Chemical probing reveals insights into the signaling mechanism of inflammasome activation  

作　　者：Yi-Nan Gong Xiaoming Wang Jiayi Wang Zhenxiao Yang Shan Li Jieling Yang Liping Liu Xiaoguang Lei Feng Shao 

机构地区：[1]College of Life Sciences, Beijing Normal University, Beijing 100875, China [2]National Institute of Biological Sciences, #7 Science Park Rd, Zhongguancun Life Science Park, Beijing 102206, China [3]School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China [4]Graduate School of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

出　　处：《Cell Research》2010年第12期1289-1305,共17页细胞研究（英文版）

摘　　要：Caspase-1-mediated IL-1β production is generally controlled by two pathways. Toll-like receptors （TLRs） recognize pathogen-derived products and induce NF-KB-dependent pro-IL-1β transcription; NOD-like receptors （NLRs） assemble caspase-l-activating inflammasome complexes that sense bacterial products/danger signals. Through a targeted chemical screen, we identify bromoxone, a marine natural product, as a specifc and potent inhibitor of the caspase-1 pathway. Bromoxone is effective over diverse inflammatory stimuli including TLR ligands plus ATP/nigeri- cin, cytosolic DNA, flagellin and Bacillus anthracis lethal toxin. Bromoxone also efficiently suppresses easpase-1 acti- vation triggered by several types of bacterial infection. Bromoxone acts upstream or at the level of the inflammasome in a transcription-independent manner. Bromoxone also inhibits pro-IL-1β expression by targeting components up- stream of IKK in the TLR-NF-kB pathway. The unique dual activities of bromoxone are shared by the known TAK1 inhibitor that specifically blocks Nalp3 inflammasome activation. Hinted from the mechanistic and pharmacological properties of bromoxone, we further discover that several known NF-KB inhibitors that act upstream of IKK, but not those targeting IKK or IKK downstream, are potent blockers of different NLRs-mediated caspase-1 activation. Our study uncovers a possible non-transcriptional molecular link between the NLR （Nalp3）-mediated inflammasome pathway and TLR-NF-kB signaling, and suggests a potential strategy to develop new anti-inflammatory drugs.

关 键 词：innate immunity INFLAMMASOME NOD-like receptors chemical biology signal transduction 

分 类 号：Q26[生物学—细胞生物学] TP316.81[自动化与计算机技术—计算机软件与理论]