本文選題：microRNA + NF-κB1��； 參考：《山東大學》2012年博士論文

【摘要】：固有免疫是機體抵抗病原微生物感染的第一道防線。巨噬細胞作為固有免疫中的一個重要成分,在清除病毒和細菌感染中發(fā)揮著重要的作用。它們通過其表面的模式識別受體(PRR)識別細菌和病毒結(jié)構上高度保守的病原相關分子模式(PAMP),然后經(jīng)過一系列的信號轉(zhuǎn)導機制最終激活NF-κB、IRF3和AP-1等轉(zhuǎn)錄因子,這些轉(zhuǎn)錄因子與相應的反應原件結(jié)合,產(chǎn)生大量的促炎性細胞因子、趨化因子等,從而促進炎癥反應的發(fā)生。盡管巨噬細胞活化后,產(chǎn)生的促炎性細胞因子和趨化因子在清除微生物感染中發(fā)揮著重要的作用,但是巨噬細胞過度活化,促炎性細胞因子和趨化因子的過度產(chǎn)生,將引發(fā)一些與炎癥相關的疾病或自身免疫性疾病。因此,嚴格的控制促炎性細胞因子的產(chǎn)生顯得尤為重要。 MicroRNA (miRNA)是近年來發(fā)現(xiàn)的進化上高度保守的一類長度約為21-25個核苷酸(nt)的內(nèi)源性非編碼小RNA分子,它通過與靶mRNA的3’-UTR互補結(jié)合,使靶mRNA被剪切或轉(zhuǎn)錄抑制。然而,miRNA是否可以負性調(diào)控LPS誘導的巨噬細胞的炎癥反應尚知之甚少。因此,本研究擬從以下幾個方面進行： 研究目的： 1、檢測LPS誘導巨噬細胞活化后,那些microRNA的表達被上調(diào)或下調(diào)； 2、研究被上調(diào)或下調(diào)的microRNA對LPS誘導的巨噬細胞活化發(fā)揮什么樣的作用； 3、探討上調(diào)或下調(diào)的microRNA對LPS誘導的巨噬細胞活化發(fā)揮作用的機制。 研究方法： 1、在LPS誘導活化的巨噬細胞中,檢測表達變化的microRNA。 1.1LPS誘導巨噬細胞活化情況的檢測 分離了小鼠骨髓來源的巨噬細胞(Bone marrow derived macrophages, BMDM),經(jīng)LPS刺激24h后,mRNA水平檢測iNOS、TNF-a和IL-12p40的表達,以確定巨噬細胞是否被LPS活化。 1.2microRNA Assay分析表達變化的microRNA 將上述經(jīng)過鑒定的樣本進行microRNA Assay分析,與未刺激組相比,觀察那些microRNA被上調(diào)或下調(diào)。 1.3Real-time驗證上調(diào)或下調(diào)的microRNA 用real-time的方法驗證microRNA Assay分析的數(shù)據(jù),進一步的確定表達變化的microRNA。 2、表達變化的microRNA對LPS誘導的巨噬細胞活化的影響。 2.1轉(zhuǎn)染相應microRNA mimics后,檢測巨噬細胞促炎性細胞因子的表達和分泌情況 將microRNA mimics轉(zhuǎn)染入腹腔巨噬細胞48h后,再用LPS刺激巨噬細胞使其活化,PCR分析炎性細胞因子mRNA水平上的變化,ELISA檢測炎性細胞因子蛋白水平的變化。 2.2轉(zhuǎn)染相應microRNA inhibitor后,檢測巨噬細胞促炎性細胞因子的表達和分泌情況 將microRNA inhibitor轉(zhuǎn)染入腹腔巨噬細胞48h后,再用LPS刺激巨噬細胞使其活化,PCR分析炎性細胞因子mRNA水平上的變化,ELISA檢測炎性細胞因子蛋白水平的變化。 3、表達變化的microRNA對LP8誘導的巨噬細胞活化的作用機制研究。 3.1轉(zhuǎn)染microRNA mimics和不同的TLR信號通路接頭分子以及NF-κB報告質(zhì)粒后,檢測NF-κB報告基因的活性 將：microRNA mimics和不同的接頭分子轉(zhuǎn)染HEK293細胞后,用報告基因的方法檢測microRNA mimics對NF-κB報告質(zhì)�；钚缘挠绊�。 3.2報告基因分析確定表達變化的microRNA對LPS誘導的巨噬細胞活化發(fā)揮作用的靶點 通過microRNA靶基因預測軟件分析microRNA有可能發(fā)揮作用的靶點,構建相應靶點的野生型或突變型3’-UTR報告基因質(zhì)粒,轉(zhuǎn)染HEK293細胞后,分析熒光素酶活性的變化,確定microRNA的作用靶點。 3.3WB檢測表達變化的microRNA對內(nèi)源性靶蛋白表達的影響 將microRNA mimics轉(zhuǎn)染巨噬細胞48h后,western blot檢測靶基因表達的變化,確定microRNA對內(nèi)源性靶基因的影響。 3.4表達變化的microRNA對LPS誘導的巨噬細胞活化發(fā)揮作用的方式 將microRNA mimics轉(zhuǎn)染巨噬細胞48h后,再用LPS刺激1h,染色質(zhì)免疫共沉淀(Chromatin immunoprecipitation, CHIP)方法檢測靶基因與促炎性細胞因子啟動子區(qū)的結(jié)合情況,揭示microRNA影響巨噬細胞促炎性細胞因子分泌的機制。 研究結(jié)果： 1、LPS誘導巨噬細胞活化后,microRNA-210的表達被顯著上調(diào)。 1.1LPS刺激BMDM24h后,促炎性細胞因子的表達顯著增加 我們用LPS刺激BMDM24h后,在mRNA水平上檢測了iNOS、TNF-a和IL-12p40的表達水平,發(fā)現(xiàn)與未刺激組相比,這些炎性細胞因子的表達被明顯的上調(diào)。