title: Directly interact with Keap1 and LPS is involved in the anti-inflammatory mechanisms of (-)-epicatechin-3-gallate in LPS-induced macrophages and endotoxemia.
abstract: Disruption of the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2) interaction has emerged as a promising strategy to reduce oxidative stress-induced inflammation. However, its roles in regulating downstream events, including the cross talk between Nrf2 and nuclear factor-kappa B (NF-κB), are not well defined. The objective of this study was to elucidate the mechanistic connection between Keap1-Nrf2 signaling and the transcription factor NF-κB and to investigate the function of (-)-epicatechin-3-gallate (ECG) in the repression of multiple inflammatory mediators. ECG attenuated lipopolysaccharide (LPS)-induced inflammatory mediator expression and intracellular reactive oxygen species (ROS) generation through the induction of Nrf2/antioxidant response element (ARE)-driven glutathione (GSH) and hemeoxygenase-1 (HO-1) levels, interference with NF-κB and Nfr2/ARE transcriptional activities, and suppression of the MAPKs (JNK1/2 and p38) and PI3K/Akt signaling pathways. Importantly, anti-inflammatory effects of ECG partly require activation of ERK1/2 signaling to mediate HO-1 expression and Nrf2/ARE signaling activation. Furthermore, ECG may directly interact intracellularly with the Kelch repeat domains of Keap1 and bind to extracellular LPS, thereby promoting the nuclear accumulation of the Nrf2 protein and blockading the activation of LPS-induced downstream target signaling pathways. Consistent with in vitro studies, ECG attenuates pathological syndromes of LPS-induced sepsis and systemic inflammation. Our results identified ECG as a novel Keap1-Nrf2 interaction disruptor and LPS-induced TLR4 activation inhibitor, thereby providing an innovative strategy to prevent or treat immune, oxidative stress and inflammatory-related diseases.
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan 704, Taiwan; Institute of Food Science and Technology, National Taiwan University, No.1, Section 4, Roosevelt Road, Taipei 10617, Taiwan.
authors.forename: Yi-Shiou
authors.initials: YS
authors.lastname: Chiou
authors.affiliation: Department of Food Science, Rutgers University, New Brunswick, NJ 08901-8520, USA.
authors.forename: Qingrong
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Food Science, Rutgers University, New Brunswick, NJ 08901-8520, USA.
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan 704, Taiwan; Department of Biomedical Informatics, Asia University, Taichung 413, Taiwan. Electronic address: yjwang@mail.ncku.edu.tw.
authors.forename: Ying-Jan
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Institute of Food Science and Technology, National Taiwan University, No.1, Section 4, Roosevelt Road, Taipei 10617, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address: mhpan@ntu.edu.tw.
authors.forename: Min-Hsiung
authors.initials: MH
authors.lastname: Pan
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D002392:Catechin; C062669:epicatechin gallate; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D005978:Glutathione
keywords: (-)-epicatechin-3-gallate; Hemeoxygenase-1; Kelch-like ECH-associated protein 1; Nuclear factor erythroid-derived factor 2-related factor 2; Nuclear factor-kappa B; Reactive oxygen species