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研究生:游宗啟
研究生(外文):Chung-Chi yu
論文名稱:Bradykinin刺激人類肺臟上皮細胞環氧酵素-2表現的訊息傳遞路徑探討
論文名稱(外文):Studies on the signaling pathway of bradykinin-induced cyclooxygenase-2 expression in human pulmonary epithelial cells (A549)
指導教授:陳炳常林建煌林建煌引用關係
指導教授(外文):bing-Chang ChenChien-Huang Lin
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:生物醫學技術研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:中文
論文頁數:109
中文關鍵詞:緩激肽環氧酵素人類肺臟上皮細胞MAPKNF-kB酪氨酸激酵素
外文關鍵詞:bradykinincyclooxygenase-2A549MAPKNF-kBtyrosine kinase
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Bradykinin (BK)為kinin類的成員,是一種具有免疫活性的胜肽,為9個胺基酸所組成。BK屬於自泌素(autacoid)的一種,在體內會誘導許多發炎的反應。本論文所要探討的是bradykinin引發人類肺臟上皮細胞環氧酵素-2(cyclooxygenase-2, COX-2)釋放的訊息傳遞路徑。BK以劑量與時間相關的反應刺激COX-2的表現,此反應可被actinomycin D (轉錄抑制劑)及cycloheximide (轉譯抑制劑)所抑制。而給予B2 receptor antagonist (HOE140)也可以阻斷BK誘導的COX-2表現。相反地,給予B1 receptor antagonist (Lys-(leu8)des-Arg9-bradykinin)則不會抑制BK所引起的反應。Ras抑制劑(manumycin A)、Raf抑制劑(GW 5074)、MEK抑制劑(PD 98059)、p38 mitogen-activated protein kinase (MAPK) 抑制劑(SB 203580)及tyrosine kinase抑制劑(tyrphostin AG126及genistein)也會降低BK誘導COX-2的表現。同樣地,BK會進一步活化p44/42 和p38 MAPK,並且會被HOE140、tyrphostin AG126及genistein所抑制。此外,bradykinin所誘導p44/42及p38 MAPK的活性也分別被PD 98059及SB 203580特異性地抑制。NF-B抑制劑pyrrolidine dithiocarbamate (PDTC)及IB protease抑制劑L-1-tosylamido-2-phenylenylethyl chloromethyl ketone (TPCK)都可以抑制A549細胞中,BK所引發的COX-2表現。BK也可以活化IKK、使IB降解(degradation)及NF-B p65/p50轉位到細胞核,而BK所引發IKK的活性可以被PD 98059、SB 203580及Manumycin A抑制。我們使用electrophoretic mobility shift assay (EMSA)與轉染B-Luciferase來測量NF-B的結合能力與活性,則發現BK可以誘發NF-B與DNA結合能力及活性,此作用也可以被HOE140、PD 98059與SB 203580所抑制。綜合以上的實驗結果,BK可以活化tyrosine kinase、p44/42 MAPK、p38 MAPK以及IKK的作用,促使NF-B活化,最終導致A549細胞COX-2的表現,而這些訊號傳遞是經由bradykinin B2 receptor的路徑而來。

Bradykinin (BK), a membrane of kinins, is a 9 amino acid peptide which actives the innate immune system. BK, also an autatoid, induces many inflammation response. In this study, we investigated the signaling pathway of bradykinin-induced COX-2 expression in human pulmonary epithelial cells (A549). Bradykinin caused concentration- and time-dependent increases in COX-2 expression and this effect was inhibited by transcriptional inhibitor (actinomycin D) or translational inhibitor (cycloheximide). The B2 receptor antagonist, HOE140, could block bradykinin-induced COX-2 expression. In constract, B1 receptor antagonist (Lys-(leu8)des-Arg9-bradykinin) did not inhibit the bradykinin response. The Ras inhibitor (manumycin A), Raf inhibitor (GW 5074), MEK inhibitor (PD 98059), p38 MAPK inhibitor (SB 203580) and tyrosine kinase inhibitor (tyrphostin AG126 and genistein) attenuated bradykinin-induced COX-2 expression in A549 cells. In parallel, bradykinin induced p44/42 mitogen-activated protein kinase (p44/42 MAPK) and p38 MAPK activation; these effects were inhibited by HOE140, tyrphostin AG126, genistein. In similar, bradykinin induced activations of p44/42 MAPK and p38 MAPK were inhibited by the MEK inhibitor PD 98059 and the p38 MAPK inhibitor SB 203580, respectively. The NF-B inhibitor (pyrrolidine dithiocarbamate, PDTC) and IB protease inhibitor (L-1-tosylamido-2-phenylenylethyl chloromethyl ketone, TPCK) also decreased bradykinin-induced COX-2 expression in A549 cells. BK also caused IB Kinase activation, IB degradation, NF-B translocation and activation. Furthermore, the BK-induced increase in IKK activity were inhibited by PD 98059, SB 203580 and manumycin A. Using electrophoretic mobility shift assay (EMSA) and transient transfeced with B-luciferase to detect NF-B binding activity and NF-B activity, respectively, we found that bradykinin increased NF-B DNA-binding activity and NF-B activity; These effects were inhibited by HOE140, PD 98059 and SB 203580. In summary, these results indicated that bradykinin might activate tyrosine kinase, p44/42 and p38 MAPK and IKK pathway, which is turn initiates NF-B activation, and finally induced COX-2 expression in A549 cells, and this signaling transduction is through B2 receptor pathway.

致謝............................................................................................................ I
縮寫表...................................................................................................... II
藥物表.....................................................................................................IV
目錄...........................................................................................................V
圖表目次...............................................................................................VIII
壹、中文摘要...........................................................................................1-2
貳、英文摘要.........................................................................................3-4
参、緒論...............................................................................................5-16
肆、實驗材料和方法.........................................................................17-24
一、實驗材料....................................................................................17
二、實驗方法....................................................................................18
伍、結果.............................................................................................25-34
一、Bradykinin (BK)刺激A549細胞COX-2的表現....................25
二、Bradykinin 誘導COX-2 的表現是經由合成新蛋白而來.....25
三、Bradykinin經由B2 receptor刺激A549細胞COX-2表現...............................................................................................26
四、Bradykinin經由tyrosine kinase、Ras、Raf、MEK調控COX-2表現...........................................................................................26
五、Bradykinin經由B2 receptor刺激p44/42 MAPK的活化...............................................................................................27
六、Bradykinin經由tyrosine kinase、MEK活化p44/42 MAPK.28
七、Bradykinin經由活化p38 MAPK來調控COX-2表現..........29
八、Bradykinin引發p38 MAPK 的活化.......................................29
九、Bradykinin經由B2 receptor與tyrosine kinase來誘導p38 MAPK活化...........................................................................................30
十、Bradykinin活化轉錄因子NF-B來誘導COX-2的表現.....30
十一、Bradykinin引發 IB磷酸化、IB降解及p65/p50 NF-B轉位.......................................................................................31
十二、Bradykinin 增加IKK/ 磷酸化和激酶的活性...............32
十三、Bradykinin增加NF-B對DNA結合能力及活性............33
十四、Bradykinin經由B2 receptor活化p44/42 MAPK、p38 MAPK來調控NF-B 活化............................................................34
陸、討論.............................................................................................35-41
柒、參考文獻.....................................................................................42-52
捌、圖表.............................................................................................53-96
玖、附圖.............................................................................................97-98
附圖一 Bradykinin的生合成...........................................................97
附圖二 Bradykinin在呼吸道之作用機轉.....................................98

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