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B Kinase-
Complex in Fibroblast-Like Synoviocytes1
Division of Rheumatology, Allergy, and Immunology, University of California-San Diego School of Medicine, La Jolla, CA 92093
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 I
B kinase (IKK)-related kinase, IKK
/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 IKK 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 IKK kinase activity is rapidly induced by cytokines, although IB phosphorylation is significantly less compared with IKK2. Because NF-B activation is similar in wild-type and IKK knockout murine FLS, studies were performed to identify an alternative substrate for IKK. Interestingly, c-Jun is a more efficient substrate for IKK immunocomplexes in human FLS and this activity appears to be independent of JNK. The functional relevance of IKK was examined using murine IKK–/– cultured FLS. IL-1-, TNF-
-, and LPS-mediated induction of matrix metalloproteinases, MMP3 and MMP13, is significantly decreased in the IKK–/– cells. These data suggest a novel role for the IKK complex in synovial inflammation, extracellular matrix destruction, and activation of the viral program and innate immune response in RA.
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