IKKi expression and regulation in rheumatoid arthritis

University Of California San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory arthritis marked by synovial hyperplasia with local invasion of bone and cartilage. RA fibroblast-like synoviocytes (FLS), along with macrophage-like synoviocytes, form the destructive front of rheumatoid synovium and contribute to the inflammatory milieu. Of the signal transduction pathways that participate in this process, NF-kB is thought to be especially important by virtue of its ability to regulate cytokine and metalloproteinase gene expression. Recent studies suggest that the IkB kinase (IKK) signal complex, which contains IKKbeta, is a key convergence point for the rapid transient increase in NF-kB activation after cytokine stimulation. However, systemic targeting IKKbeta or other proteins that ablate NF-kB activity has significant safety concerns because NF-kB protects many cells from apoptosis and participates in host defense. To address safety issues as well as the mechanisms of chronic NF-kB activation, we propose to explore the function and regulation of a novel inducible IKK (IKKi). This kinase was originally identified as an inducible signal transduction protein in LPS-stimulated macrophages and tumor cell lines. We have demonstrated that it is constitutively expressed in primary human synoviocytes, can be induced by cytokines, and may be in the intimal lining of RA synovial tissue. The kinetics of IKKi induction and its mechanism of action suggest that it might contribute to NF-kB function in chronic inflammation. Using patient material and animal models, the role of IKKi in synovial inflammation will be evaluated. We propose to test the hypothesis that IKKi is an important signal transduction pathway that regulates inflammation in chronic arthritis and is a novel target for development of anti-rheumatic agents.