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    請使用永久網址來引用或連結此文件: http://libir.tmu.edu.tw/handle/987654321/53365


    題名: CCAAT/ Enhancer Binding Protein β 訊息路徑參與Thrombin誘導肺部上皮細胞IL-8/CXCL8表現之探討
    Signal pathway of CCAAT/Enhancer Binding Protein β mediates Thrombin-Induced IL-8/CXCL8 Expression in Human Lung Epithelial Cells
    作者: 乃柏齡
    Nai, Po-Ling
    關鍵詞: c/EBP beta;IL-8/CXCL8;thrombin
    日期: 2012-07-20
    上傳時間: 2018-11-09 16:46:26 (UTC+8)
    摘要: Thrombin是一種serine蛋白酶，為已知凝血因子，會從受傷的血管釋放出來，且在肺部的發炎也扮演著很重要的角色。IL-8/CXCL8是ㄧ種嗜中性趨化因子，在氣喘病人中參與調節發炎細胞的移動。先前的研究顯示CCAAT/enhancer binding protein β (c/EBPβ) 在調控呼吸道發炎基因的表現扮演著重要的角色。我們先前的研究證明，thrombin可經由PKCalpha/c-Src和Rac/PI3K/Akt調控NF-κB的路徑來誘導肺部上皮細胞IL-8/CXCL8的表現。本論文將深入探討MEKK1、ERK、RSK1及c/EBPbeta等訊息傳遞在thrombin誘導人類上皮細胞IL-8/CXCL8表現所扮演的角色。我們結果顯示，thrombin誘導IL-8/CXCL8 釋放以及IL-8/CXCL8-luciferase活性可受到c/EBPβ siRNA及細胞轉染c/EBPbeta單點突變所抑制。再者，thrombin誘導IL-8/CXCL8 釋放以及IL-8/CXCL8-luciferase活性也可受到MEKK siRNA、PD98059 (MEK抑制劑)及RSK1 siRNA所抑制。Thrombin可誘導增加c/EBPβ磷酸化及c/EBPβ-luciferase活性。Thrombin誘導c/EBPβ磷酸化和c/EBPβ-luciferase活性會受到MEKK1 siRNA、PD98059及RSK1 siRNA所抑制。Thrombin可誘導增加RSK1磷酸化，且會受到MEKK1 siRAN及PD98059抑制。Thrombin可促使c/EBPβ結合於IL-8/CXCL8 promoter上。綜合以上所有結果，我們首次發現在人類肺部上皮細胞中，thrombin經由活化MEKK1/ERK/RSK1訊息傳遞路徑，誘導c/EBPβ的活化且與IL-8/CXCL8的promoter結合，進而促使IL-8/CXCL8的表現及釋放。

    Thrombin is a serine protease, a well-known coagulation factor generated in vascular injury and which also play an important role in lung inflammation. IL-8/CXCL8 is a neutrophil chemoattractant that is involved in regulating inflammation cell influx in airway. Previous study demonstrated that CCAAT/enhancer binding protein β (c/EBPβ) plays a critical role in the regulation of airway inflammatory gene expression. We previously showed that thrombin-induced IL-8/CXCL8 expression through PKCalpha/c-Src- and Rac/PI3K/Akt-dependent NF-κB pathways in human lung epithelial cells (A549). In this study, we further investigated the roles of MEKK1, ERK, RSK1, and c/EBPβ in thrombin-induced IL-8/CXCL8 expression. Thrombin-induced IL-8/CXCL8-luciferase activity and IL-8/CXCL8 release were inhibited by small interfering RNA of c/EBPβ (c/EBPβ siRNA) and by cells transfeted with the c/EBPβ site mutation of IL-8/CXCL8 construct in A549 cells. Moreover, thrombin-induced IL-8/CXCL8-luciferase and IL-8/CXCL8 release were also inhibited by MEKK siRNA, PD98059 (a MEK inhibitor), and RSK1 siRNA. Treatment of cells with thrombin caused increase in c/EBPβ phosphorylation and c/EBPβ-luciferase activity. The thrombin-induced increase in c/EBPβ phosphorylation and c/EBPβ-luciferase activity were inhibited by MEKK1 siRNA, PD98059, and RSK1 siRNA. Stimulation of cells with resulted in increase in RSK1 phosphorylation, this effect was inhibited by MEKK1 siRNA and PD98059. Treatment of cells with thrombin causes recruitment of c/EBPβ to the IL-8/CXCL8 promoter. These results suggest for the first time that thrombin activates MEKK1/ERK/RSK1 signaling pathway, which in turn initiates c/EBPβ activation and recruitment of c/EBPβ to the IL-8/CXCL8 promoter and ultimately induces IL-8/CXCL8 expression and release in human lung epithelial cells.
    描述: 碩士
    委員-顏茂雄
    委員-黃聰龍
    委員-許銘仁
    共同指導教授-陳炳常
    指導教授-林建煌
    資料類型: thesis
    顯示於類別:[醫學科學研究所] 博碩士論文

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