Rheumatoid arthritis (RA) causes a symmetric, inflammatory polyarthritis that results in joint destruction and significant disability. Signaling pathways that regulate the production of cytokines and destructive enzymes have been implicated in its pathogenesis and represent potential therapeutic targets. The IκB kinase (IKK)-related kinase, IKKε/IKKi, which plays a pivotal role in regulating antiviral gene transcription, is constitutively expressed by cultured fibroblast-like synoviocytes (FLS) and could participate in the pathogenesis of RA. In the current studies we demonstrate that IKKε protein is expressed in RA and osteoarthritis synovium and that the protein is found primarily in the synovial intimal lining. Functional studies in cultured FLS showed that IKKε kinase activity is rapidly induced by cytokines, although IκB phosphorylation is significantly less compared with IKK2. Because NF-κB activation is similar in wild-type and IKKε knockout murine FLS, studies were performed to identify an alternative substrate for IKKε. Interestingly, c-Jun is a more efficient substrate for IKKε immunocomplexes in human FLS and this activity appears to be independent of JNK. The functional relevance of IKKε was examined using murine IKKε -/- cultured FLS. IL-1-, TNF-α-, and LPS-mediated induction of matrix metalloproteinases, MMP3 and MMP13, is significantly decreased in the IKKε -/- cells. These data suggest a novel role for the IKKε complex in synovial inflammation, extracellular matrix destruction, and activation of the viral program and innate immune response in RA. Copyright © 2005 by The American Association of Immunologists, Inc.
Sweeney, S. E., Hammaker, D., Boyle, D. L., & Firestein, G. S. (2014). Regulation of c-Jun Phosphorylation by the I B Kinase- Complex in Fibroblast-Like Synoviocytes. The Journal of Immunology, 174(10), 6424–6430. https://doi.org/10.4049/jimmunol.174.10.6424