title: Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome.
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.
authors.affiliation: Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
authors.forename: Christine
authors.initials: C
authors.lastname: Juliana
authors.affiliation: Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
authors.forename: Teresa
authors.initials: T
authors.lastname: Fernandes-Alnemri
authors.affiliation: Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Wu
authors.affiliation: Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
authors.forename: Pinaki
authors.initials: P
authors.lastname: Datta
authors.affiliation: Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
authors.forename: Leobaldo
authors.initials: L
authors.lastname: Solorzano
authors.affiliation: Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
authors.forename: Je-Wook
authors.initials: JW
authors.lastname: Yu
authors.affiliation: Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Rong
authors.initials: R
authors.lastname: Meng
authors.affiliation: Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Quong
authors.affiliation: Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605; Institute of Innate Immunity, University of Bonn, D53012 Bonn, Germany.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Scott
authors.affiliation: Departments of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania 19107. Electronic address: E_Alnemri@mail.jci.tju.edu.
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
mesh_terms: 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*
chemical_list: 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