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研究生:林曉筠
研究生(外文):Hsiao-Yun Lin
論文名稱:金黃色葡萄球菌細胞壁成份---肽聚醣誘發微膠細胞造成神經性發炎之機轉
論文名稱(外文):Staphylococcus aureus-derived peptidoglycan induces neuroinflammatory responses in microglia
指導教授:賴志河盧大宇
指導教授(外文):Chih-Ho LaiDah-Yuu Lu
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:79
中文關鍵詞:微膠細胞神經性發炎一氧化氮合成酶第二環氧化酶介白素6
外文關鍵詞:MicroglianeuroinflammationPGNiNOSCOX-2NF-kBIL-6AP-1
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微膠細胞(microglia)是中樞神經系統吞噬細胞,它調控許多的免疫反應,同時扮演著防禦的角色,幫助中樞神經系統抵禦外來微生物。在本論文中利用金黃色葡萄球菌細胞壁成分peptidoglycan (PGN),探討其對microglia的活化及誘發發炎物質iNOS、COX-2和IL-6釋放,所造成的神經發炎機轉。素隨著PGN濃度和作用時間的增加iNOS、COX-2的mRNA和蛋白的表現量都增加,此外PGN刺激microglia產生發炎前驅物IL-1b、TNF-a和IL-6的mRNA大量表現;我們也證實了PGN刺激microglia產生 iNOS 和COX-2的蛋白和mRNA的表現是透過TLR2/MyD88訊息路徑,而NF-kB的抑制劑(PDTC、TPCK 和 Bay117082)都能抑制PGN刺激microglia產生 iNOS 和COX-2蛋白的表現,PGN也增加NF-kB transcription activity,進而啟動下游轉錄因子;我們證實了PGN增加iNOS 和COX-2的表現是透過TLR2/MyD88訊息路徑,並且活化PI3K/AKT訊息傳遞,進而活化IKKa/b和NF-kB。我們也針對PGN增加IL-6的表現做探討,在microglia和primary culture microglia,PGN增加IL-6的蛋白和mRNA的表現,此外PGN也會活化JNK和c-Jun。前處理JNK抑制劑(SP600125)和AP-1抑制劑(Tanshinone IIA 和curcumin)都會抑制PGN增加IL-6的蛋白和mRNA的表現,PGN會促進c-Fos和c-Jun由細胞質進入細胞核內;此外在EMSA的實驗中證明PGN會增加細胞核萃取蛋白和轉錄因子AP-1結合的活性,此現象則在前處理c-Fos和c-Jun 抗體後,產生競爭性抑制。PGN也會增加IL-6 luciferase activity,反之,前處理JNK抑制劑(SP600125)和將細胞轉殖JNK-DN (dominant-negative mutant)都會抑制IL-6 luciferase activity,綜合以上結果,PGN增加IL-6的表現是透過TLR2 receptor 經由 JNK/c-Jun 和 AP-1 pathways 。我們的研究結果提供PGN刺激microglia產生proinflammatory cytokine的機轉。PGN對於活化microglia扮演重要的角色;藉由了解microglia的活化及其造成的神經性發炎以及其中的訊息傳遞路徑,對於開發新的治療策略及能減少革蘭氏陽性菌成分引起的神經發炎的藥物有很大的幫助。

