Received for publication October 26, 2005.
Revised March 3, 2006.
Accepted for publication March 6, 2006.

A Selective Small Molecule IKK Inhibitor Blocks NF-B Mediated Inflammatory Responses in Human Fibroblast Like Synoviocytes, Chondrocytes and Mast Cells

Abstract

IKK is essential for inflammatory cytokine- induced activation of NF-B (Yamamoto and Gaynor, 2004). NF-B plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA) (Yamamoto and Gaynor, 2001). Here we report the mechanism and the effect of the IKK inhibitor ML120B, a -carboline derivative (Castro et al., 2003), on NF-B signaling and gene activation in RA relevant cell systems. ML120B is a potent, selective, reversible and ATP competitive inhibitor of IKK with an IC₅₀ of 60 nM when evaluated in an IB kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentration- dependently inhibits TNF stimulated NF-B signaling via inhibition of IB phosphorylation, degradation and NF-B translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast like synoviocytes (HFLS), TNF or IL-1 induced RANTES and MCP-1 production is IKK dependent. Also for the first time, we have demonstrated that LPS or peptidoglycan (PGN) induced cytokine production in human cord blood derived mast cells (MC) is IKK dependent. In addition, in human chondrocytes ML120B inhibits IL-1 induced matrix metalloproteinase (MMP) production with an IC₅₀ of approximately 1 µM. ML120B also blocked IL-1 induced prostaglandin E₂ (PGE₂) production. In summary, ML120B blocks numerous NF-& [kappa]B regulated cell responses which are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKK inhibitors as anti-inflammatory agents for the treatment of rheumatoid arthritis (RA).

Key words: Fibroblast like synoviocytes, IKK inhibitor, NF-B, Rheumatoid Arthritis, TNF, mast cell

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