探討Theissenolactone C 抑制人類單核球細胞基質金屬蛋白 酵素活性表現之作用機制

Investigation of Inhibitory Mechanisms of the Theissenolactone C on Matrix Metalloproteinase-9 Expression in Activated Human Monocytic Cells

李昱潔(Yu-Cheih Lee)

指導教授 ： 蕭哲志

臺北醫學大學/醫學院/醫學科學研究所/碩士(2014年)

摘要

循環系統中的單核球，會被聚集到感染或受傷的組織，並分化為巨嗜
細胞及樹突細胞。在許多文獻指出，血液中的單核球當受到外來的刺激時，會分泌許多調節免疫功能的細胞激素 (cytokines) 或引發發炎反應。LPS 會誘發人類單核球細胞產生許多的促發炎介質 (pro-inflammatory)。它們所分泌的細胞激素如：TNF-α、IL-6 及IL-1β 在敗血症 (sepsis) 及慢性感染中扮演重要的角色。這些細胞激素可以提高單核球製造相關發炎酵素(matrix metalloproteinases, MMPs) 並導致嚴重的組織損傷。Theissenolactone C ( 簡稱LC53) 是源自於台灣株炭角菌科(Xylariaceae) Theissenia cinerea。我們發現LC53 在THP-1 細胞中會明顯在二十四小時內減少LPS 所引發的細胞外MMP-9、TNF-α 及IL-1β 的產生。並也具有抑制LPS 誘導的細胞外MMP-9 蛋白及mRNA 的表現。在訊息研究中，LC53 可以阻斷LPS 誘導的IκBα 降解、p65 的轉位及NF-κB 調控的基因報導 (gene reporter) 活性。LC53 也減少了IKKα/β 的磷酸化，而
不會影響到p38 的磷酸化。將microarray 結果利用IPA 資料庫分析，得知經由LC53 處理之後NF-κB 路徑與MMP-9 表現之相關性一致。未來將再評估LC53 在敗血症的活體實驗之療效與潛力。

關鍵字

基質金屬蛋白酶敗血症 ； 脂多醣體 ； 單核球

並列摘要

Circulation monocytes can be recuited to the infected or injured tissue and differentiate into macrophages or dendritic cells. In many documents, blood monocytes can be stimulated and secrete cytokines which regulate immune
function or cause inflammation. LPS can induce the experssion of many pro-inflammatory mediators in human monocytes, such as TNF-α、IL-6 and IL-1β, play important roles in sepsis or chronic infection. These cytokines
could also enhance the proteinase. (such as matrix metalloproteinase-9) production in monocytes, which leads to serious tissue injury. Theissenolactone C (LC53) is derived from the Taiwan strains Xylariaceae (Xylariaceae) Theissenia cinerea. We found LC53 obviously decrease LPS-induced extracellular MMP-9, TNF-α and IL-6 expression in THP-1 cells within 24 hours. It also inhibits LPS-induced extracellular MMP-9 protein and mRNA expression. In signaling studies, LC53 could block the LPS-induced degradation of IκBα, p65 translocation, and NF-κB regulated gene reporter activity . It also decreased the phosphorylation of IKKα/β while not affected the p38 phosphorylation. Consistently, after LC53 treatment, the NF-κB signaling and IPA-related gene network of MMP-9 was apparently interacted by microarray analyses. It will be interesting to evaluate the therapeutic potential of LC53 in animal septic model.

並列關鍵字

mmp--9 ； Sepsis ； LPS ； monocyte

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