title: A selective small molecule IkappaB Kinase beta inhibitor blocks nuclear factor kappaB-mediated inflammatory responses in human fibroblast-like synoviocytes, chondrocytes, and mast cells.
abstract: IkappaB kinase (IKK) beta is essential for inflammatory cytokine-induced activation of nuclear factor kappaB (NF-kappaB). NF-kappaB plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA). Here, we report the mechanism and the effect of the IKKbeta inhibitor N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a beta-carboline derivative, on NF-kappaB signaling and gene activation in RA-relevant cell systems. ML120B is a potent, selective, reversible, and ATP-competitive inhibitor of IKKbeta with an IC50 of 60 nM when evaluated in an IkappaBalpha kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentration-dependently inhibits tumor necrosis factor alpha (TNFalpha)-stimulated NF-kappaB signaling via inhibition of IkappaBalpha phosphorylation, degradation, and NF-kappaB translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast-like synoviocytes, TNFalpha- or interleukin (IL)-1beta-induced monocyte chemoattractant protein-1 regulated on activation, normal T cell expressed and secreted and production is IKKbeta-dependent. In addition, for the first time, we have demonstrated that lipopolysaccharide- or peptidoglycan-induced cytokine production in human cord blood-derived mast cells is IKKbeta-dependent. In addition, in human chondrocytes, ML120B inhibited IL-1beta-induced matrix metalloproteinase production with an IC50 of approximately 1 microM. ML120B also blocked IL-1beta-induced prostaglandin E2 production. In summary, ML120B blocked numerous NF-kappaB-regulated cell responses that are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKKbeta inhibitors as anti-inflammatory agents for the treatment of RA.
authors.affiliation: Inflammation Department, Millennium Pharmaceuticals, Inc., 35 Landsdowne Street, Cambridge, MA 02139, USA. wen@mpi.com
authors.forename: Danyi
authors.initials: D
authors.lastname: Wen
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Nong
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Morgan
authors.forename: Pranoti
authors.initials: P
authors.lastname: Gangurde
authors.forename: Andrew
authors.initials: A
authors.lastname: Bielecki
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dasilva
authors.forename: Marie
authors.initials: M
authors.lastname: Keaveney
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.forename: Chris
authors.initials: C
authors.lastname: Fraser
authors.forename: Lisa
authors.initials: L
authors.lastname: Schopf
authors.forename: Michael
authors.initials: M
authors.lastname: Hepperle
authors.forename: Geraldine
authors.initials: G
authors.lastname: Harriman
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Jaffee
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Ocain
authors.forename: Yajun
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D003239:Connective Tissue Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000166:cytology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D051550:I-kappa B Kinase; D015232:Dinoprostone