Defining Therapeutic Targets by Using Adenovirus: Blocking NF-kappa B Inhibits Both Inflammatory and Destructive Mechanisms in Rheumatoid Synovium but Spares Anti-Inflammatory Mediators
Abstract
The role of the transcription factor NF-kappa B in the pathogenesis of rheumatoid arthritis has long been a subject of controversy. We used an adenoviral technique of blocking NF-kappa B through overexpression of the inhibitory subunit Ikappa Bα , 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 α and other pro-inflammatory cytokines is NF-kappa B-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, Ikappa Bα overexpression inhibited the production of matrix metalloproteinases 1 and 3 while not affecting their tissue inhibitor. Blocking NF-kappa B 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.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- May 1999
- DOI:
- 10.1073/pnas.96.10.5668
- Bibcode:
- 1999PNAS...96.5668B