Defining therapeutic targets by using adenovirus: Blocking NF-kappa B inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators

The role of the transcription factor NF-kappa B in the pathogenesis of rheu matoid arthritis has long been a subject of controversy. We used an adenovi ral technique of blocking NF-kappa B through overexpression of the inhibito ry subunit I kappa B alpha, which has the advantage that it can be used in the diseased tissue itself, with >90% of the synovial macrophages, fibrobla sts, and T cells infected. We found that the spontaneous production of tumo r necrosis factor alpha and other pro-inflammatory cytokines is NF-kappa B- dependent in rheumatoid synovial tissue, in contrast to the main anti-infla mmatory mediators, like IL-10 and -11, and the IL-1 receptor antagonist. Of even more interest, I kappa B alpha overexpression inhibited the productio n of matrix metalloproteinases 1 and 3 while not affecting their tissue inh ibitor. Blocking NF-kappa B in the rheumatoid joint thus has a very benefic ial profile, reducing both the inflammatory response and the tissue destruc tion. 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.