Directly interact with Keap1 and LPS is involved in the anti-inflammatory mechanisms of (-)-epicatechin-3-gallate in LPS-induced macrophages and endotoxemia

作者：Chiou Yi Shiou; Huang Qingrong; Ho Chi Tang; Wang Ying Jan^*; Pan Min Hsiung^*

来源：Free Radical Biology and Medicine, 2016, 94: 1-16.

DOI：10.1016/j.freeradbiomed.2016.02.010

• Kelch-like ECH-associated protein 1
• Nuclear factor erythroid-derived factor
• 2-related factor 2
• Nuclear factor-kappa B
• (-)-epicatechin-3-gallate
• Reactive oxygen species
• Hemeoxygenase-1

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-kappa B), are not well defined. The objective of this study was to elucidate the mechanistic connection between Keapl-Nrf2 signaling and the transcription factor NF-kappa B 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-kappa B 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 extra cellular 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 Keapl-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.

• 出版日期2016-5
• 单位中国医科大学