本文關(guān)鍵詞： Toll樣受體 單核巨噬細(xì)胞 SHP-1 熱休克 CpG ODN　出處：《浙江大學(xué)》2005年博士論文　論文類型：學(xué)位論文

【摘要】：Toll樣受體(Toll like receptors,TLRs)作為一種重要的模式識(shí)別受體,主要表達(dá)于巨噬細(xì)胞和樹突狀細(xì)胞表面。TLRs是Ⅰ型跨膜蛋白,屬于IL-1R/TLR受體超家族,通過(guò)辨認(rèn)識(shí)別生物體內(nèi)保守的病原相關(guān)分子模式(Pathogen-associated molecule patterns,PAMPs),活化巨噬細(xì)胞和樹突狀細(xì)胞,產(chǎn)生細(xì)胞因子和趨化因子,啟動(dòng)天然免疫應(yīng)答,構(gòu)成機(jī)體免疫反應(yīng)的第一道防線。Toll蛋白最早發(fā)現(xiàn)在調(diào)控果蠅的胚胎發(fā)育過(guò)程中起重要作用,目前,在哺乳動(dòng)物細(xì)胞中相繼發(fā)現(xiàn)并克隆了11種TLR分子,選擇性識(shí)別病原體中特定的分子結(jié)構(gòu),以抵抗病原菌的入侵,TLR家族成員的缺失導(dǎo)致機(jī)體對(duì)病原體高度易感。本課題研究了單核巨噬細(xì)胞酪氨酸磷酸酶和熱休克對(duì)Toll樣受體信號(hào)轉(zhuǎn)導(dǎo)的調(diào)節(jié)以及相應(yīng)的作用機(jī)制。 第一部分 SHP-1參與巨噬細(xì)胞TLR9信號(hào)轉(zhuǎn)導(dǎo)通路的研究 細(xì)菌DNA不僅是遺傳的物質(zhì)基礎(chǔ),其中某些特定序列還具有免疫活性。人工合成CpG寡核苷酸(CpG-Oligodeoxynucleotides,CpG ODN)能模擬細(xì)菌DNA的免疫活性效應(yīng)。CpG ODN可活化自然殺傷細(xì)胞(Natural killer cell,NK細(xì)胞)、單核/巨噬細(xì)胞、樹突狀細(xì)胞、T細(xì)胞等,活化后的細(xì)胞可分泌IL-1、IL-6、TNFa等細(xì)胞因子、趨化因子、NO等免疫效應(yīng)分子,誘導(dǎo)天然免疫應(yīng)答。CpG ODN的辨認(rèn)和信號(hào)傳導(dǎo)通過(guò)TLR9所介導(dǎo)。TLR9識(shí)別配體后,通過(guò)MyD88-IRAK-TRAF6激酶途徑募集接頭蛋白髓系分化蛋白88(MyD88),結(jié)合并活化IL-1受體相關(guān)激酶(IRAKs)、腫瘤壞死因子受體相關(guān)因子6(TRAF6),活化下游MAPKs和NF-κB誘導(dǎo)激酶(NIK)、IKK、IκBa,活化后的NF-κB入核引起特定基因的表達(dá)。 信號(hào)轉(zhuǎn)導(dǎo)過(guò)程中許多信號(hào)分子相互作用,使信號(hào)轉(zhuǎn)導(dǎo)保持一定的強(qiáng)度能順利傳導(dǎo)并能及時(shí)終止。SHP-1酪氨酸磷酸酶SHP-1(Src homology 2 domain containingphosphatase 1)最早也命名為SHPTP-1,SHP,HCP和PTP1C,是個(gè)胞內(nèi)酪氨酸磷酸酶,主要表達(dá)于造血細(xì)胞。SHP-1含兩個(gè)N端SH2區(qū),單個(gè)磷酸酶區(qū),以及C端尾部的兩個(gè)酪氨酸磷酸化區(qū),是個(gè)淋巴細(xì)胞、巨噬細(xì)胞內(nèi)常見(jiàn)的信號(hào)調(diào)節(jié)分子。本實(shí)驗(yàn) 浙江大學(xué)博士學(xué)位論文 研究了在CpG ODN活化巨噬細(xì)胞TLRg誘導(dǎo)產(chǎn)生細(xì)胞因子等細(xì)胞免疫反應(yīng)過(guò)程中, SHP一1參與的調(diào)節(jié)作用及其可能的作用機(jī)制。 我們構(gòu)建了SHP一1高表達(dá)載體,PCR定點(diǎn)突變法構(gòu)建SHP一1催化活性突變載體 (C4535),經(jīng)測(cè)序鑒定正確。合成SHP一1 RNA干擾片段,轉(zhuǎn)染RAW264.7細(xì)胞以抑制 SHP一1蛋白合成。G418篩選穩(wěn)定表達(dá)SHP一1和催化活性突變mu一SHP一1 RAW細(xì)胞, 經(jīng)CpG ODN刺激后,發(fā)現(xiàn)穩(wěn)定高表達(dá)SHP一1的巨噬細(xì)胞的細(xì)胞因子IL6的分泌顯著 增加,而對(duì)于SHP一1催化活性突變的巨噬細(xì)胞,經(jīng)CpG ODN刺激后其IL一6的分泌水 平依然升高,與高表達(dá)SHP一1巨噬細(xì)胞相比沒(méi)有明顯變化。而RNA干擾SHP一1蛋白 表達(dá)后,IL6的分泌水平下降。熒光素酶報(bào)告基因檢測(cè)顯示SHP一1高表達(dá)的巨噬細(xì)胞 經(jīng)CpG ODN刺激后NF一忍的活化水平增高。