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Regulation of IL-6 and IL-8 Expression in Rheumatoid Arthritis Synovial Fibroblasts: the Dominant Role for NF-B But Not C/EBPß or c-Jun¹

Constantinos Georganas^2,*, Hongtao Liu^*, Harris Perlman^*, Alexander Hoffmann, Bayar Thimmapaya and Richard M. Pope^3,*

^* Division of Rheumatology, Department of Medicine and the Department of Microbiology and Immunology, Northwestern University VA Chicago, Lakeside Medical School, Chicago, IL 60611; and Division of Biology, California Institute of Technology, Pasadena, CA 91125

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) produce IL-6 and IL-8, which contribute to inflammation and joint damage. The promoters of both cytokines possess binding sites for NF-B, C/EBPß, and c-Jun, but the contribution of each to the regulation of IL-6 and IL-8 in RA FLS is unknown. We employed adenoviral-mediated gene delivery of a nondegradable IB, or dominant-negative versions of C/EBPß or c-Jun, to determine the contribution of each transcription factor to IL-6 and IL-8 expression. Inhibition of NF-B activation significantly reduced the spontaneous and IL-1ß-induced secretion of IL-6 and IL-8 by RA FLS and the IL-1ß-induced production of IL-6 and IL-8 by human dermal fibroblasts. Inhibition of C/EBPß modestly reduced constitutive and IL-1ß-induced IL-6 by RA FLS, but not by human dermal fibroblasts, and had no effect on IL-8. Inhibition of c-Jun/AP-1 had no effect on the production of either IL-6 or IL-8. Employing gel shift assays, NF-B, C/EBPß, and c-Jun were constitutively activated in RA FLS, but only NF-B and c-Jun activity increased after IL-1ß. The reduction of cytokines by IB was mediated through inhibition of NF-B activation, which resulted in decreased IL-6 and IL-8 mRNA. NF-B was essential for IL-6 expression, because fibroblasts in which both NF-B p50/p65 genes were deleted failed to express IL-6 in response to IL-1. These findings document the importance of NF-B for the regulation of the constitutive and IL-1ß-stimulated expression of IL-6 and IL-8 by RA FLS and support the role of inhibition of NF-B as a therapeutic goal in RA.

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