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標題: | 類黃鹼素在肺泡上皮細胞抑制丙型干擾素引發
黏著分子表現之研究 Inhibitory Effect of Flavonoids on the Intercellular Adhesion Molecule-1 Expression Induced by IFN-γ in Human Alveolar Epithelial Cells |
作者: | Yu-Fan Chang 張宇凡 |
指導教授: | 陳青周 |
關鍵字: | 丙型干擾素,黏著分子,類黃鹼素, IFN,flavonoids, |
出版年 : | 2005 |
學位: | 碩士 |
摘要: | 黏著分子ICAM-1被證實,在發炎反應以及癌化反應中扮有重要角色;而類黃鹼素具強抗發炎效果,並廣泛存在於植物界中。在本論文中,以一系列類黃鹼素處理後,篩選出flavonol類的kaempferol和quercetin以及flavone類的apigenin和luteolin,可抑制IFN-γ所誘發之ICAM-1表現和NCI-H292細胞之侵入作用。在IFN-γ引發ICAM-1表現之路徑中,STAT1 tyrosine 701以及serine 727之磷酸化扮有重要角色;kaempferol和quercetin會抑制STAT1 serine 727之磷酸化,而apigenin和luteolin則是對STAT1 serine 727及tyrosine 701之磷酸化皆有抑制作用。進一步探討IFN-γ引發STAT1 serine727磷酸化之相關路徑,發現Y27632(ROCK抑制劑)、LY294002(PI3K抑制劑)和SP600125(JNK抑制劑)均會抑制IFN-γ所引發之STAT1 serine 727之磷酸化,但IFN-γ在NCI-H292細胞並不活化AKT和JNK,而LY294002和SP600125會抑制mTOR之磷酸化,表示LY294002和SP600125會直接抑制mTOR之活化,因此,IFN-γ造成STAT1 serine 727之磷酸化可能是經由活化mTOR而來。本實驗中,kaempferol、quercetin、apigenin和luteolin皆抑制mTOR之磷酸化,因此,推論類黃鹼素可能是經由抑制mTOR之活化,因而抑制STAT1 serine 727之磷酸化,進而抑制IFN-γ所引發之ICAM-1表現,並抑制癌細胞之侵入。 The intercellular adhesion molecule-1 (ICAM-1) has been implicated in the process of inflammation. Flavonoids which are naturally occurring polyphenolic compounds with a wide distribution throughout the plant kingdom, have potent anti-inflammatory property. Pretreatment of cells with flavonols ( kaempferol and quercetin ) and flavones ( apigenin and luteolin ) inhibited the IFN-γ-stimulated ICAM-1 expression and cell invasion of NCI-H292 cells. The ICAM-1 promoter activity induced by IFN-γ was attenuated using serine 727 or tyrosine 701 mutant of STAT1, indicating the critical role of tyrosine 701 or serine 727 phosphorylation in the IFN-γ-induced ICAM-1 expression. Kaempferol and quercetin inhibited the phosphorylation of serine 727, while apigenin and luteolin inhibited that of serine 727 and tyrosine 701. The ROCK inhibitor(Y27632), PI3K inhibitor(LY294002)and JNK inhibitor(SP600125)inhibited the phosphorylation of STAT1 serine at 727. However, activation of AKT or JNK was not induced by IFN-γ. IFN-γ-induced phosphorylation of mTOR was inhibited by LY294002 and SP600125, indicating the direct inhibition on mTOR activation by these two inhibitors. These results also suggested that IFN-γ-induced phosphorylation of serine 727 is through the activation of mTOR. Kaempferol, quercetin, apigenin and luteolin inhibited the phosphorylation of mTOR as well. In summary, the inhibitory effects of flavonoids on ICAM-1 expression are mediated by the sequential attenuation of mTOR/p70 s6kinase signaling pathways and serine 727 phosphorylation of STAT1 |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/36594 |
全文授權: | 有償授權 |
顯示於系所單位: | 藥理學科所 |
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