介白質-10對肺上皮細胞在呼吸道發炎反應上的調控探討

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题名:	介白質-10對肺上皮細胞在呼吸道發炎反應上的調控探討 Study of modulation of bronchial epithelial cells on airway inflammation by interleukin-10
作者:	張兼豪 Chien-Hao Chang
贡献者:	醫學科學研究所
关键词:	氣喘慢性阻塞性肺部疾病肺上皮細胞細胞激素 TNF-α IL-17 IL-6 IL-8 IκBα ERK1/2
日期:	2008
上传时间:	2009-08-28 11:05:44 (UTC+8)
摘要:	肺上皮細胞在氣喘及COPD上皆扮演一重要的角色。在TNF-α及IL-17等發炎激素刺激下，其會分泌出許多細胞激素(IL-6、IL-8)及介質(eotaxin、RANTES)來吸引發炎細胞的聚集以共同造成肺的發炎反應。IL-10一開始被定義為Th 2的細胞激素，後來發現其具有抗發炎之作用，可抑制發炎細胞激素IL-6和IL-8產生。而在我們之前的研究結果也證實IL-10 在治療氣喘發作小鼠上有不錯的療效，因此我們想更進一步要去了解IL-10在對TNF-α、IL-4、IL-13及IL-17所造成的肺上皮細胞之發炎時的抑制效果以及其調控的機制為何。首先我們建立起培養小鼠肺上皮細胞的平台，初步評估IL-4和TNF-α對小鼠肺上皮細胞誘發發炎反應的效果，觀察到在給予不同劑量的IL-4、TNF-α和不同作用時間下刺激肺上皮細胞，可促其分別表現發炎介質eotaxin 和IL-6；而在IL-10抑制發炎實驗結果，証實IL-10可有效抑制eotaxin 和IL-6的生成。之後更進一步用人的肺上皮細胞株A549 和BEAS-2B 為平台建立起在給予細胞激素(TNF-α、IL-4、IL-13和IL-17)刺激下，可誘發IL-6、IL-8、eotaxin和RANTES的表現。由結果得知：IL-10的確具有降低細胞表現IL-6、IL-8和RANTES的能力，且其抑制作用的大小與是否會誘發高量的IL-10R無關。我們觀察到IL-10主要可藉由減少TNF-α刺激A549細胞所誘發之IκBα的降解來降低IL-6和IL-8在mRNA及蛋白質的表現;此外IL-10也可以藉由抑制IL-17所誘發MAPK pathway中磷酸化ERK1/2蛋白的表現來阻斷IL-6和IL-8mRNA及蛋白質的生成，以達共同抗發炎的作用。綜合以上結果可得知：IL-10的確可藉由抑制各別的細胞活化訊號傳遞以及降低發炎激素IL-6與IL-8在mRNA及蛋白質上的表現，來達到對抗TNF-α和IL-17對表皮細胞所造成的發炎反應。 Bronchial epithelial cells play an important role in the asthma and COPD disease. Under the stimulation of pro-inflammatory cytokine (TNF-α, IL-17), lung epithelial cells produce many types of cytokines and chemokines, and many contribute to lung inflammation by recruiting inflammatory cells. IL-10 originally had been described as a Th2-associated cytokine. However, further studies revealed that IL-10 was a cytokine with potent anti-inflammatory properties and it could repress the expression of inflammatory cytokines such as IL-6 and IL-8. Our previous studies had demonstrated that IL-10 might have a therapeutic effect on animal model of asthma. Therefore, we wanted to investigate whether IL-10 plays an anti-inflammatory role on airway inflammation induced by TNF-α、IL-4、IL-13 and IL-17. Our preliminary data showed that TNF-α and IL-4 could stimulate mouse lung epithelium to secret IL-6 and eotaxin, respectively. Furthermore, we observed that IL-10 could significantly suppress IL-6 and eotaxin production from lung epithelium. In addition, human pulmonary epithelial cells A549 and BEAS-2B were used to investigate the expression of inflammatory mediators induced by TNF-α, IL-4, IL-13 and IL-17. The results showed that IL-10 could reduce the production of IL-6, IL-8 and RANTES from A549 cells. IL-10 had no effect on induction of IL-10 receptor expression. However, the mRNA expression of IL-6 and IL-8 was reduced by IL-10 treatment. In addition, TNF-α activated the NF-κB pathway and pretreatment of A549 cells with IL-10 reversed the effect of TNF-α on IκBα degradation. IL-10 also could attenuate IL-17- induced-IL-6 and IL-8 production by reducing the phosphorylation of ERK1/2 in MAPK pathway. In conclusion, we suggest that IL-10 markedly inhibits TNF-α- and IL-17-induced airway inflammation on A549 cells by decreasing IL-6 and IL-8 production.
数据类型:	thesis
显示于类别:	[醫學科學研究所] 博碩士論文

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