這些實(shí)驗(yàn)現(xiàn)象表明SHP一1高表達(dá)可能促 進(jìn)CpG ODN刺激后NF一沼的活化,從而促進(jìn)細(xì)胞因子IL一6的分泌。而催化活性的高 低與SHP一1促進(jìn)細(xì)胞因子的表達(dá)關(guān)系不大。為進(jìn)一步探討SHP一1促進(jìn)CpG ODN刺激 巨噬后IL一6分泌的原因,檢測(cè)了MApK活化水平的改變。CpG ODN刺激后,發(fā)現(xiàn)SHP一1 高表達(dá)的巨噬細(xì)胞ERK、JNK的磷酸化水平?jīng)]有改變,而p38的磷酸化水平顯著增高, 說(shuō)明sHP一1促進(jìn)IL6的分泌可能部分與p38的磷酸化水平增高有關(guān)。免疫共沉淀進(jìn) 一步檢測(cè)了cpG ODN刺激后與SHP一1在巨噬細(xì)胞內(nèi)相互作用的一些信號(hào)分子,發(fā)現(xiàn) IKK、TRA王6與SHP一1形成蛋白復(fù)合物,顯示SHP一1可能通過(guò)與IKK、TRAF6結(jié)合活 化NF一慮,從而促進(jìn)IL6的分泌。 上述實(shí)驗(yàn)結(jié)果表明,SHP一1促進(jìn)CpG ODN刺激巨噬細(xì)胞IL6的表達(dá),其催化酶 活性的下降對(duì)IL6的表達(dá)沒(méi)有明顯影響,而RNA干擾后IL6的分泌水平下降,顯示 SHP一1的表達(dá)參與CpG ODN刺激后巨噬細(xì)胞p38、NF一慮的活化,而使IL一6的分泌增 高,表明SHP一1是個(gè)參與CPG ODN江LRg信號(hào)通路一個(gè)重要的胞內(nèi)調(diào)控分子。本實(shí)驗(yàn) 結(jié)果為深入認(rèn)識(shí)cpG oDN月1,R9介導(dǎo)的信號(hào)轉(zhuǎn)導(dǎo)的調(diào)控提供了一個(gè)新的機(jī)制。 第二部分熱休克調(diào)節(jié)單核細(xì)胞Toll樣受體信號(hào)轉(zhuǎn)導(dǎo)研究 熱休克能通過(guò)誘導(dǎo)熱休克蛋白(Heat shock protein:3,HSPs)等應(yīng)激蛋白誘導(dǎo)機(jī)體 的固有免疫應(yīng)答。免疫反應(yīng)中抗原遞呈細(xì)胞(Antigen一Presenting een,APC)通過(guò)調(diào)節(jié)病 原識(shí)別受體(pathogen reeo邵ition reeeptors,pRRs),識(shí)別病原相關(guān)的分子模式(RAMPs)
[Abstract]:Toll like receptors (Toll like receptors, TLRs) as a kind of important pattern recognition receptors expressed mainly in macrophages and dendritic cell surface.TLRs is a type I transmembrane protein, belongs to the IL-1R/TLR superfamily, by identifying the pathogenic organisms related to conserved recognition molecules (Pathogen-associated molecule patterns, PAMPs model), and activated macrophages dendritic cells, cytokines and chemokines, initiate innate immune response, the immune response constitutes the first line of defense.Toll protein was found to play an important role in the process, regulation of Drosophila embryonic development at present, have been found and cloned 11 TLR molecules in mammalian cells. The specific molecular structure of selective recognition of pathogens, to resist the invasion of pathogens, the lack of a member of the TLR family will cause the body to be highly susceptible to pathogens. The subject of mononuclear macrophage The regulation of phagocytic tyrosine phosphatase and heat shock to the signal transduction of Toll like receptor and the corresponding mechanism of action.
