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博碩士論文 etd-0129113-122530 詳細資訊
Title page for etd-0129113-122530
論文名稱
Title
微小核醣核酸-142-3p 經由後轉錄作用調控新生兒臍帶血多型核白血球之介白素-6 表現
miRNA-142-3p regulates interleukin-6 production in neonatal cord blood PMNs via posttranscriptional regulation
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
62
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2013-01-07
繳交日期
Date of Submission
2013-01-29
關鍵字
Keywords
脂多糖、多型核白血球、人類臍帶血、微小核醣核酸-142-3p、介白素-6
IL-6, LPS, miRNA-142-3p, PMNs, Human umbilical cord blood
統計
Statistics
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The thesis/dissertation has been browsed 5697 times, has been downloaded 484 times.
中文摘要
新生兒比幼童及成人容易罹患敗血症,一旦患病嚴重度及死亡率亦高。已有文獻表示這跟免疫系統尚未發育完備有關;然而,亦有文獻發現,在新生兒敗血症患者的介白素-6 ( Interleukin-6,簡稱IL-6 )、介白素-8 ( Interleukin-8,簡稱IL-8 )、腫瘤壞死因子- α ( Tumor necrosis factor,簡稱TNF-α ) 皆有較高的表現。由此可知,新生兒受到感染時並非無能力產生發炎反應,而是調控異常的反應。微小核醣核酸 ( microRNAs ) 在發炎反應當中可經由後轉錄作用來抑制相關基因的表現。已知 microRNAs 的表現增減與免疫反應有關,但是 microRNAs 對於新生兒多型核白血球受到內毒素刺激反應的基因表現之調控機制尚未明朗。因此,本篇論文之目的欲探討在新生兒及成人多型核白血球受到內毒素作用誘導介白素-6表現的調控反應是否有所不同,同時並了解其作用機轉。
由結果得知,在成人樣品的對照下,經由內毒素 ( LPS ) 的作用,新生兒臍帶血多型核白血球確實會產生較高的介白素-6。在 Actinomycin D (ActD) 作用下測介白素-6 的 mRNA 半衰期,在成人及新生兒樣品中的表現無顯著差異。給予 Cycloheximide (CHX) 作用後,發現內毒素仍會促進新生兒臍帶血介白素-6 的 mRNA 表現,這暗示著後轉錄作用 (例如 miRNA 表現) 可能參與新生兒多型核白血球之介白素-6 的產生。由 miRNA 的實驗中發現新生兒臍帶血的多型核白血球受到內毒素的作用後,miR-142-3p 表現下降與介白素-6 的表現增加極有相關。在轉染 miR-142-3p precursor 到新生兒臍帶血的多型核白血球內,發現介白素-6 的訊息核醣核酸及蛋白質受到抑制。這顯示 miR-142-3p 表現在新生兒偏低,又因其可負向調控新生兒多型核白血球的介白素-6 表現,所以造成介白素-6 表現增加。在臨床上,希望可藉由調控微小核醣核酸的表現,進而調控新生兒多型核白血球之介白素-6 的產生。
Abstract
Neonates are particularly susceptible to sepsis than older children and adults, and are prone to morbidity and mortality in sepsis. Broad deficits across both innate and adaptive immune functions in neonates had been identified. However, it was found that IL-6, IL-8, TNF-α levels increased significantly in septic neonates. This suggests that altered but not deficient proinflammatory response is involved in neonatal infections. The microRNAs (miRNAs), contributing to the regulation of inflammation by repressing gene expression at the posttranscriptional level, have been linked to various immune responses, however, information on the regulation of miRNA in neonatal neutrophils (PMNs) in response to endotoxin is lacking. We investigated the differented IL-6 response of PMNs to endotoxin between newborns and adults, and studied the mechanism of augmented IL-6 production by neonatal PMNs. Our results found that cord blood PMNs expressed significantly higher IL-6 mRNA and protein than adult PMNs after stimulation by endotoxin. Addition of Actinomycin D (ActD) to assess the half-life of IL-6 mRNA revealed no significant difference of the LPS-induced IL-6 mRNA half-life between adult and neonatal, whereas addition of cycloheximide ( CHX ) found increase neonatal IL-6 mRNA significantly. This suggested that posttranscriptional mechanism involved the augmentation of IL-6 expression by neonatal PMNs. The functional validation identified that decrease of miR-142-3p was significantly associated with the higher IL-6 expression by umbilical cord blood PMNs after LPS stimulation. Transfection of the miR-142-3p precursor into umbilical cord blood PMNs significantly repressed the IL-6 mRNA and protein expression, suggesting that lower miR-142-3p expression associated with negative regulation of IL-6 production is involved in LPS stimulation of neonatal PMNs activation. Modulation of miRNA expression may be used to regulate IL-6 production in newborns with altered proinflammatory reactions.
目次 Table of Contents
論文審定書…………….……………………………………….……..……………i
誌謝…………………………………………………………………………ii
中文摘要……………………………………………………………….………iii
英文摘要………………………………………………..………………………iv
目錄……………………………………………………………………………v
圖次…………………………………………………………………………vii
表次……………………………………………………………………………viii
第一章 緒 論………………………………………………..……………….......1
1.1人體先天免疫……………………………………………………...1
1.2多型核白血球的免疫功能…………………………………………...1
1.3介白素-6 的結構及形成………………………………………......2
1.4介白素-6在免疫上的功能………………………………….………...3
1.5 微小核醣核酸 (microRNA) 的起源…………………………………..4
1.6 微小核醣核酸在免疫中的功能…….……………..………….…….…..5
1.6.1. miR-26b 調控的基因……….……………..…….…………....5
1.6.2. miR-155 調控的基因………………..……….….….…..........5
1.6.3. miR-146a 調控的基因……………………..…..……..…..……..6
1.7 新生兒敗血症的免疫生物指標……………….………………………….6
1.8 成人及兒童的免疫功能差異………………………..…………………..6
第二章 實 驗 目 的……………….………….…………………………8
第三章 實驗材料及方法………………….………..…….……………….9
3.1 血液的收集………..…………………………………………………...9
3.2分離血球細胞………..………………………….……………………9
3.3偵測細胞毒殺性及存活率…………………..…………………………9
3.4細胞培養及引發發炎反應………………………………….……….10
3.5核醣核酸 ( RNA ) 萃取及定量………………………………….....10
3.6 以即時定量聚合酶鏈鎖反應偵測介白素-6 訊息核醣核酸表現….…11
3.7 以酵素連結免疫吸附法偵測介白素-6 蛋白質表現……………………11
3.8 確認多型核白血球 (PMNs) 的純度…………………………………...12
3.8.1以細胞流式儀確認多型核白血球的純度…………..….….12
3.8.2 以劉氏染色法確認多型核白血球的純度..…….……..…..12
3.9 細胞免疫染色…………………………...…………………12
3.10 微小核醣核酸晶片陣列分析圖譜…………….……………………13
3.11以即時定量聚合酶鏈鎖反應分析miRNA表現…..………..…13
3.12 介白素-6 訊息核醣核酸轉錄作用的調控………………….………..14
3.13 介白素-6 後轉錄作用的調控 ………….…………………….….……14
3.14 miRNA-26b-5p 及 miR-142-3p precursor 轉染………………...15
3.15 微小核醣核酸 (miRNA) 資料庫應用……..………………………..15
3.16 資料統計分析………...……………………………………..…………..15
第四章 結 果…………………………………………....……………….………17
4.1 新生兒及成人多型核白血球純度大於 96% ,二者之純度無差異….17
4.2 內毒素誘導新生兒臍帶血多型核白血球產生較高的介白素-6
訊息核醣核酸及蛋白質表現…………….….....…………………..........…17
4.3 後轉錄作用調控新生兒臍帶血介白素-6 mRNA表現……………...18
4.4新生兒臍帶血及成人多型核白血球之miRNA表現………...…….18
4.5 有效的轉染miRNA到多型核白血球內…………………..…………..19
4.6 miR-26b 與介白素-6 蛋白質的表現無關……….….……..………20
4.7 miRNA-142-3p 抑制介白素-6 蛋白質及 mRNA 表現……...…….20
第五章 討 論…………………………………………………….………22
參考文獻…………………………………………….…………..……………….47
圖 次

