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The role of the transcription factor NF-kappaB in the pathogenesis of rheumatoid arthritis has long been a subject of controversy. We used an adenoviral technique of blocking NF-kappaB through overexpression of the inhibitory subunit IkappaBalpha, which has the advantage that it can be used in the diseased tissue itself, with >90% of the synovial macrophages, fibroblasts, and T cells infected. We found that the spontaneous production of tumor necrosis factor alpha and other pro-inflammatory cytokines is NF-kappaB-dependent in rheumatoid synovial tissue, in contrast to the main anti-inflammatory mediators, like IL-10 and -11, and the IL-1 receptor antagonist. Of even more interest, IkappaBalpha overexpression inhibited the production of matrix metalloproteinases 1 and 3 while not affecting their tissue inhibitor. Blocking NF-kappaB in the rheumatoid joint thus has a very beneficial profile, reducing both the inflammatory response and the tissue destruction. The adenoviral technique described here has widespread applicability, allowing rapid testing of the effects of blocking a potential therapeutic target in either cultures of normal cells or in the diseased tissue itself.

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

11/05/1999

Volume

96

Pages

5668 - 5673

Keywords

Adenoviridae, Anti-Inflammatory Agents, Arthritis, Rheumatoid, Cells, Cultured, Cytokines, DNA-Binding Proteins, Humans, I-kappa B Proteins, Inflammation, Lymphocytes, Macrophages, Metalloendopeptidases, NF-KappaB Inhibitor alpha, NF-kappa B, Synovial Membrane, Time Factors, Tissue Inhibitor of Metalloproteinases