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標題: | 前列腺素15-keto-PGE2經由轉譯後修飾NF-κB pathway調控發炎反應 15-keto-PGE2 exhibited anti-inflammatory properties through post-translationally modifying the NF-κB pathway |
作者: | Lynn Su 蘇寧 |
指導教授: | 莊立民(Lee-Ming Chuang) |
關鍵字: | 前列腺素,轉譯後修,發炎反應, Prostaglandin,15-keto-PGE2,inflammation,anti-inflammatory,PTM,post-translational modification, |
出版年 : | 2018 |
學位: | 碩士 |
摘要: | 發炎反應可以透過許多促炎分子與抗發炎分子來調控訊息傳遞路徑,核因子NF-κB pathway為一經典的促炎信號傳導路徑,已有許多以此為標靶的抗發炎藥物被研究。NF-κB pathway可被多種誘導物刺激,包括促炎因子如IL-6,MCP-1和TNF-α,並隨後活化發炎因子。前列腺素也是參與發炎反應的分子之一,在先天性發炎反應中前列腺素及其代謝物的調節作用也已被廣泛研究也了解其重要性。 在本篇研究中,我們探討了前列腺素代謝物15-keto-PGE2的抗發炎性質。我們發現,於RAW 264.7細胞中在LPS刺激下15-keto-PGE2會透過抑制NF-κB pathway達到抗發炎的效果。15-keto-PGE2會抑制促炎因子的表達並且降低NF-κB調控基因表現量。我們也進一步證實15-keto-PGE2可造成 NF-κB轉錄因子的轉譯後修飾,其包括分別在p50及其先驅體p105第59位點的Cysteine以及 RelA,又稱p65第120位點的Cysteine。最後,我們證明了15-keto-PGE2加速了p105的降解,可能是透過泛素所調節的,而不影響其入核的機制。 最後,本篇研究證實了15-keto-PGE2對於調節發炎反應的重要性,也提供了一個未來可以使用15-keto-PGE2的抗發炎治療方法。 The inflammatory response can be depicted as coordinated activation of a myriad of signaling pathways that come together to regulate the expressions of both pro- and anti-inflammatory mediators. One of the most classic pro-inflammatory signaling pathway, the nuclear factor NF-κB pathway has long been studied as a target for new anti-inflammatory drugs. NF-κB pathway can be stimulated by several inducers, including pro-inflammatory cytokines such as IL-6, MCP-1, and TNF-α. Subsequently, pro-inflammatory genes will be activated. A class of molecules that also play a part in the inflammatory pathways are the prostaglandins. The regulatory roles that prostaglandins and their metabolites play in innate inflammation have also been extensively studied. In this study, we investigate the anti-inflammatory property of a prostaglandin metabolite 15-keto-PGE2. We saw that 15-keto-PGE2 have anti-inflammatory effects in LPS-stimulated RAW 264.7 cells by inhibiting the NF-κB inflammatory pathway. The treatment of 15-keto-PGE2 led to a reduction of the pro-inflammatory cytokine expressions and Igκ-mediated reporter activities. 15-keto-PGE2 further demonstrated post-translational modification to NF-κB transcription factors, NF-κB1, which include the p50 subunit and its precursor p105, and RelA, or p65, at Cysteine 59 and Cysteine 120 sites, respectively. Finally, we demonstrated that the treatment of 15-keto-PGE2 accelerated the degradation of p105, potentially ubiquitin-mediated yet it did not affect nuclear translocation of p50. Taken together, our study affirms the significance of 15-keto-PGE2 in attenuating inflammatory responses and suggests a novel anti-inflammatory therapy for LPS-induced inflammation through administering 15-keto-PGE2. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69568 |
DOI: | 10.6342/NTU201801102 |
全文授權: | 有償授權 |
顯示於系所單位: | 分子醫學研究所 |
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