Anti-inflammatory Compounds Parthenolide and Bay 11-7082 Are Direct Inhibitors of the Inflammasome

被引:498
作者
Juliana, Christine [1 ]
Fernandes-Alnemri, Teresa [1 ]
Wu, Jianghong [1 ]
Datta, Pinaki [1 ]
Solorzano, Leobaldo [1 ]
Yu, Je-Wook [1 ]
Meng, Rong [2 ]
Quong, Andrew A. [2 ]
Latz, Eicke [3 ,4 ]
Scott, Charles P. [1 ]
Alnemri, Emad S. [1 ]
机构
[1] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Dept Canc Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
[3] Univ Massachusetts, Dept Immunol & Infect Dis, Sch Med, Worcester, MA 01605 USA
[4] Univ Bonn, Inst Innate Immun, D-53012 Bonn, Germany
基金
美国国家卫生研究院;
关键词
NF-KAPPA-B; CYSTEINE PROTEASE INHIBITORS; NALP3; INFLAMMASOME; VINYL SULFONES; CASPASE-1; ACTIVATION; CELL-DEATH; SESQUITERPENE LACTONES; NLRP3; ASC PYROPTOSOME; MECHANISM;
D O I
10.1074/jbc.M109.082305
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-kappa B 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-kappa B inhibitors revealed that the synthetic I kappa B 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-kappa B 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.
引用
收藏
页码:9792 / 9802
页数:11
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