Regulatory effect of EGCG on sRAGE secretion and inflammasome activation

• Main Authors: Yin-Hsuan Chang, 張尹宣
• Other Authors: 顏國欽
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/87263661106362131021

碩士 === 國立中興大學 === 食品暨應用生物科技學系所 === 99 === 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.