Volume 20, No 12, Dec 2010

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 20 Issue 12, December 2010: 1289-1305

ORIGINAL ARTICLES

Chemical probing reveals insights into the signaling mechanism of inflammasome activation

Yi-Nan Gong^1,2, Xiaoming Wang^2,4, Jiayi Wang^2,4, Zhenxiao Yang^2,4, Shan Li², Jieling Yang², Liping Liu², Xiaoguang Lei^2,3 and Feng Shao²

¹College of Life Sciences, Beijing Normal University, Beijing 100875, China

²National Institute of Biological Sciences, #7 Science Park Rd, Zhongguancun Life Science Park, Beijing 102206, China

³School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China

⁴Graduate School of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China Correspondence: Feng Shao,(shaofeng@nibs.ac.cn)

Caspase-1-mediated IL-1β production is generally controlled by two pathways. Toll-like receptors (TLRs) recognize pathogen-derived products and induce NF-κB-dependent pro-IL-1β transcription; NOD-like receptors (NLRs) assemble caspase-1-activating inflammasome complexes that sense bacterial products/danger signals. Through a targeted chemical screen, we identify bromoxone, a marine natural product, as a specific and potent inhibitor of the caspase-1 pathway. Bromoxone is effective over diverse inflammatory stimuli including TLR ligands plus ATP/nigericin, cytosolic DNA, flagellin and Bacillus anthracis lethal toxin. Bromoxone also efficiently suppresses caspase-1 activation 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 upstream of IKK in the TLR-NF-κB 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-κB 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-κB signaling, and suggests a potential strategy to develop new anti-inflammatory drugs.

Cell Research (2010) 20:1289-1305. doi:10.1038/cr.2010.135; published online 21 September 2010

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