title: Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: the dominant role for NF-kappa B but not C/EBP beta or c-Jun.
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-kappaB, C/EBPbeta, 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 IkappaBalpha, or dominant-negative versions of C/EBPbeta or c-Jun, to determine the contribution of each transcription factor to IL-6 and IL-8 expression. Inhibition of NF-kappaB activation significantly reduced the spontaneous and IL-1beta-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/EBPbeta modestly reduced constitutive and IL-1beta-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-kappaB, C/EBPbeta, and c-Jun were constitutively activated in RA FLS, but only NF-kappaB and c-Jun activity increased after IL-1beta. The reduction of cytokines by IkappaBalpha was mediated through inhibition of NF-kappaB activation, which resulted in decreased IL-6 and IL-8 mRNA. NF-kappaB was essential for IL-6 expression, because fibroblasts in which both NF-kappaB p50/p65 genes were deleted failed to express IL-6 in response to IL-1. These findings document the importance of NF-kappaB for the regulation of the constitutive and IL-1beta-stimulated expression of IL-6 and IL-8 by RA FLS and support the role of inhibition of NF-kappaB as a therapeutic goal in RA.
authors: Division of Rheumatology, Department of Medicine and the Department of Microbiology and Immunology, Northwestern University VA Chicago, Lakeside Medical School, Chicago, IL 60611, USA.
authors: C
authors: C
authors: Georganas
authors: H
authors: H
authors: Liu
authors: H
authors: H
authors: Perlman
authors: A
authors: A
authors: Hoffmann
authors: B
authors: B
authors: Thimmapaya
authors: R M
authors: RM
authors: Pope
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism*; D005822:Genetic Vectors / Q000276:immunology; D006801:Humans; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D000093242:Interleukin-6 Inhibitors; C000606204:NFKBIA protein, human