Defining Therapeutic Targets by Using Adenovirus: Blocking NF-κ B Inhibits Both Inflammatory and Destructive Mechanisms in Rheumatoid Synovium but Spares Anti-Inflammatory Mediators

• Published in: Proceedings of the National Academy of Sciences - PNAS 1999-05, Vol.96 (10), p.5668-5673
• Main Authors: Bondeson, Jan, Foxwell, Brian, Brennan, Fionula, Feldmann, Marc
• Format: Article
• Language: English
• Subjects: Adenovirus; Adenoviruses; Arthritis; Biological Sciences; Cell lines; Cytokines; HEK293 cells; Infections; Joints; Macrophages; Synovial membrane; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.10.5668

The role of the transcription factor NF-κ B in the pathogenesis of rheumatoid arthritis has long been a subject of controversy. We used an adenoviral technique of blocking NF-κ B through overexpression of the inhibitory subunit Iκ 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-κ 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, Iκ Bα overexpression inhibited the production of matrix metalloproteinases 1 and 3 while not affecting their tissue inhibitor. Blocking NF-κ 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.