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研究生:梁高誌
研究生(外文):Kao-Chih Liang
論文名稱:探討IL-1β誘發氣管平滑肌細胞上基質金屬蛋白酶-9表現的機轉
論文名稱(外文):Mechanisms of IL-1β-induced Matrix Metalloproteinase-9 Expression in Tracheal Smooth Muscle Cells
指導教授:楊春茂楊春茂引用關係
指導教授(外文):Chuen-Mao Yang
學位類別:碩士
校院名稱:長庚大學
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:2005
畢業學年度:93
語文別:英文
論文頁數:113
中文關鍵詞:細胞激酶1beta型基質金屬蛋白酶-9表皮生長因子受體血小板生長因子受器轉活化
外文關鍵詞:Interleukin-1betaMMP-9EGFRPDGFRTransactivation
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在一些文獻中已經發現在許多不同種類的細胞中,細胞激素(IL-1β)可以去誘導細胞基質金屬蛋白酶九型(matrix metalloproteinase-9)的表現並且接著參與發炎反應的整個進程。在整篇論文中,我針對人類呼吸管道細胞(human tracheal smooth muscle cells ; HTSMCs)來探討Mitogen-activated protein kinases (MAPKs) 以及 Nuclear factor-κB (NF-κB) 這些調控細胞發炎反應的常見訊號傳遞路徑如何參與細胞激素(IL-1β)誘導細胞基質金屬蛋白酶九型(matrix metalloproteinase-9)的表現。我們利用Gelatin Zymography, 西方點漬分析法(Western blotting), 以及Reverse transcriptase-polymerase chain reaction(RT-PCR)分析法探討在細胞先行處理MEK1/2 的抑制劑U0126、p38的抑制劑SB202190、c-Jun N-terminal kinase (JNK)的抑制劑SP600125之後, 我們可以看到:IL-1β 的確可以去使得p42/p44 MAPK、p38 MAPK、以及JNK磷酸化,並且這三種MAPKs的磷酸化反應各別也受到U0126、SB202190、以及SP600125的明顯抑制。此外我們也可以發現在相同的實驗模式之下細胞基質金屬蛋白酶九型的蛋白和mRNA表現亦會受到PI3-K的抑制劑LY294002、EGFR的抑制劑AG1478、PDGFR的抑制劑AG1296、Src的抑制劑PP1以及NF-κB的抑制劑helenalin抑制。另外,為了更進一步確定Akt、EGFR、PDGFR以及Src之間上下游的關係,我們使用共同免疫沉澱的方式來做探討。我們的實驗結果意味著IL-1β誘導在人類呼吸道平滑肌細胞中細胞基質金屬蛋白酶九型的表現時,Src是PDGFR以及EGFR的一個上游蛋白,而AKT則是PDGFR以及EGFR的一個下游蛋白。總歸而言,根據我們所完成的結果可以推測IL-1β誘導人類呼吸道平滑肌細胞中細胞基質金屬蛋白酶九型的表現時透過p42/p44 MAPK、p38 MAPK、JNK三者的磷酸化,以及Tyrosine kinase receptors的轉活化和NF-B的translocation皆是相當重要的訊號傳遞及調控途徑。這些實驗的結果針對呼吸管道上的疾病提供了細胞激素中的IL-1β如何去調控發炎反應的發生以及機轉上的新觀念, 並可以增加我們對IL-1β誘導人類呼吸道平滑肌細胞細胞基質金屬蛋白酶九型的表現機轉和發炎上的調控關係之了解,進而可以對我們在治療呼吸管道上的疾病有更多的幫助。
Interleukin-1β (IL-1β) has been shown to induce matrix metalloproteinase (MMP)-9 expression in various cell types and contribute to inflammatory responses. Here, we report that in human tracheal smooth muscle cells (HTSMC), the mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) pathways participate in MMP-9 expression by IL-1β. Zymographic, Western blotting, and RT-PCR analyses showed that IL-1β increased expression of MMP-9 mRNA and protein, which was inhibited by inhibitors of MEK1/2 (U0126), p38 (SB202190), and JNK (SP600125). Accordingly, IL-1β stimulated phosphorylation of p42/p44 MAPK, p38, and JNK which was attenuated by U0126, SB202190, and SP600125, respectively. On the other hands, IL-1β-induced MMP-9 mRNA and protein expression in HTSMCs were also significantly inhibited by PI3-K inhibitor LY294002, EGFR inhibitor AG1478, PDGFR inhibitor AG1296, Src inhibitor PP1 and NF-B inhibitor helenalin. Consistently, IL-1β-stimulated phosphorylation of Akt, EGFR, PDGFR and Src was attenuated by pretreatment with LY294002, AG1478, AG1296 and PP1, respectively. Otherwise, in order to find out the relationship of Akt, EGFR, PDGFR and Src, we used the method called co-immunoprecipitation. According to our results, we indicated that Src is the