圖4-1. 劉氏細胞染色法確認多型核白血球的細胞型態……………...….…..……..25
圖4-2. 以CD66b專一性抗體確認多型核白血球純度………...……………….…..26
圖4-3. 內毒素對多型核白血球的型態造成改變……………………………………27
圖4-4. 以免疫染色法確認新生兒多型核白血球之介白素-6 表現高於成人…..….28
圖4-5. 內毒素誘導新生兒多型核白血球產生較高的介白素-6 蛋白質表現….…..29
圖4-6. 內毒素誘導新生兒多型核白血球產生較高的介白素-6 mRNA表現………30
圖4-7. 新生兒及成人的介白素-6 mRNA穏定性差異…….……...…..…….31
圖4-8. 後轉錄作用調控多型核白血球介白素-6 表現……………...…….………...32
圖4-9. 新生兒臍帶血及成人多型核白血球的 miRNA 表現圖譜…………………33
圖4-10. 內毒素誘導成人及新生兒臍帶血多型核白血球之 miR-146a 的表現......35
圖4-11. 內毒素誘導成人及新生兒臍帶血多型核白血球之 miR-155 的表現........36
圖4-12. 內毒素誘導成人多型核白血球的 miR-26b 表現;抑制新生兒
臍帶血多型核白血球的 miR-26b 表現.......................................................37
圖4-13. 內毒素誘導成人多型核白血球 miR-142-3p 表現;抑制新生兒
臍帶血多型核白血球的 miR-142-3p 表現..................................................38
圖4-14. miRNA-26b precusor轉染效益分析…………….....……………..........39
圖4-15. miRNA-26b 對介白素-6 蛋白質無顯著的調控作用………….....…......40
圖4-16. miRNA-142-3p precusor 轉染效益分析…………....…..............….…..41
圖4-17. miRNA 轉染對細胞的毒殺性……..........……….....………..........…...…42
圖4-18. miRNA-142-3p 抑制介白素-6 mRNA的表現……................…….…..43
圖 4-19. miRNA-142-3p 對介白素-6 蛋白質的調控..……........................………44
圖 4-20. 人類和老鼠的 miR-142-3p 與介白素-6 mRNA 3’UTR 結合位比對.....45
圖 4-21. miR-142-3p 經由後轉錄機制調控介白素-6 的表現.............................46

表 次

表1. 以miRNA資料庫演算搜尋可與介白素-6 mRNA 3’UTR 結合的miRNA….34
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