由此也證明了我們樣本的收集是非常完美的。 1.2microRNA Assay分析發(fā)現(xiàn)microRNA-210的表達被上調(diào)了大約6倍 我們用上述經(jīng)過驗證的LPS未刺激和刺激組的總RNA進行了microRNA Assay分析,發(fā)現(xiàn)miR-155、miR-147和miR-146的表達分別被上調(diào)了344、18和4倍。這與以前的報道是非常一致的,從而也證明了我們實驗結(jié)果的可信性。未報道的microRNA,如miR-210被上調(diào)了大約6倍。 1.3Real-time PCR證實了miR-210的表達情況與芯片結(jié)果一致,其表達被顯著上調(diào) 我們合成了針對miR-210的特異性莖環(huán)引物,用real-time PCR方法分析了miR-210的表達,結(jié)果與芯片分析相符,與對照組相比,LPS刺激可顯著上調(diào)miR-210的表達。 2、m i R-210對LPS誘導的巨噬細胞活化起到一定的抑制作用。 2.1miR-210mimics抑制促炎性細胞因子的分泌 我們將miR-210mimics轉(zhuǎn)染入原代腹腔巨噬細胞后,用real-time PCR方法檢測了miR-210的表達情況,發(fā)現(xiàn)miR-210被上調(diào)了800倍左右。然后,我們再對轉(zhuǎn)染過的細胞進行LPS刺激,發(fā)現(xiàn)巨噬細胞促炎性細胞因子的分泌顯著下調(diào)。 2.1miR-210inhibitor促進促炎性細胞因子的分泌 我們將miR-210inhibitor轉(zhuǎn)染入原代腹腔巨噬細胞后,用real-time PCR方法檢測了miR-210的表達情況,發(fā)現(xiàn)miR-210被顯著下調(diào)。然后,我們再對轉(zhuǎn)染過的細胞進行LPS刺激,發(fā)現(xiàn)巨噬細胞促炎性細胞因子的分泌顯著增強。 3、miR-210通過靶向于NF-κ B1的3‘-UTR來發(fā)揮它的抑制效果。 3.1miR-210抑制NF-κ報告基因的活性 我們將control mimics或miR-210mimics和不同的接頭分子以及NF-κB報告質(zhì)粒共轉(zhuǎn)染HEK293細胞后,發(fā)現(xiàn)與對照組相比,miR-210mimics組可顯著降低MyD88、TRAF6、TAK1和IKK-P所誘導的NF-κB報告質(zhì)粒的熒光素酶活性。這也揭示了miR-210的作用靶點位于NF-κB本身或其下游。 3.2miR-210可與NF-κ B1的3’-UTR相互作用 經(jīng)過軟件預測分析,我們發(fā)現(xiàn)miR-210可與NF-κB1的3’-UTR發(fā)生相互作用。所以我們構建了NF-κB13'-UTR的野生型和突變型報告質(zhì)粒。miR-210mimics和報告質(zhì)粒共轉(zhuǎn)染實驗證實了miR-210確實可作用于NF-κB1的3’-UTR,影響報告基因的活性。這與我們前期的預測結(jié)果也是非常一致的。 3.3miR-210抑制內(nèi)源性NF-κ B1的表達 基于以上的實驗結(jié)果,我們用Western blot方法檢測了轉(zhuǎn)染miR-210mimics后內(nèi)源性NF-κB1的表達情況,發(fā)現(xiàn)NF-κB1的表達被顯著抑制。 3.4miR-210抑制p50/p65異二聚體與促炎性細胞因子啟動子區(qū)的結(jié)合 我們用CHIP的方法分析了p50/p65異二聚體與炎性細胞因子啟動子區(qū)的結(jié)合情況,發(fā)現(xiàn)在轉(zhuǎn)染miR-210mimics后,p50/p65異二聚體向啟動子區(qū)的結(jié)合顯著減少。 結(jié)論： 1、在LPS誘導活化的巨噬細胞中,miR-210的表達顯著上調(diào)； 2、miR-210抑制LPS誘導的巨噬細胞活化； 3、miR-210通過與NF-κB1的3’-UTR相互作用,從而抑制其蛋白的表達,最終使p50/p65異二聚體與促炎性細胞因子啟動子區(qū)的結(jié)合減少。 創(chuàng)新點及意義： 1、本研究首次證實了miR-210可抑制LPS誘導的巨噬細胞活化,而且闡明了這種抑制作用主要是miR-210通過它的"seed sequence"作用于NF-κB1的3’-UTR影響p105/p50的表達,最終導致了p50/p65異二聚體與促炎性細胞因子啟動子區(qū)的結(jié)合下降。 2、本研究為負性調(diào)控巨噬細胞提供新的實驗證據(jù),為巨噬細胞參與的炎癥反應性疾病的研究、診斷和治療提供新的思路。
[Abstract]:As an important component of innate immunity , the innate immunity plays an important role in removing viruses and bacterial infections . These transcription factors play an important role in removing viruses and bacterial infections . These transcription factors play an important role in clearing microbial infections through a series of signal transduction mechanisms .