upstream protein of PDGFR and EGFR, and then AKT is downstream protein of PDGFR and EGFR in the model of IL-1β induce expression of MMP-9 in HTSMCs. Taken together, these results suggest that in HTSMCs, phosphorylation of p42/p44 MAPK, p38, and JNK transactivation of RTK and NF-B pathways are important for IL-1β-induced MMP-9 gene expression. These results provide new insight into the mechanisms of IL-1β action that cytokines may promote inflammatory responses in the airway disease. An increased understanding of mechanisms in IL-1β-induced MMP-9 expression on HTSMCs may contribute potential therapeutic value in the treatment of airway inflammation.
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目錄 (Contents)………………………………………………………………............................i
縮寫表 (Abbreviations)…………………………………………………………………….…iii
抑制劑表 (Inhibitors)………………………………………………………………….……....v
中文摘要 (Abstract in Chinese)…………………………………………………………...…..1
英文摘要 (Abstract in English)…………………………………………………………..........3
緒論 (Introduction)……………………………………………………………..………….…..4
材料和方法 (Materials and Methods)…………………………………………………….…..22
Materials.……………………………………………………………...……….…….…..22
Cell culture………………….…………………………………………….……………..22
Preparation of cell extracts and Western blot analysis………...………………………...23
Total RNA extraction and RT-PCR analysis………………………….………………....24
Immunofluorescence staining……………………………………………………….…..25
MMP-2 and MMP-9 gelatin zymogram………………………………………………...25
Co-immunoprecipitation assay……………………………………...………....………..26
Statistical Analysis……………………………….…….………………………….…….26
實驗結果 (Results)……………………………………………………………………..…….27
PART I:What signal components participate in IL-1β-induced the expression of MMP-9 in HTSMCs?......................................................................................…..…….27
IL-1β induces expression of MMP-9 in HTSMCs………………………………………….………...27
NF-κB participates in IL-1β-induced the expression of MMP-9 in HTSMCs………………...….…..27
MAPKs participate in IL-1β-induced the expression of MMP-9 in HTSMCs………………..…..…..27
p-Akt participates in IL-1β-induced the expression of MMP-9 in HTSMCs……….……..……...…..28
Src participates in IL-1β-induced the expression of MMP-9 in HTSMCs…………………..……......29
EGFR and PDGFR participate in IL-1β-induced the expression of MMP-9 in HTSMCs……………29
MAPKs, NF-κB, PI3-K, Src, EGFR, and PDGFR participate in IL-1β-induced the expression of mRNA of MMP-9 in HTSMCs…………………………………………………………………..……………29
PART II:What signaling components participate in IL-1β-induced the activation of Akt in HTSMCs?.............................................................................................................30
IL-1β induced phosphorylation of Akt in HTSMCs…………………………………………………..30
NF–κB do not participate in IL-1β-induced phosphorylation of Akt in HTSMCs……………………30
MAPKs do not participate in IL-1β-induced phosphorylation of Akt in HTSMCs…………………...31
PI3-K participates in IL-1β-induced phosphorylation of Akt in HTSMCs…………………………....31
