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

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Abstract
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-κB, C/EBPβ, 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 IκBα, or dominant-negative versions of C/EBPβ or c-Jun, to determine the contribution of each transcription factor to IL-6 and IL-8 expression. Inhibition of NF-κB activation significantly reduced the spontaneous and IL-1β-induced secretion of IL-6 and IL-8 by RA FLS and the IL-1β-induced production of IL-6 and IL-8 by human dermal fibroblasts. Inhibition of C/EBPβ modestly reduced constitutive and IL-1β-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-κB, C/EBPβ, and c-Jun were constitutively activated in RA FLS, but only NF-κB and c-Jun activity increased after IL-1β. The reduction of cytokines by IκBα was mediated through inhibition of NF-κB activation, which resulted in decreased IL-6 and IL-8 mRNA. NF-κB was essential for IL-6 expression, because fibroblasts in which both NF-κB p50/p65 genes were deleted failed to express IL-6 in response to IL-1. These findings document the importance of NF-κB for the regulation of the constitutive and IL-1β-stimulated expression of IL-6 and IL-8 by RA FLS and support the role of inhibition of NF-κB as a therapeutic goal in RA.