RT Journal Article
SR Electronic
T1 A Selective Small Molecule IκB Kinase β Inhibitor Blocks Nuclear Factor κB-Mediated Inflammatory Responses in Human Fibroblast-Like Synoviocytes, Chondrocytes, and Mast Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 989
OP 1001
DO 10.1124/jpet.105.097584
VO 317
IS 3
A1 Danyi Wen
A1 Yuhua Nong
A1 Jennifer G. Morgan
A1 Pranoti Gangurde
A1 Andrew Bielecki
A1 Jennifer DaSilva
A1 Marie Keaveney
A1 Hong Cheng
A1 Chris Fraser
A1 Lisa Schopf
A1 Michael Hepperle
A1 Geraldine Harriman
A1 Bruce D. Jaffee
A1 Timothy D. Ocain
A1 Yajun Xu
YR 2006
UL http://jpet.aspetjournals.org/content/317/3/989.abstract
AB IκB kinase (IKK) β is essential for inflammatory cytokine-induced activation of nuclear factor κB (NF-κB). NF-κB 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 IKKβ inhibitor N-(6-chloro-7-methoxy-9H-β-carbolin-8-yl)-2-methylnicotinamide (ML120B), a β-carboline derivative, on NF-κB signaling and gene activation in RA-relevant cell systems. ML120B is a potent, selective, reversible, and ATP-competitive inhibitor of IKKβ with an IC50 of 60 nM when evaluated in an IκBα kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentration-dependently inhibits tumor necrosis factor α (TNFα)-stimulated NF-κB signaling via inhibition of IκBα phosphorylation, degradation, and NF-κB translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast-like synoviocytes, TNFα- or interleukin (IL)-1β-induced monocyte chemoattractant protein-1 regulated on activation, normal T cell expressed and secreted and production is IKKβ-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 IKKβ-dependent. In addition, in human chondrocytes, ML120B inhibited IL-1β-induced matrix metalloproteinase production with an IC50 of approximately 1 μM. ML120B also blocked IL-1β-induced prostaglandin E2 production. In summary, ML120B blocked numerous NF-κB-regulated cell responses that are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKKβ inhibitors as anti-inflammatory agents for the treatment of RA. The American Society for Pharmacology and Experimental Therapeutics