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

Bondeson, Jan, Foxwell, Brian, Brennan, Fionula and Feldmann, Marc 1999. Defining therapeutic targets by using adenovirus: blocking NF-kB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. Proceedings of the National Academy of Sciences of the United States of America 96 (10) , pp. 5668-5673. 10.1073/pnas.96.10.5668

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Abstract

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

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Last Modified:	30 Jun 2017 03:21
URI:	https://orca.cardiff.ac.uk/id/eprint/55270

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