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系統識別號 U0026-0812200911132879
論文名稱(中文) 腸病毒七十一型藉由細胞外調節激酶及NF-kB訊息傳導途徑誘發細胞介白素8之產生
論文名稱(英文) Enterovirus 71 Induces Interleukin-8 Production via Activation of Extracellular Regulated Kinase (ERK) and NF-kB pathway
校院名稱 成功大學
系所名稱(中) 醫事技術學系
系所名稱(英) Department of Medical Technology
學年度 92
學期 2
出版年 93
研究生(中文) 簡孟萱
研究生(英文) meng-xuan jian
電子信箱 autoimmune1@yahoo.com.tw
學號 t3691401
學位類別 碩士
語文別 中文
論文頁數 111頁
口試委員 口試委員-劉校生
口試委員-楊孔嘉
口試委員-林尊湄
指導教授-王貞仁
中文關鍵字 細胞介白素-8  細胞外調節激酶  腸病毒 
英文關鍵字 IL-8  Enterovirus  ERK  NF-KB 
學科別分類
中文摘要 中文摘要

  腸病毒71型( Enterovirus 71;EV71)分類上屬於小RNA病毒科( Picornaviridae),腸病毒屬(Enterovirus genus);不含外套膜的正股RNA病毒,其基因大小約7.5 kb,臨床症狀主要造成手足口症,而對於三歲以下嬰幼兒則較常併發神經系統病變或肺部發炎浸潤,甚至造成死亡,且腸病毒併發肺水腫的原因除了中樞神經系統病變外,也可能與感染期間誘發過度發炎反應促使細胞分泌過量的細胞激素進而造成肺部細胞的浸潤有關。屬於CXC chemokine的細胞介白素-8 (interleukin-8, IL-8)在過去的文獻中便是一個調節細胞發炎反應的細胞激素,可藉由許多物質所刺激產生,這其中包括:病毒;而在我們的實驗設計中以腸病毒七十一型感染肺部上皮細胞A549來探討在病毒感染的過程中其促細胞分裂原活化蛋白激酶(mitogen-activated protein kinase;MAP Kinase)訊息傳導之途徑對於誘發細胞分泌IL-8的產生所扮演的角色。
  在我們的實驗結果中利用各種蛋白之抗體包括: anti-Ras、anti-Raf-1、anti-P-MEK、anti-P-ERK及anti-IκB以西方墨點法(Western blotting)證明腸病毒感染A549細胞後可因病毒之外殼蛋白與細胞上之接受器結合後誘發Ras/Raf/MEK/ERK 及其下游的NF-κB 訊息傳導途徑之活化及IL-8的分泌;且分別以ERK及NF-kB訊息傳導之抑制劑-PD98059、Bay11-7802作用於細胞後顯示其會抑制腸病毒71型感染細胞分泌細胞激素IL-8,然而以JNK及p38之抑制劑作用下對於IL-8的誘發則無影響;此外,以病毒斑溶解試驗(Plaque assay)及RT-PCR的結果也顯示若阻止了ERK 傳導路徑的活化同樣也會影響病毒mRNA的合成及病毒的複製能力,因此於我們的實驗中顯示病毒感染後藉由NF-kB及ERK訊息傳導途徑的活化可誘發細胞激素IL-8的產生且增加病毒的感染能力,此可能可進一步解釋腸病毒七十一型感染的患者常併發肺水腫的致病機轉之一。



英文摘要 Abstract

  Enterovirus 71 (EV71), which belongs to the enterovirus genus within the family Picornaviridae, consists of a non-enveloped capsid surrounding a positive single-stranded RNA genome approximately 7.5 kb in size. EV71 infection can cause not only hand- foot- and- mouth disease or herpangina in children but may also cause progressive sympathetic hyperactivity, pulmonary edema (PE) and/or pulmonary hemorrhage that are associated with severe lung inflammation and neutrophil infiltration. Recent studies showed PE may be caused by increased pulmonary vascular permeability as the result of either brainstem lesions or a systemic inflammatory response caused by the excessive release of cytokines. The CXC chemokine interleukin-8 (IL-8) is an important mediator of the inflammatory response to much stimulation, including viruses. In this study, we explored the role of the mitogen-activated protein kinase (MAPK) pathway in the EV71-associated induction of IL-8 using a model system of A549 epithelial cells. We found that human pulmonary epithelial cells (A549) can induce the Ras/Raf/MEK signal pathways and release IL-8 upon infection with EV71. In addition, EV71 infection also induced a rapid activation of epithelial cell-derived extracellular regulated kinase (ERK), which can be blocked by MEK-specific inhibitor PD98059 and U0126 in dose- and time- dependent manners. Besides MEK-specific inhibitor, pretreatment of A549 cells with NF-kB inhibitors (bay11-7082) can also block the IL-8 production induced by enterovirus 71. However, IL-8 production was not affected by specific inhibitors for p38 MAP kinase (SB202190) and c-jun N-terminal kinase (SP60125). Furthermore, inhibitions of ERK activation by PD98059 prevent viral mRNA synthesis and viral replication. Taken together, these results indicated that EV71-mediated activation of the ERK and NF-kB pathways are causally related to the subsequent production of IL-8, which can contribute to the pathogenesis of pulmonary edema that associated with EV71 infection.



論文目次 目錄
中文摘要....................................................I
英文摘要....................................................III
圖目錄......................................................V
圖附錄......................................................VII
致謝........................................................VIII
第一章、緒論.................................................1
第二章、材料與方法..........................................21
A-1耗材儀器.................................................21
A-2培養液及相關藥品.........................................22
A-3抗體.....................................................25
A-4 抑制劑..................................................25
B-1細胞培養.................................................26
B-2繼代培養.................................................27
B-3細胞株之冷凍保存.........................................28
B-4 實驗用細胞之準備........................................28
B-5腸病毒71型之製備.........................................29
B-6病毒效價測定.............................................29
B-7 腸病毒71型的RNA萃取.....................................31
B-8 反轉錄聚合酵素連鎖反應(RT-PCR)..........................32
B-9聚合酶鏈鎖反應 (Polymerase chain reaction;PCR)..........33
B-10 酵素免疫法 (ELISA).....................................35
B-11 膠體電泳分析 (SDS-PAGE)................................37
B-12 西方墨點法 (Western blot)..............................39
B-13 偵測訊息傳導分子之表現.................................42
B-14 偵測抑制訊息傳導分子之表現.............................46
第三章、結果................................................47
1.腸病毒71型感染A549細胞於免疫螢光染色及誘發
細胞病變之形態..............................................47
2. 腸病毒71型感染A549細胞誘發訊息傳導途徑之活化.............47
2-1. Ras pathway之活化......................................47
2-2. Raf pathway之活化......................................48
2-3. MAP ERK Kinase (MEK) pathway之活化.....................49
2-4. ERK pathway之活化......................................49
2-5. IkB降解之情形..........................................53
3.腸病毒71型感染A549細胞誘發細胞激素IL-8之產生..............55
3-1. ERK pathway調控IL-8之表現............................56
3-2. JNK 及p38 pathways對於誘發IL-8之情形.................57
3-3. NF-kB pathway調控IL-8之表現............................58
4. ERK pathway調控病毒之複製................................59
4-1.抑制ERK pathway影響病毒感染力之效價...................59
4-2.聚合酶連鎖反應(PCR)偵測病毒吸附及病毒複製之情形.......60
第四章、討論................................................63
參考文獻....................................................73
圖..........................................................84
圖附錄.....................................................107
自述.......................................................111
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