Dimethyl fumarate ameliorates dextran sulfate sodium-induced murine experimental colitis by activating Nrf2 and suppressing NLRP3 inflammasome activation

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• 作者：Xiuting Liu ; Wei Zhou ; Xin Zhang ; Ping Lu ; Qianming Du ; Lei Tao ; Yang Ding ; Yajing Wang ; Rong Hu ; ^{ronghu@cpu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：NLR ; NOD-like receptor ; IL-1β ; interleukin-1β ; IL-18 ; interleukin-18 ; IL-6 ; interleukin-6 ; TNF-α ; tumor necrosis factor α ; ASC ; apoptosis-associated speck-like protein which contains a CARD ; NF-κB ; nuclear factor-κB ; Nrf2 ; nuclear factor erythroid 2-related factor 2 ; ARE ; antioxidant response element ; NAC ; N-acetyl-cysteine ; ROS ; reactive oxygen species ; mROS ; mitochondrial reactive oxygen species ; mtDNA ; mitochondrial DNA ; THP-Ms ; THP-1 cell-derived macrophages ; DMF ; dimethyl fumarate ; MMF ; mon
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：112
• 期：Complete
• 页码：37-49
• 全文大小：5522 K

文摘

In the present study, we examined the effects of dimethyl fumarate (DMF) on dextran sulfate sodium (DSS)-induced murine colitis, an animal model which mimics human IBD. Oral administration of DMF dose-dependently attenuated body weight loss, colon length shortening and colonic pathological damage including decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities in DSS-treated mice. Increased glutathione (GSH) induced by DMF demonstrated its potential antioxidant capacity. In addition, Nrf2 and its downstream genes were markedly activated by DMF. Furthermore, protein and mRNA levels of pro-inflammatory cytokines, including IL-1β, TNF-α and IL-6 were markedly suppressed by DMF. At the same time, decreased activation of caspase-1 was detected in DMF-treated mice, indicating that the NLRP3 inflammasome activation was suppressed. The in vitro study verified a negative regulation of DMF and its intestinal metabolite on NLRP3 inflammasome. Moreover, the inhibitory effect was found to be mostly dependent on Nrf2 which decreased mitochondrial ROS (mROS) generation and mitochondrial DNA (mtDNA) release. Taken together, our results demonstrated the ability of DMF to inhibit NLRP3 inflammasome activation and its potential use in the treatment of NLRP3-associated diseases.