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Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome

Authors
 Christine Juliana  ;  Teresa Fernandes-Alnemri  ;  Jianghong Wu  ;  Pinaki Datta  ;  Leobaldo Solorzano  ;  Je-Wook Yu  ;  Rong Meng  ;  Andrew A. Quong  ;  Eicke Latz  ;  Charles P. Scott  ;  Emad S. Alnemri 
Citation
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.285(13) : 9792-9802, 2010 
Journal Title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN
 0021-9258 
Issue Date
2010
MeSH
Animals ; Anti-Inflammatory Agents/pharmacology* ; Bone Marrow Cells/metabolism ; Caspase 1/metabolism ; Cell Death ; Humans ; Immunoblotting ; Inflammation/drug therapy* ; L-Lactate Dehydrogenase/metabolism ; Macrophages/metabolism ; Mice ; NF-kappa B/metabolism ; Nitriles/pharmacology* ; Sesquiterpenes/pharmacology* ; Sulfones/chemistry ; Sulfones/pharmacology*
Abstract
Activation of the inflammasome generates the pro-inflammatory cytokines interleukin-1 beta and -18, which are important mediators of inflammation. Abnormal activation of the inflammasome leads to many inflammatory diseases, including gout, silicosis, neurodegeneration, and genetically inherited periodic fever syndromes. Therefore, identification of small molecule inhibitors that target the inflammasome is an important step toward developing effective therapeutics for the treatment of inflammation. Here, we show that the herbal NF-kappaB inhibitory compound parthenolide inhibits the activity of multiple inflammasomes in macrophages by directly inhibiting the protease activity of caspase-1. Additional investigations of other NF-kappaB inhibitors revealed that the synthetic I kappaB kinase-beta inhibitor Bay 11-7082 and structurally related vinyl sulfone compounds selectively inhibit NLRP3 inflammasome activity in macrophages independent of their inhibitory effect on NF-kappaB activity. In vitro assays of the effect of parthenolide and Bay 11-7082 on the ATPase activity of NLRP3 demonstrated that both compounds inhibit the ATPase activity of NLRP3, suggesting that the inhibitory effect of these compounds on inflammasome activity could be mediated in part through their effect on the ATPase activity of NLRP3. Our results thus elucidate the molecular mechanism for the therapeutic anti-inflammatory activity of parthenolide and identify vinyl sulfones as a new class of potential therapeutics that target the NLRP3 inflammasome.
Files in This Item:
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DOI
10.1074/jbc.M109.082305
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/103244
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