本文選題：腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體 + 凋亡��； 參考：《北京協(xié)和醫(yī)學(xué)院》2011年博士論文

【摘要】：細胞凋亡是機體免疫調(diào)節(jié)的重要方式,是機體維持免疫系統(tǒng)穩(wěn)定,避免自身免疫性疾病發(fā)生的重要機制。單核/巨噬細胞是一類重要的免疫細胞,同時具有效應(yīng)細胞和抗原遞呈細胞的功能。了解單核/巨噬細胞復(fù)雜的生存和凋亡的分子調(diào)控網(wǎng)絡(luò),協(xié)調(diào)細胞的命運,實現(xiàn)單核/巨噬細胞基本生物學(xué)功能,對腫瘤、炎癥和自身免疫等疾病的研究和干預(yù)都有著極為重要的指導(dǎo)作用。 TRAIL(tumor necrosis factor (TNF)-related apoptosis-inducing ligand)是腫瘤壞死因子(TNF)超家族的成員,可特異性地誘導(dǎo)腫瘤細胞凋亡,而對大多數(shù)的正常細胞沒有毒副作用,顯示TRAIL在腫瘤治療方面具有廣闊的應(yīng)用前景。除此以外,TRAIL還參與炎癥、感染和自身免疫性疾病的調(diào)節(jié)。 本論文首次發(fā)現(xiàn)TRAIL不僅能夠誘導(dǎo)caspase依賴的單核/巨噬細胞凋亡,而且可以引起自噬。 在TRAIL誘導(dǎo)單核/巨噬細胞凋亡過程中,加入自噬特異性抑制劑3-MA可以顯著激活caspase-3、-8和-9,使細胞凋亡率上升40-60%；而且,細胞內(nèi)LC3(microtubule-associated protein1A/1B-light chain3)表達顯著增強,RIP1表達逐漸上調(diào),IKK復(fù)合體聚集,NF-κB活性增強,細胞自噬水平呈先增強的趨勢；隨著TRAIL和3-MA刺激時間的延長,RIP1發(fā)生去泛素化,與NEMO形成的線性泛素鏈解體,致使細胞由自噬向凋亡轉(zhuǎn)變,DISC復(fù)合物內(nèi)caspase-8和c-FLIP切割形式發(fā)生轉(zhuǎn)變,隨著caspase-8的p41/43和c-FLIP的p22相應(yīng)剪切體的形成,caspase-8活性明顯增強；隨后,RIP1進一步降解,其蛋白量減少,NF-κB活性受到抑制,從而促進細胞凋亡增加。提示在TRAIL誘導(dǎo)單核/巨噬細胞凋亡的初期,自噬對細胞的存活起保護作用,RIP1泛素化修飾狀態(tài)改變成為細胞凋亡新的起始點,調(diào)節(jié)細胞凋亡。 綜上所述,TRAIL誘導(dǎo)單核／巨噬細胞凋亡過程中,自噬起重要保護作用,TRAIL通過調(diào)節(jié)RIP1表達及其泛素化修飾調(diào)節(jié)自噬到凋亡的轉(zhuǎn)變,凋亡與自噬的調(diào)節(jié)決定細胞的命運。 本論文首次發(fā)現(xiàn)TRAIL不僅能夠誘導(dǎo)單核／巨噬細胞凋亡,而且可以引起自噬。RIP1是調(diào)節(jié)TRAIL誘導(dǎo)單核/巨噬細胞凋亡和自噬的關(guān)鍵分子。這一研究結(jié)果對于更加深入地理解細胞凋亡和自噬調(diào)節(jié)的分子機制、以及TRAIL用于腫瘤、炎癥和自身免疫等疾病的研究和治療都具有重要指導(dǎo)意義。
[Abstract]:Apoptosis is an important way of immune regulation and an important mechanism to maintain the stability of immune system and avoid autoimmune diseases. Mononuclear / macrophages are important immune cells with the functions of effector cells and antigen presenting cells. Understand the complex molecular regulatory network of mononuclear / macrophage survival and apoptosis, coordinate the fate of cells, realize the basic biological functions of mononuclear / macrophage, The research and intervention of diseases such as inflammation and autoimmune play an important role in guiding. TRAIL(tumor necrosis factor TNF-related apoptosis-inducing ligand is a member of the tumor necrosis factor-related apoptosis-inducing (TNF-related) superfamily, which can specifically induce apoptosis of tumor cells, but has no side effects on most normal cells, indicating that TRAIL has a broad application prospect in tumor therapy. In addition, trail is involved in the regulation of inflammation, infection and autoimmune diseases. In this paper, we first found that TRAIL can not only induce caspase dependent mononuclear / macrophage apoptosis, but also induce autophagy. In the process of mononuclear / macrophage apoptosis induced by TRAIL, the addition of autophagy specific inhibitor 3-MA could significantly activate caspase-3, caspase-3, caspase-3, and increase the apoptosis rate by 40 to 60 percent. The expression of LC3(microtubule-associated protein1A/1B-light chain3) increased significantly, the expression of RIP1 increased gradually, the activity of NF- 魏 B increased and the level of autophagy increased first, and with the prolongation of TRAIL and 3-MA stimulation time, the expression of RIP1 became diubiquitin, and the activity of NF- 魏 B increased gradually, and the level of autophagy increased at first. The dissolution of the linear ubiquitin chain formed with NEMO resulted in the transformation of caspase-8 and c-FLIP cleavage from autophagy to apoptosis, which increased with the formation of corresponding shearing bodies of p41 / 43 of caspase-8 and p22 of c-FLIP, and further degradation of RIP1. The activity of NF- 魏 B was inhibited by the decrease of its protein content, which promoted the increase of apoptosis. These results suggest that autophagy may protect the survival of mononuclear / macrophage cells from apoptosis induced by TRAIL. The alteration of RIP1 Ubiquification modification may become a new starting point for apoptosis and regulate apoptosis. In the process of trail inducing monocyte / macrophage apoptosis, autophagy plays an important protective role. Trail regulates the transition from autophagy to apoptosis by regulating RIP1 expression and Ubiquitin modification. Apoptosis and autophagy regulate the fate of cells. In this paper, we first found that TRAIL can not only induce monocyte / macrophage apoptosis, but also induce autophagy. RIP1 is the key molecule to regulate monocyte / macrophage apoptosis and autophagy induced by TRAIL. These results are of great significance for further understanding the molecular mechanisms of apoptosis and autophagy, and for the application of TRAIL in the study and treatment of tumor, inflammation and autoimmune diseases.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2011
【分類號】：R363

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