MicroRNA ( miRNA ) is an endogenous non - coding small RNA molecule of approximately 21 - 25 nucleotides ( nt ) , which has been found to be highly conserved in recent years , which binds the target mRNA by cleavage or transcription by complementary binding to the 3 ' - untranslated region of the target mRNA . However , it is unknown whether the miRNA can negatively regulate the inflammatory response of LPS - induced macrophages . Therefore , the present study is to be conducted from the following aspects :

Purpose of study :

1 . After LPS - induced activation of macrophages , the expression of those microRNA was up - regulated or down regulated ;


2 . The effect of the up - regulated or down - regulated microRNA on LPS - induced activation of macrophages was studied .


3 . To investigate the mechanism of up - regulated or down - regulated microRNA on LPS - induced activation of macrophages .

Study method :

1 . In LPS - induced activated macrophages , the expression change of microRNA was detected .

1.1 Detection of LPS - induced activation of macrophages

The expression of iNOS , TNF - a and IL - 12p40 in bone marrow derived macrophages ( BMDM ) and bone marrow derived macrophages ( BMDM ) were isolated from mouse bone marrow .

1.2 microRNA Assay Analysis of MicroRNAs Expressing Change

The identified samples were subjected to microRNA assay analysis and observed to be up - regulated or down - regulated as compared to unstimulated groups .

1.3 Real - time verification of up - regulated or down - regulated microRNA

A real - time method was used to validate the data of the microRNA assay and further determine the microRNA with the change of expression .

2 . The effect of microRNA on LPS - induced activation of macrophages .

2.1 After transfection of the corresponding microRNA , the expression and secretion of pro - inflammatory cytokines in macrophages were detected .

The expression of inflammatory cytokine protein was detected by ELISA , and the level of inflammatory cytokine protein was detected by ELISA .

2.2 After transfection of the corresponding microRNA inhibitor , the expression and secretion of pro - inflammatory cytokines in macrophages were detected .

After transfection of microRNA inhibitor into peritoneal macrophages for 48 hours , macrophages were stimulated by LPS to activate the macrophages , and the changes of inflammatory cytokine mRNA levels were analyzed by PCR , and the changes of inflammatory cytokine protein levels were detected by ELISA .

3 . The effect of microRNA on the activation of LP8 - induced macrophages was studied .

3.1 The activity of NF - 魏B reporter gene was detected after transfection of microRNA microarray and different TLR signaling pathway linker molecules and NF - 魏B reporter plasmid .

The effect of microRNA expression on the activity of NF - 魏B reporter plasmid was investigated by using the reporter gene method after the microRNA molecules and the different linker molecules were transfected into 293 cells .

3.2 Report gene analysis determines the target point for the activation of LPS - induced macrophages by microRNA expression - varying microRNA

The microRNA target gene prediction software is used for predicting the target point that the microRNA has the potential to play a role , constructing a wild - type or mutant 3 & # x2032 ; & # x2032 ; & # x2032 ;

3 . Effect of microRNA on expression of endogenous target protein in detection of expression changes in 3WB

After 48h , the expression of target gene was detected by western blot , and the effect of microRNA on endogenous target gene was determined .

3.4 Expression of varying microRNA in LPS - induced activation of macrophages

After 48 hours of transfection , the binding of the target gene and the promoter region of pro - inflammatory cytokines was detected by using the method of LPS - stimulated 1h and chromatocytes ( CHIP ) , and the mechanism of microRNA influencing the secretion of pro - inflammatory cytokines was revealed .

