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A selective small molecule IkappaB Kinase beta inhibitor blocks nuclear factor kappaB-mediated inflammatory responses in human fibroblast-like synoviocytes, chondrocytes, and mast cells.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2006 Jun; Vol. 317 (3), pp. 989-1001. Date of Electronic Publication: 2006 Mar 08. - Publication Year :
- 2006
-
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.
- Subjects :
- Anti-Inflammatory Agents, Non-Steroidal chemistry
Chondrocytes drug effects
Chondrocytes enzymology
Chondrocytes immunology
Cytokines immunology
Dinoprostone immunology
Dose-Response Relationship, Drug
Enzyme Inhibitors chemistry
Fibroblasts drug effects
Fibroblasts enzymology
Fibroblasts immunology
HeLa Cells
Humans
Mast Cells drug effects
Mast Cells enzymology
Mast Cells immunology
Molecular Structure
NF-kappa B immunology
Signal Transduction drug effects
Synovial Membrane cytology
Anti-Inflammatory Agents, Non-Steroidal pharmacology
Connective Tissue Cells drug effects
Connective Tissue Cells enzymology
Connective Tissue Cells immunology
Enzyme Inhibitors pharmacology
I-kappa B Kinase antagonists & inhibitors
NF-kappa B antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3565
- Volume :
- 317
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 16525037
- Full Text :
- https://doi.org/10.1124/jpet.105.097584