胞中廣泛表達(dá)并且具有較高的水平。在腹腔巨噬細(xì)胞中,TLR配體及病毒觸發(fā)天然免疫信號活化后,Rb的表達(dá)水平上調(diào)。髓系特異性敲除Rb (Rb1fl/flLyz2cre+)小鼠的腹腔巨噬細(xì)胞經(jīng)TLR配體、RNA或DNA病毒誘導(dǎo)之后產(chǎn)生IFN-β產(chǎn)生顯著增加,而其產(chǎn)生IFN-α, TNF-α, IL-6的水平?jīng)]有明顯變化。由于IFN-γ的產(chǎn)生增多,在致死劑量病毒感染時,Rb1fl/flyz2cre+小鼠與對照組相比生存率明顯增高。c-Jun是IFN-γ enhancesome的組分之一,Rb通過與其相互作用選擇性結(jié)合到Ifnb1的啟動子區(qū),而不與Ifna4、Tnf、116的啟動子區(qū)結(jié)合。之后Rb進(jìn)一步招募HDAC1和HDAC8使Ifnb1啟動子區(qū)的組蛋白3 (Histone3, H3)和H4去乙�；�,從而選擇性抑制Ifnb1的轉(zhuǎn)錄活化。綜上所述,我們發(fā)現(xiàn)了Rb通過促進(jìn)Ifnb1啟動區(qū)組蛋白去乙酰化而選擇性抑制病原體觸發(fā)的IFN-β的產(chǎn)生,揭示了經(jīng)典腫瘤抑制因子Rb在天然免疫中新的非經(jīng)典調(diào)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- 偽, TNF- 偽 and IL-6 did not change significantly. Due to the increase of IFN- 緯 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- 緯 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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R730.3

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