Part one SHP-1 participates in the study of TLR9 signal transduction pathway in macrophages
DNA is not only based on the genetic material of bacteria, which also has a certain sequence of immune activity of synthetic CpG oligonucleotides (CpG-Oligodeoxynucleotides, CpG ODN) to.CpG ODN immune effect simulation of bacterial DNA can activate natural killer cells (Natural killer cell, NK cells), monocytes / macrophages, dendritic cells, T cells and so on. The activated cells can secrete IL-1, IL-6, TNFa and other cytokines, chemokines, NO and other immune effector molecules induced by the innate immune response.CpG ODN recognition and signal transduction mediated by TLR9.TLR9 ligand recognition, through the MyD88-IRAK-TRAF6 adaptor protein kinase pathway to raise myeloid differentiation protein 88 (MyD88), combined with and the activation of IL-1 receptor associated kinase (IRAKs), tumor necrosis factor receptor associated factor 6 (TRAF6), activation of downstream MAPKs and NF- K B induced kinase (NIK), IKK, I K Ba activation of NF- kappa B nuclear special cause The expression of the fixed gene.
The interaction of many signal molecules in signal transduction, signal transduction to maintain a certain strength of the smooth transmission and timely termination of.SHP-1 tyrosine phosphatase SHP-1 (Src homology 2 domain containingphosphatase 1) was also named as SHPTP-1, SHP, HCP and PTP1C, is an intracellular tyrosine phosphatase, mainly expressed in hematopoietic cells containing.SHP-1 two N SH2, a single phosphatase domain two tyrosine phosphorylation and C tail, is a common signal molecular regulation of lymphocytes, macrophages in vitro.
Doctoral Dissertation of Zhejiang University
The immunoreaction of cytokines, such as cytokines, induced by CpG ODN activated macrophage TLRg, was studied.
The regulatory role of SHP 1 participation and its possible mechanism of action.
We constructed a SHP 1 high expression vector and PCR fixed-point mutation method for the construction of SHP 1 catalytic active mutation carrier
(C4535), correct by sequencing, synthesis of SHP 1 RNA interference fragments, transfection of RAW264.7 cells to inhibit
SHP 1 protein synthesis.G418 screening stable expression of SHP 1 1 and catalytic activity mutation mu SHP 1 RAW cells,
After CpG ODN stimulation, it was found that the secretion of cytokine IL6, which was stable and high expression of SHP 1 macrophages, was significant
Increase, and for macrophages with SHP 1 catalytic activity mutation, the IL 6 secreted water after the stimulation of CpG ODN
The level still increased, and there was no significant change compared with the high expression of SHP 1 1 macrophages. RNA interfered with SHP 1 protein.
After expression, the secretory level of IL6 decreased. The luciferase reporter gene detection showed the high expression of SHP 1 macrophages
The activation level of NF was increased after CpG ODN stimulation. These experimental phenomena suggest that the high expression of SHP 1 may be promoted.
The activation of NF marsh after the stimulation of CpG ODN stimulates the secretion of cytokine IL 1 6, and the catalytic activity is high
The relationship between low and SHP 1 promoting the expression of cytokines is not significant. To further explore the promotion of SHP 1 1 to promote CpG ODN stimulation
The cause of IL 6 secretion after Mega phagocytosis, detection of MApK activation level changes.CpG ODN stimulation, found SHP 1
The high expression of macrophage ERK, the level of phosphorylation of JNK did not change, and the level of phosphorylation of p38 was significantly higher.
This shows that the possible part of sHP 1 to promote the secretion of IL6 is related to the increased phosphorylation level of p38.
One step detected some of the signal molecules interacting with SHP 1 in macrophages after cpG ODN stimulation.
IKK, TRA King 6 and SHP - 1 forming protein complex, showing that SHP 1 1 may be combined with IKK, TRAF6
The consideration of NF, thus promoting the secretion of IL6.
The results of these experiments showed that SHP 1 promoted CpG ODN to stimulate the expression of IL6 in macrophage, and its catalytic enzyme
The decrease of activity had no significant effect on the expression of IL6, but the secretion level of IL6 decreased after RNA interference.
The expression of SHP 1 participates in the activation of p38, NF in macrophages after CpG ODN stimulation, and increases the secretion of IL 6.
High level, indicating that SHP 1 is an important intracellular regulator involved in the CPG ODN LRg signaling pathway.
The results provide a new mechanism for the in-depth understanding of cpG oDN 1, and the regulation of signal transduction mediated by R9.
Study on the signal transduction of Toll like receptor in the second part of heat shock regulating monocyte
Heat shock can induce the body by inducing stress proteins such as Heat shock protein:3 (HSPs) and other stress proteins
The intrinsic immune response. The antigen presenting cell (Antigen Presenting een, APC) in the immune response is mediated by the regulation of the disease
The original recognition receptor (pathogen reeo Shao ition reeeptors, pRRs), identifying the molecular pattern associated with the pathogen (RAMPs)

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2005
【分類號(hào)】：R392.1

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