Results of the study :

1 . After LPS - induced activation of macrophages , the expression of microRNA - 210 was significantly increased .

1 . After LPS stimulated BMDM24h , the expression of pro - inflammatory cytokines increased significantly .

After stimulated BMDM24h with LPS , the levels of iNOS , TNF - a and IL - 12p40 were detected at mRNA level . It was found that the expression of these inflammatory cytokines was up - regulated in comparison with unstimulated group .

1.2 microRNA Assay found that microRNA - 210 expression was up - regulated by about 6 times

We analyzed the total RNA of the non - stimulated and stimulated groups of LPS , and found that the expression of miR - 155 , miR - 147 and miR - 146 was up - regulated 344 , 18 and 4 times , respectively . This was consistent with previous reports , thus demonstrating the credibility of our experimental results . Unreported microRNA , such as miR - 210 , were up - regulated by about 6 times .

1.3Real - time PCR confirmed that the expression of miR - 210 was consistent with the results of the chip , and its expression was up - regulated .

We synthesized a specific stem - loop primer for miR - 210 , analyzed the expression of miR - 210 by real - time PCR , and the results were consistent with the analysis of the chip . Compared with the control group , LPS stimulation could significantly increase the expression of miR - 210 .

2 . m i R - 210 inhibited LPS - induced activation of macrophages .

2.1 . 1miR - 210D3 inhibits the secretion of pro - inflammatory cytokines

The expression of miR - 210 was detected by real - time PCR , and miR - 210 was increased by about 800 fold after transfected into the primary peritoneal macrophages by real - time PCR . Then , we stimulated the transfected cells and found that the secretion of pro - inflammatory cytokines was down - regulated .

2.1 miR - 210inhibitor promotes the secretion of pro - inflammatory cytokines

After transfection of miR - 210 inhibitor into the primary peritoneal macrophages , the expression of miR - 210 was detected by real - time PCR , and it was found that miR - 210 was downregulated . Then , we stimulated the transfected cells and found that the secretion of pro - inflammatory cytokines was significantly enhanced .

3 . miR - 210 exerts its inhibitory effect by targeting the 3 ' - untranslated region of NF - . kappa . B1 . 3.1 miR - 210 Inhibition of NF - 魏B Activity After co - transfection of the control kinase or miR - 210bp with different linker molecules and the NF - . kappa . B reporter plasmid , it was found that the miR - 210bp group significantly reduced the luciferase activity of the NF - . kappa . B reporter plasmid induced by MyD88 , TRAF6 , TAK1 and IKK - P compared to the control group , which also revealed that the target point of the miR - 210 is located at or downstream of the NF - . kappa . B itself . 3 . 2miR - 210 can interact with the 3 ' - untranslated region of NF - 魏B

We have found that miR - 210 can interact with the 3 ' - untranslated region of NF - 魏B , so we constructed the wild - type and mutant reporter plasmid of NF - kappa B - 1 . The co - transfection of miR - 210 and reporter plasmid confirmed that miR - 210 can act on the 3 ' - untranslated region of NF - 魏B , which affects the activity of the reporter gene . This is also very consistent with the results of our earlier prediction .

3.3miR - 210 inhibits the expression of endogenous NF - 魏B

Based on the above experimental results , we detected the expression of endogenous NF - 魏B in transfected miR - 210bp by Western blot , and found that the expression of NF - 魏B was significantly inhibited .

3 . 4miR - 210 Inhibits the Binding of p50 / P65 Heterodimer with pro - inflammatory cytokine promoter region

We analyzed the binding of p50 / P50 heterodimer and the promoter region of inflammatory cytokines by using CHIP method , and found that after transfected with miR - 210bp , the binding of p50 / P65 heterodimer to the promoter region was significantly reduced .

Conclusion :

1 . In LPS - induced activated macrophages , the expression of miR - 210 was significantly increased .


2 . miR - 210 inhibits LPS - induced macrophage activation ;


3 . miR - 210 inhibits the expression of its protein by interacting with the 3 ' - untranslated region of NF - . kappa . B1 , resulting in a reduction in the binding of the p50 / p50 heterodimer to the pro - inflammatory cytokine promoter region .

Innovation point and significance :

1 . For the first time , the study demonstrated that miR - 210 can inhibit LPS - induced activation of macrophages , and that this inhibitory action is mainly the expression of miR - 210 by its " seed sequence " in the 3 ' - untranslated region of NF - . kappa . B1 , which ultimately leads to a decrease in the binding of the p50 / p50 heterodimer with the pro - inflammatory cytokine promoter region .

2 . This study provides new experimental evidence for negative regulatory macrophages , and provides a new idea for the study , diagnosis and treatment of inflammatory response diseases involving macrophages .

【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R392

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