Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome.
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.
Juliana
Christine
C
Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
Fernandes-Alnemri
Teresa
T
Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
Wu
Jianghong
J
Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
Datta
Pinaki
P
Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
Solorzano
Leobaldo
L
Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
Yu
Je-Wook
JW
Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
Meng
Rong
R
Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Quong
Andrew A
AA
Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Latz
Eicke
E
Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605; Institute of Innate Immunity, University of Bonn, D53012 Bonn, Germany.
Scott
Charles P
CP
Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
Alnemri
Emad S
ES
Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107. Electronic address: E_Alnemri@mail.jci.tju.edu.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D016923:Cell Death; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000188:drug therapy*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D009570:Nitriles; D012717:Sesquiterpenes; D013450:Sulfones; C002669:parthenolide; C009873:divinyl sulfone; D007770:L-Lactate Dehydrogenase; D020170:Caspase 1