過氧化物增殖因子活化受體調控NF-κB的活化在廣東住血線蟲感染鼷鼠誘發腦膜腦炎之研究

Regulation of NF-κB activation by PPARγ in mice with meningoencephalitis caused by Angiostrongylus cantonensis

彭啟揚(Chi-Yang Peng)

指導教授 ： 賴世展 ； 蔡崇弘

中山醫學大學/醫學院/醫學研究所/碩士(2011年)

https://doi.org/10.6834/CSMU.2011.00167

摘要

過氧化物增殖因子活化受體（Peroxisome-proliferator activated receptor gamma, PPARγ）為可受ligand活化的轉錄因子，可調控體內脂肪平衡、醣類平衡及發炎反應相關基因，在腦部中樞神經系統病變中也扮演著重要角色。過去的文獻顯示活化的PPARγ可藉由抑制nuclear factor kappa-light-chain-enhancer of activated B cells（NF-κB）蛋白，調控發炎相關蛋白表現，進而達到抗發炎效果，但PPARγ在寄生蟲性腦膜腦炎中所扮演的角色還是未知，因此本研究以廣東住血線蟲所造成的嗜伊紅性腦膜腦炎探討PPARγ所扮演的角色及其分子機制。本研究將廣東住血線蟲感染鼷鼠的動物模型，給予PPARγ的專一性拮抗劑GW9662抑制PPARγ活化。試驗結果顯示抑制PPARγ的活化可造成IκB-α蛋白表現減少而p-IκB-α、p-NF-κB表現增加，並使COX-2、NOSs的表現量增加、MMP-9活性上升、細胞激素IL-1β濃度增加。這些結果顯示在廣東住血線蟲症中，PPARγ透過增加IκB-α蛋白表現量的機制，進而在許多與NF-κB相關的層面扮演著抗發炎的角色，包含了NOSs所產生的氧化性壓力、細胞激素、前列腺素化合物、以及MMPs參與之蛋白水解反應。

關鍵字

廣東住血線蟲 ； 嗜伊紅性腦膜腦炎 ； 過氧化物增值因子活化受體 ； 核轉錄因子 ； 一氧化氮合成酶環氧化酶基質金屬蛋白酶

並列摘要

Peroxisome-proliferator activator receptor gamma (PPARγ) is a member of the nuclear receptor family of ligand-dependent transcription factors that regulate glucose homeostasis, lipid and lipoprotein metabolism, inflammatory genes, and consequently a key role in CNS disorders. Previous studies revealed that activated PPARγ functioned as an anti-inflammatory role which inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and regulates the expressions of inflammatory proteins, whereas its role in parasitic meningoencephalitis is still unknown. In this study, we investigated the role of PPARγ and related mechanisms in eosinophilic meningoencephalitis caused by A. cantonensis. By using GW9662, the specific antagonist of PPARγ, in animal model of angiostrongyliasis, we observed decreased proteins expression of IκB-α and increased proteins expression of phospho-IκB-α, phospho-NF-κB in mice brain. Then we investigated NF-κB related downstream proteins such as COX-2, NOSs, IL-1β by Western blot or Enzyme-linked immunosorbent assay (ELISA), and the proteins expression were upregulated. The results of gelatin zymography showed that the activities of MMP-9 were upregulated also. These results suggest that PPARγ, in angiostrongyliasis, may acts anti-inflammation role in many NF-κB related categories, including NOS related oxidative stress, cytokines, prostanoids, and MMPs cascade through increasing IκB-α protein levels.

並列關鍵字

Angiostrongylus cantonensis ； eosinophilic meningoencephalitis ； PPAR ； NF-κB ； NOS ； COX-2 ； MMP

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