Src participates in IL-1β-induced phosphorylation of Akt in HTSMCs………………………….……31
EGFR and PDGFR participate in IL-1β-induced phosphorylation of Akt in HTSMCs…………….…31
Whether MAPKs, NF-κB, PI3-K, Src, EGFR, and PDGFR participate in IL-1β-induced the phosphorylation of Akt in HTSMCs……………………………………...……………………………32
PART III:Src participates in IL-1β-induced the phosphorylation of EGFR and PDGFR in HTSMCs……..……………………………………………………………..33
IL-1β induces the phosphorylation of Src, EGFR, and PDGFR in HTSMCs…..………………….…..33
Src, but not Akt involves in transactivation of EGFR stimulated by IL-1β in HTSMCs………………33
Src, but not Akt involves in transactivation of PDGFR stimulated by IL-1β in HTSMCs…………….34
PART IV:Association between Src, EGFR, and PDGFR in IL-1β-stimulated HTSMCs…………………………………………………………………………......….35
IL-1β induces phosphorylation of Src, EGFR, and PDGFR, and forms a complex with Src in HTSMCs………………………………….....…………………………………………………….…...35
Sequential activation of Src, PDGFR and EGFR, and Akt stimulated by IL-1β in HTSMCs………...35
PART V:Cross-talk among MAPKs, NF-κB, and Akt stimulated by IL-1β in HTSMCs…………………………………………………………………………….…..36
IL-1β induces p42/p44 MAPK phosphorylation in HTSMCs…………………………………………36
IL-1β induces p38 MAPK phosphorylation in HTSMCs……………………………………………...37
IL-1β induces JNK phosphorylation in HTSMCs……………………………………………………..37
IL-1β induce the phosphorylation of p42/p44 MAPK in HTSMCs and Src、EGFR、PDGFR、AKT do not have interaction of p42/p44 MAPK………………………………………………………………..38
IL-1β induce the phosphorylation of p-38 MAPK in HTSMCs and Src、EGFR、PDGFR、AKT do not have interaction of p-38 MAPK………………………………………………………………………..39
IL-1β induce the phosphorylation of JNK in HTSMCs and Src、EGFR、PDGFR、AKT do not have interaction of JNK………………………………………………………………………………………39
IL-1β induces the translocation of NF-κB not mediated through MAPKS in HTSMCs……………….40
圖表 (Legends)…………….………………………………………………………...………...42
討論 (Discussion)…………………….……………………………………..………………....99
參考文獻 (References)………………………………………………………………….…....106
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2. 江振昌(2003),「大陸網際網路發展現況之研究」,《展望與探索》,第一卷第十二期,頁71-85。
3. 王信賢(2000),「當代西方『中國研究』之新制度主義典範分析」,《中國大陸研究》,第四十三卷第八期,頁23-46。
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5. 江振昌(2003),「大陸網際網路發展現況之研究」,《展望與探索》,第一卷第十二期,頁71-85。
6. 高少凡、倪炎元(2000),「國家主權在網路時代所面臨的處境與衝突」,《美歐季刊》,第十四卷第四期,頁471-501。
7. 王信賢(2000),「當代西方『中國研究』之新制度主義典範分析」,《中國大陸研究》,第四十三卷第八期,頁23-46。
8. 范傑臣(2002),「從多國網路內容管制政策談台灣網路規範努力方向」,《資訊社會研究》,頁205-223。
9. 梁正清(2003),「中國大陸網路傳播的發展與政治控制」,《資訊社會研究》,二頁211-260。
10. 梁正清(2003),「中國大陸網路傳播的發展與政治控制」,《資訊社會研究》,二頁211-260。
11. 梁正清(2003),「中國大陸國際宣傳策略研究:網際網路之發展與運用」,《東亞季刊》,第三十四卷第三期,頁31-50。
12. 梁正清(2003),「中國大陸國際宣傳策略研究:網際網路之發展與運用」,《東亞季刊》,第三十四卷第三期,頁31-50。
13. 張惠玲(2002),「中國發展市民社會的條件與限制」,《中國事務》,第九期,頁106-122。
14. 張惠玲(2002),「中國發展市民社會的條件與限制」,《中國事務》,第九期,頁106-122。
15. 寇健文(2001),「中共對網路資訊傳播的政治控制」,《問題與研究》,第四十卷第二期,頁33-54。
 
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