化学线粒体解偶联剂通过抑制 NFκB 核易位对 NLRP3 炎性小体的激活具有共同的抑制作用。
Chemical mitochondrial uncouplers share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation.
机构信息
Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, People's Republic of China.
Department of Pharmacology, China Pharmaceutical University, Nanjing, People's Republic of China.
出版信息
Toxicol Appl Pharmacol. 2021 Mar 1;414:115426. doi: 10.1016/j.taap.2021.115426. Epub 2021 Jan 30.
Activation of NLRP3 inflammasome is implicated in varieties of pathologies, the aim of the present study is to characterize the effect and mechanism of mitochondrial uncouplers on NLRP3 inflammasome activation by using three types of uncouplers, niclosamide, CCCP and BAM15. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increases of NLRP3 protein and IL-1β mRNA levels in RAW264.7 macrophages and THP-1 derived macrophages. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increase of NFκB (P65) phosphorylation, and inhibited NFκB (P65) nuclear translocation in RAW264.7 macrophages. Niclosamide and BAM15 inhibited LPS-induced increase of IκBα phosphorylation in RAW264.7 macrophages, and the inhibitory effect was dependent on increased intracellular [Ca]; however, CCCP showed no significant effect on IκBα phosphorylation in RAW264.7 macrophages stimulated with LPS. In conclusion, chemical mitochondrial uncouplers niclosamide, CCCP and BAM15 share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation.
NLRP3 炎性小体的激活与多种病理有关，本研究旨在用三种解偶联剂（尼可刹米、CCCP 和 BAM15）来表征线粒体解偶联剂对 NLRP3 炎性小体激活的作用和机制。尼可刹米、CCCP 和 BAM15 抑制 LPS 加 ATP 诱导的 RAW264.7 巨噬细胞和 THP-1 衍生巨噬细胞中 NLRP3 蛋白和 IL-1β mRNA 水平的增加。尼可刹米、CCCP 和 BAM15 抑制 LPS 加 ATP 诱导的 NFκB（P65）磷酸化增加，并抑制 RAW264.7 巨噬细胞中 NFκB（P65）核易位。尼可刹米和 BAM15 抑制 LPS 诱导的 RAW264.7 巨噬细胞中 IκBα 磷酸化的增加，这种抑制作用依赖于细胞内[Ca2+]的增加；然而，CCCP 对 LPS 刺激的 RAW264.7 巨噬细胞中 IκBα 磷酸化没有显著影响。总之，化学线粒体解偶联剂尼可刹米、CCCP 和 BAM15 通过抑制 NFκB 核易位，对 NLRP3 炎性小体的激活具有共同的抑制作用。
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