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    題名: ORMDL3在thrombin誘導人類呼吸道上皮細胞IL-8/CXCL8表現之角色探討
    Studies on the role of ORMDL3 in thrombin-induced IL-8/CXCL8expression in human lung epithelial cells
    作者: 邵彥瑋
    Shao, Yen-Wei
    貢獻者: 陳炳常
    關鍵詞: ORMDL3、ATF6、Thrombin、IL-8/CXCL8、AP-1
    日期: 2015-07-16
    上傳時間: 2020-08-28 16:10:35 (UTC+8)
    摘要: 氣喘影響全世界人口約佔7%，每年因氣喘發作而死亡約有25萬人。氣喘的特徵為呼吸道發炎反應及呼吸道重組。Thrombin 是已知的凝血因子，可從受傷血管釋放出來，在呼吸道發炎扮演著重要的角色。 Orosomucoid 1-like 3 (ORMDL3) 與氣喘緊密聯繫在一起，它可經由過敏的作用誘導肺部上皮細胞ORMDL3大量表現。然而 ORMDL3 訊息路徑是否參與 thrombin 誘導呼吸道上皮細胞 AP-1 活化及 IL-8/CXCL8 的表現目前還不清楚。在本研究我們發現在人類肺部上皮細胞中 thrombin 誘導 IL-8/CXCL8 釋放可受到 ORMDL3 小分子干擾 RNA (ORMDL3 siRNA) 所抑制。細胞給予 ORMDL3 siRNA 明顯抑制thrombin 誘導 ORMDL3 蛋白的表現。再者，thrombin 誘導 IL-8/CXCL8 釋放也可被 ATF6 siRNA 所抑制。細胞給予 ATF6 siRNA 明顯抑制ATF6 蛋白的表現。Thrombin 誘導 ATF6 從細胞質位轉至細胞核，此作用可被 ORMDL3 siRNA 所抑制。此外，thrombin 誘導 IL-8/CXCL8-luciferase 活性可受到細胞轉染單點突變 AP-1 之IL-8 載體所抑制。Thrombin 誘導 IL-8/CXCL8 釋放也會被 curcumin (AP-1抑制劑) 及 c-Jun siRNA 所抑制。細胞給予 c-Jun siRNA 明顯抑制 c-Jun 蛋白的表現。細胞刺激 thrombin 可依時間依賴增加 c-Jun 磷酸化及 JNK 磷酸化。Thrombin 誘導 c-Jun 磷酸化可被 ORMDL3 siRNA 及 ATF6 siRNA 所抑制。再者，我們也發現 thrombin 也會誘導 c-Jun 及 ATF6 複合體的形成及導致 ATF6、c-Fos 及 c-Jun 結合至 IL-8/CXCL8 之 AP-1 啟動子序列之中。這些結果顯示 ORMDL3、ATF6 及 AP-1 在 thrombin 誘導 IL-8/CXCL8 表現及釋放扮演著重要的角色。
    Orosomucoid 1-like 3 (ORMDL3) strongly associates with asthma, and its expression could be induced by allergen in lung epithelial cells. However, it remains unclear whether ORMDL3 signaling pathway plays a role in thrombin-induced AP-1 activation and IL-8/CXCL8 expression in lung epithelial cells. In this study, We found that thrombin-induced IL-8/CXCL8 release is attenuated by small interfering RNA of ORMDL3 (ORMDL3 siRNA) and ATF6 siRNA in human lung epithelial cells. Treatment of cells with thrombin caused an increase in the expression of ORMDL3 and ATF6, which were inhibited by ORMDL3 siRNA. In addition, thrombin caused ATF6 translocation from the cytosol to the nucleus, which was inhibited by ORMDL3 siRNA. Moreover, thrombin-induced IL-8/CXCL8-luciferase activity was inhibited by cells transfected with AP-1 mutation of IL-8 construct. Furthermore, thrombin-induced increase in IL-8/CXCL8 release was also attenuated by c-Jun siRNA and curcumin (an AP-1 inhibitor). Treatment of cells with c-Jun siRNA reduced c-Jun protein expression. Stimulation of cells with thrombin caused an increase in c-Jun phosphorylation and JNK phosphorylation in time-dependent manners. Thrombin-induced c-Jun phosphorylation was reduced by ORMDL3 siRNA and ATF6 siRNA. Furthermore, scientific evidence reveals that treatment of cells with thrombin induced ATF6 and c-Jun complex formation and recruits of ATF6, c-Fos, and c-Jun to the AP-1 of IL-8/CXCL8 promoter region. Taken together, these results suggest that the ORMDL3/ATF6/AP-1 signaling pathway plays a critical role in thrombin-induced IL-8/CXCL8 expression and release in human lung epithelial cells.
    描述: 碩士
    指導教授:陳炳常
    委員:陳彥州
    委員:黃聰龍
    資料類型: thesis
    顯示於類別:[醫學檢驗暨生物技術學系所] 博碩士論文

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