Microglia are the phagocytes of central nervous system and involved in immune responses , providing an initial line defence against invading pathogens. Here we explored the effect of cell wall component of Gram positive bacteria , Staphylococcus aureus, on glia activation and neuroinflammation. In particular, we investigate the signaling pathways of iNOS, COX-2 and IL-6 production caused by Staphylococcus aureus-derived peptidoglycan (PGN) and it’s signal transduction. PGN increased iNOS and COX-2 mRNA and protein expression in concentration and time dependent manner. In addition, PGN also induced IL-1b, TNF-a and IL-6 mRNA over-expression. We further confirmed that PGN induced iNOS and COX-2 expression is mediated by TLR2/MyD88. On the other hand, PGN-induced iNOS and COX-2 up-regulation were also attenuated by PI3K inhibitors (LY294002 and wortmanin) and AKT inhibitor. Treatment of microglia with NF-kB inhibitor, PDTC, TPCK and Bay117082, inhibited PGN-induced iNOS and COX-2 expression. PGN also increased kB-luciferase activity in microglia. Our data demonstrate that PGN-induced iNOS, COX-2 and proinflammatory cytokine expression in microglia are mediated by the TLR2/MyD88 and PI3K/AKT pathways, which in turn initiate IKKa/b and NF-kB activation. Moreover, we investigated the signaling pathways involved in PGN-induced IL-6 production. PGN increased IL-6 mRNA and protein expression in microglia and rat primary culture microglia time-dependently. PGN also increased JNK activation and c-Jun phosphorylation. Pretreatment with JNK inhibitor (SP600125) and AP-1 inhibitors (Tanshinone IIA and curcumin) reduced PGN-induced IL-6 mRNA and protein expression. PGN also increased p-c-Jun and c-Fos translocation from cytosol to nucleus. In addition, PGN-increased binding activity of activator protein-1 (AP-1) transcription factor was determined by electrophoretic mobility shift assay (EMSA). Moreover, PGN-increased AP-1 binding activity was reduced by treatment with c-Fos- and c-Jun-neutralized antibody. PGN also increased IL-6 luciferase activity, which was attenuated by JNK inhibitor, AP-1 inhibitors and JNK dominant-negative mutant (JNK-DN). Taken together these data suggest that PGN increases IL-6 production in microglia are through the TLR2receptor/JNK /c-Jun and AP-1 signaling pathway. Our results provide a mechanism of PGN induce proinflammatory cytokine expression, which indicates that PGN plays an important role in microglia activation. With a further understanding of these signal transduction pathways, we can develop novel therapeutic strategies to reduce neuroinflammation caused by Gram-positive organisms.

目錄--------------------------------------i
縮寫表----------------------------------iii
中文摘要----------------------------------1
英文摘要----------------------------------3
第一章、前言------------------------------5
研究背景----------------------------------6
1-1.中樞神經系統的發炎反應----------------6
1-2.革蘭氏陽性細菌細胞壁成分對中樞神經系統的影響-----------8
1-3.誘發性一氧化氮合成酶和第二環氧化酶在中樞神經系統的調節作用--------9
1-4.IL-6在中樞神經系統的作用和調控----------------10
第二章、研究方法----------------------------------23
2-1. 實驗材料-----------------------------------23
2-2. 實驗方法------------------------------------24
第三章、Peptidoglycan在microglia所誘發的iNOS 和COX-2合成機轉之探討-----32
3-1. PGN增加iNOS 和COX-2在microglia的表現----------------------------32
3-2. PGN刺激microglia產生proinflammatory cytokines的表現.-33
3-3. PGN透過TLR2 receptor/MyD88增加iNOS和COX-2 的表現-----------33
3-4. PGN透過PI3K/AKT訊息傳遞增加iNOS和COX-2 的表現34
3-5. NF-kB參與 PGN增加iNOS 和 COX-2 的表現---------------35
3-6. PGN活化IKKa/b和IkB啟動下游訊息傳遞------------------36
第四章、Peptidoglycan 在microglia 誘發IL-6的表現機轉之探討--------48
4-1. PGN刺激microglia產生IL-6的蛋白和mRNA的表現-----------48
4-2. PGN透過 TLR2 receptor 增加IL-6 蛋白的表現------------49
4-3. PGN調節IL-6的表現是透過JNK/c-Jun傳遞訊息-------------50
4-4. AP-1參與 PGN調節 IL-6的表現--------------51
第五章、結論與討論----------------------------------------64
參考文獻--------------------------------------------------69


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