| 中文摘要 |
內皮細胞功能異常導致免疫失調及發炎反應的發生，在粥狀動脈硬化過程中扮演著決定性的角色。Caffeic Acid Phenethyl Ester （CAPE） 為蜂膠中有效的抗發炎成分，曾被討論對於內皮細胞具有抗發炎與抗氧化的功效。訊息傳導與活化轉錄因子1 （STAT1） 與發炎反應及細胞週期轉錄過程有關，在內皮細胞中IFN-γ可以活化JAK-STAT之訊息傳遞途徑。本研究中主要是評估在內皮細胞受損時CAPE是否能夠扮演著抗發炎角色的保護作用，首先發現CAPE本身對於內皮細胞之毒性極低，若事先以CAPE處理過後，可以明顯抑制由IFN-γ所誘導的STAT1 的Tyr701及Ser727 磷酸化現象，且呈現劑量的相關性，但對於JAK1 及JAK2 的磷酸化則無明顯的抑制作用。同樣的，CAPE會進一步的抑制具有STAT偶合體連接之啟動子基因IP-10 的啟動子活化，IP-10 基因表現及蛋白質的分泌也都受到明顯的抑制。此外，T細胞沾黏到內皮細胞的多寡會經由干擾素的誘導而增加，此反應也會被CAPE預處理而壓制。總言之，CAPE對於干擾素所誘導的JAK-STAT1 活化路徑的抑制所代表的抗發炎特徵在本研究中獲得充分的闡釋，同時這些相關的認知可以提供用於血管動脈硬化之預防與治療劑之開發參考。Dysfunction of the endothelium contributes to pathological conditions of the arterial wall including atherosclerosis as a result of immunological and/or inflammatory responses. Caffeic acid phenethyl ester (CAPE) is an anti-inflammatory component of propolis (honeybee resin). CAPE was discussed for its anti-inflammatory and anti-oxidant properties on endothelial cells (ECs). Signal transducer and activator of transcription protein 1 (STAT1), a transcription factor involved in inflammation and the cell cycle, is activated by IFN-γ. In this study, we evaluated whether CAPE can serve as an anti-inflammatory agent during endothelial injuries. Pretreatment of ECs with CAPE dose-dependently inhibited IFN-γ-induced Tyr701 and Ser727 phosphorylation in STAT1 without affecting the phosphorylation of JAK1 and JAK2. Consistently, IFN-γ-induced STAT1 downstream target CXC chemokine, IP-10, was suppressed by CAPE pretreatment. It was also observed that CAPE inhibited promoter activity of IP-10 gene and the secretion of IP-10 protein. Furthermore, the T cell adhesion to IFN-γ-treated ECs was observed to be reduced after CAPE pretreatment. The anti-inflammatory properties of CAPE on IFN- γ-induced JAK-STAT1 activation were approved in the present study, and which provides a molecular basis for further therapeutic usage on vascular disorders. |
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