Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1073/pnas.96.10.5668

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

05/1999

Volume

96

Pages

5668 - 5673

Addresses

Kennedy Institute of Rheumatology, 1 Aspenlea Road, Hammersmith, London W6 8LH, United Kingdom.

Keywords

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