EGCG stimulates autophagy and reduces cytoplasmic HMGB1 levels in endotoxin-stimulated macrophages

• Published in: Biochemical pharmacology 2011-05, Vol.81 (9), p.1152-1163
• Main Authors: Li, Wei, Zhu, Shu, Li, Jianhua, Assa, Andrei, Jundoria, Arvin, Xu, Jianying, Fan, Saijun, Eissa, N. Tony, Tracey, Kevin J., Sama, Andrew E., Wang, Haichao
• Format: Article
• Language: English
• Subjects: Animals; atherosclerosis; autophagy; Autophagy - drug effects; Biological and medical sciences; Blotting, Western; Camellia sinensis; Catechin - analogs & derivatives; Catechin - pharmacology; Cell Line; chloroquine; Cytoplasm - drug effects; Cytoplasm - metabolism; green tea; HMGB1 Protein - metabolism; inflammation; ingredients; Lipopolysaccharides - pharmacology; macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - ultrastructure; Male; Medical sciences; Mice; Mice, Inbred BALB C; Microscopy, Electron, Transmission; Pharmacology. Drug treatments; Rats; RNA Interference
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2011.02.015

Via oxidation, EGCG spontaneously forms aggregation products (e.g. theasinensin), which interact with HMGB1 to form EGCG–HMGB1 complexes. These complexes are engulfed into autophagosomes, and degraded in an autophagy-dependent mechanism. Historically, consumption of Green tea ( Camellia sinensis) has been associated with health benefits against multiple diseases including cancer, atherosclerosis and cardiovascular disorders. Emerging evidence has suggested a pathogenic role for HMGB1, a newly identified “late” mediator of lethal systemic inflammation, in the aforementioned diseases. Here we demonstrated that a major ingredient of Green tea, EGCG, was internalized into HMGB1-containing LC3-positive cytoplasmic vesicles (likely autophagosomes) in macrophages, and induced HMGB1 aggregation in a time-dependent manner. Furthermore, EGCG stimulated LC3-II production and autophagosome formation, and inhibited LPS-induced HMGB1 up-regulation and extracellular release. The EGCG-mediated HMGB1 inhibitory effects were diminished by inhibition of class III phosphatidylinositol-3 kinase (with 3-methyladenine) or knockdown of an essential autophagy-regulating protein, beclin-1. Moreover, the EGCG-mediated protection against lethal sepsis was partly impaired by co-administration of an autophagy inhibitor, chloroquine. Taken together, the present study has suggested a possibility that EGCG inhibits HMGB1 release by stimulating its autophagic degradation.