6-dehydrogingerdione抑制內毒素誘發巨噬細胞發炎反應機轉之探討

Anti-inflammatory mechanisms of 6-dehydrogingerdione in macrophages stimulated by lipopolysaccharides

黃詩涵(Shih-Han Huang)

指導教授 ： 陳彥旭

高雄醫學大學/醫學院/醫學研究所/碩士(2012年)

摘要

敗血症是一種因嚴重感染所引發人體全身性發炎反應的複雜症候群，主要由革蘭氏陰性菌細胞壁的主成分內毒素所引起，當宿主受到感染時，巨噬細胞扮演極重要的角色，巨噬細胞會分泌免疫調節因子去對抗外來病原，敗血症是造成加護病房病人死亡的主要原因，敗血症的發生會同時引起發炎及抗發炎細胞激素分泌，造成敗血症病理過程的發生，其中IL-10、IL-6、TNF-α及IL-1β這四個細胞激素，更被發現在敗血症死亡的病患之血漿濃度遠高於敗血症存活的病患，此外當敗血症發生時除了誘發細胞激素的分泌，亦會同時誘發發炎的調控因子NO與PGE2的大量分泌，進而促使敗血性休克的發生，有效的抑制iNOS及COX-2便能有效反轉由NO與PGE2所造成的血液動力學的變化。
本篇研究我們使用薑純化物6-dehydrogingerdione (6-DG)，這一純化物在過去的研究中已被發現具有抗腫瘤及降低粥狀動脈硬化生成之藥物特性，而腫瘤與粥狀動脈硬化的發生皆與發炎反應相關，目前仍未有研究分析6-DG在敗血症抗發炎反應上的調控機轉，我們的實驗結果發現6-DG可以藉由抑制p-p38、p-IκBα及p-p65，進而抑制內毒素誘發巨噬細胞所表現的發炎相關基因：iNOS、COX-2、TNF-α、IL-1β、IL-6，此外6-DG亦藉由提高p-STAT1/p-STAT3比值，增加p-STAT1降低p-STAT3，進而抑制IL-10、IL-1β及IL-6這些受到STAT3所調控的基因，而這部份的假設我們已經藉由STAT1 esiRNA的實驗得到證實，由於我們的實驗結果顯示6-DG具備有效的降低發炎及抗發炎細胞激素分泌的能力，據此我們希望未來能有機會將6-DG運用於臨床上敗血症病人的治療。

關鍵字

薑 ； 轉錄因子 ； 內毒素 ； 細胞激素 ； 發炎 ； 敗血症

並列摘要

Sepsis, caused by serious infection occurs, a complex syndrome mainly induced by LPS, as a major cause of death in the ICU patients, can enhance production of both anti- and pro- inflammatory cytokines involved in the pathogenesis of sepsis. Plasma cytokines (IL-10, IL-6, TNF-α and IL-1β) are significantly higher in non-survival sepsis patients. In addition, sepsis also can induce overproduction of NO and PGE2 and these consequences result in increasing vascular permeability to cause septic shock eventually. The hemodynamic change can be reversed if the therapy can inhibit iNOS and COX-2 expression. In this current study we identify 6-dehydrogingerdione (6-DG), a pure compound of ginger, has some medical effects, such as anti-tumor and anti-atherosclerosis. However, 6-DG which has an anti-inflammatory effect against LPS induced inflammation in macrophages has not been investigated. The aim of our study is to figure out the possible anti-inflammatory mechanism of 6-DG in macrophages. The data showed 6-DG significantly attenuated LPS-induced inflammatory status. Moreover 6-DG decreased LPS-induced production of iNOS, COX-2, IL-1β, IL-6, TNF-α may be through inhibition of p38 and IκBα phosphorylation to avoid NFκB(p65) enter the nucleus. On the other hand, 6-DG decreased LPS-induced IL-1β, IL-6 and IL-10 may be through elevating p-STAT1/p-STAT3 ratio and downregulate those genes (IL-1β, IL-6 and IL-10) mediated by STAT3. We have verified this assumption by using STAT1 esiRNA. Based on the above experimental results, 6-DG has the ability to inhibit both anti-inflammatory and pro-inflammatory cytokine, and due to these reasons, we hope that 6-DG could be applied to patients with sepsis in the future.

並列關鍵字

6-dehydrogingerdione ； LPS ； cytokine ； transcription factor ； inflammation ； sepsis

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