NF-kb and C-Rel Transcription Factors Have Distinct Roles in Inflammatory Arthritis
Background: Many of the inflammatory mediators that play a role in the pathogenesis of rheumatoid arthritis (RA) are regulated by the Rel/nuclear factor-kb (NF-kb) transcription factor family. Consequently, Rel/NF-kb has been considered a potential target for therapeutic intervention in RA. However, because Rel/NF-kB plays a critical role in immune regulation, nonspecific inhibition might compromise normal host defenses. An alternative approach is to identify and target only the Rel/NF-kB subunits that are critical for disease development. In this study (J Clin Invest 105:1799-1806, 2000), the investigators evaluated the importance of c-Rel and p50 (two of the Rel/NF-kB subunits) in the development of a chronic polyarthritis (collagen induced), and an acute monoarthritis (methylated BSA/IL-1-induced) model, in mice. Mice deficient in the c-rel gene (c-rel-/-) and deficient in the p50 gene (nfkba-/-) were tested and compared to wild type mice.
Results: In terms of the collagen-induced arthritis model, c-Rel-deficient mice had a significantly lower incidence and reduced severity of arthritis compared to wild type controls, and p50-deficient mice were completely resistant to developing the arthritis. In terms of the acute monoarthritis model, p50-deficient mice developed a markedly reduced arthritis while c-Rel deficient mice developed severe arthritis similar to wild type controls.
Conclusion: These results indicate that Rel/NF-kB is essential for the development of inflammatory arthritis and provide the first evidence that selective blockade of Rel/NF-kB subunits may prevent it. The results also suggest that the absence of different Rel/NF-kB subunits can have differential effects suggesting distinct roles, rather than redundancy, for the various Rel/NF-kB subunits in different stages of disease. The authors conclude that p50 and genes regulated by p50 are targets for rational drug design in inflammatory arthritis.
