Title

EGCG 調控 soluble RAGE 之釋放機轉及抑制發炎體活化之研究

Translated Titles

Regulatory effect of EGCG on sRAGE secretion and inflammasome activation

Authors

張尹宣

Key Words

發炎複合體 ; 糖尿病 ; 金屬蛋白酶兒茶素 ; cRAGE ; esRAGE ; Nrf2 ; ROS ; RAGE ; sRAGE ; TXNIP ; ADAM10 ; cRAGE ; Diabetes mellitus ; EGCG ; esRAGE ; inflammasome ; Nrf2 ; ROS ; RAGE ; sRAGE ; TXNIP

PublicationName

中興大學食品暨應用生物科技學系所學位論文

Volume or Term/Year and Month of Publication

2011年

Academic Degree Category

碩士

Advisor

顏國欽

Content Language

繁體中文

Chinese Abstract

RAGE (receptor for advanced glycation endproducts) 之活化於臨床上已經證實與心血管疾病、肥胖、糖尿病、神經病變、阿茲海默氏症、癌症及老化等多種疾病之病理進程有密切相關。因此,抑制 RAGE 活化儼然已成為目前新穎藥物設計開發與臨床標靶治療之熱門研究主題。sRAGE (Soluble RAGE) 為 RAGE 之異構物,目前研究將 sRAGE 分為 esRAGE (endogenous secretory RAGE) 與 cRAGE (cleaved RAGE),其可釋放於血液循環中捕捉多種 RAGE 配體如 AGEs (advanced glycation endproducts)、Aβ (β-amyloid) 等,因此可抑制 RAGE 活化,而具減緩人體疾病之實質生理作用,推測 sRAGE 為未來臨床上治療慢性疾病之主要標靶蛋白。然而 sRAGE 於生理上之調控機轉與促進作用並不十分明確。文獻指出,兒茶素具有降血糖、抗氧化和抗發炎等功效,但是否具有促進 sRAGE 釋放之作用並不明確。故本研究模擬糖尿病患者之高血糖生理環境,將人類單核球細胞 (THP-1) 培養於高糖 (15 mM) 環境中,探討兒茶素EGCG (epigallocatechin gallate) 對 THP-1 細胞中 sRAGE 釋放之影響,同時探討 sRAGE 生成之調控機轉。本研究更進一步分析 sRAGE 對於高糖 (25 mM) 所活化之發炎複合體 (inflammasome) 是否具有抑制效應。 實驗結果顯示,高糖環境誘發過多的胞內活性氧 (ROS),促進 RAGE 與其配體 (ligands) S100A12 之表現;同時抑制細胞中基因轉錄後修飾作用 (gene splicing),降低 esRAGE 之生成。高糖亦會阻礙胞內抗氧化系統之轉錄因子 Nrf2 (nuclear factor erythroid 2-related factor 2) 活性以及 Nrf2 與 ADAM10 (a disintegrin and metalloproteinase 10) 基因啟動子 (promoter) 之結合作用,而減少基質金屬蛋白酶 ADAM10 對 RAGE 之截切機制,使 cRAGE 分泌量下降。結果顯示 THP-1 細胞在高糖環境下使細胞中 sRAGE 總分泌量下降。 EGCG 除了可清除 THP-1 細胞胞內活性氧,亦促進 RAGE 基因轉錄合成 esRAGE,降低細胞內 RAGE 蛋白質生成量。EGCG 亦可透過增加 Nrf2 之轉位活性,提升下游基質金屬蛋白酶 ADAM10 之表現,以促進 cRAGE 之釋放量,顯示 EGCG 可透過修飾基因轉錄作用與提升 ADAM10 表現而促進 THP-1 細胞中 sRAGE 之釋放。本研究進一步發現 EGCG 因促進 THP-1 細胞釋放 sRAGE,而可抑制高糖誘導之 TXNIP (thioredoxin interaction protein) 表現與 NLRP3 發炎複合體 (NLRP3 inflammasome) 活化,減少 IL-1β (interleukin-1β) 之釋放。綜合上述,本研究發現,高濃度葡萄糖可誘發胞內活性氧之生成,藉調控 RAGE 與 Nrf2 之表現,使 THP-1 細胞中 sRAGE 之總分泌量顯著下降;而介入 EGCG 具有促進 sRAGE 釋放之調控效應,進而抑制發炎複合體之活化,減少促發炎激素 IL-1β 之表現。顯示 EGCG 為未來臨床上應用於治療與預防糖尿病發炎疾病,具潛力之天然抗氧化物。

English Abstract

In the previous study, activation of receptor for advanced glycation endproduct (RAGE) is associated with many pathological progresses, including cardiovascular disease, obesity, diabetes mellitus (DM), neuropathy, Alzheimer's disease, cancer and aging. Therefore, inhibition of RAGE activation is regarded as a popular research for novel drug design and clinical therapy. Soluble RAGE (sRAGE) is an isoform of RAGE, which is classified into endogenous secretory RAGE (esRAGE) and cleaved RAGE (cRAGE). Circulating sRAGE may act as a decoy for RAGE ligands, such as glycated protein, S100 protein and amyloid-β (Aβ), and inversely reflect RAGE activation, thus providing a pre-clinical biomarker of RAGE-mediated pathogenesis. However, the regulatory mechanism of sRAGE secretion in human body is still unknown. Many studies indicate that catechins possess anti-hyperglycemia effect, anti-oxidative effect and anti-inflammation. Moreover, effect of EGCG on the secretion of sRAGE remains unclear. Thus, the aim of this study was to investigate the regulatory effect of epigallocatechin-3-gallate (EGCG) on sRAGE secretion in HG-induced THP-1 cells. The inhibitory effect of sRAGE on inflammasome activation induced by high glucose was also investigated. The results showed that excessive intracellular ROS (reactive oxygen species) induced by high glucose increased the expression of RAGE and its ligand (S100A12). Moreover, ROS decreased the production of esRAGE by inhibiting the alternative splicing process of RAGE gene in THP-1 cells. High glucose also suppressed nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and direct binding of Nrf2 to the ADAM10 (a disintegrin and metalloproteinase) promoter. In addition, ADAM10 was inhibited by reduction of Nrf2 nuclear translocation, leading to the decreased levels of cRAGE in HG-induced THP-1 cells. EGCG could scavenge ROS to increase esRAGE levels through post-transcriptional regulation of RAGE gene in HG-induced THP-1 cells. EGCG induced ADAM10 expression after increasing Nrf2 translocation and thus promoted the secretion of cRAGE. These results suggest that EGCG stimulates the release of sRAGE through ADAM10-mediated proteolysis of extracellular RAGE in HG-induced THP-1 cells. Furthermore, EGCG-stimulated sRAGE and then blocked the activation of thioredoxin interaction protein (TXNIP) and NOD-like receptor protein 3 (NLRP3) inflammasome, which subsequently decreased the IL-1β secretion in HG-induced THP-1 monocytes. Taken together, high glucose induced intracellular ROS to suppress the sRAGE secretion by up-regulating RAGE and down-regulating Nrf2 nuclear translocation in THP-1 monocytes. Moreover, treatment with EGCG promoted sRAGE release to reduce the secretion of IL-1β by inhibiting the activation of NLRP3 inflammasome. Therefore, EGCG might be a potent agent for the management of diabetes.

Topic Category 農業暨自然資源學院 > 食品暨應用生物科技學系所
生物農學 > 生物科學
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