Distinct roles for the NF-κB1 (p50) and c-Rel transcription factors in inflammatory arthritis
Ian K. Campbell, … , Kristy O’Donnell, Ian P. Wicks
Ian K. Campbell, … , Kristy O’Donnell, Ian P. Wicks
Published June 15, 2000
Citation Information: J Clin Invest. 2000;105(12):1799-1806. https://doi.org/10.1172/JCI8298.
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Article

Distinct roles for the NF-κB1 (p50) and c-Rel transcription factors in inflammatory arthritis

Abstract

Rheumatoid arthritis (RA) is a complex disease, with contributions from systemic autoimmunity and local inflammation. Persistent synovial joint inflammation and invasive synovial pannus tissue lead to joint destruction. RA is characterized by the production of inflammatory mediators, many of which are regulated by the Rel/NF-κB transcription factors. Although an attractive target for therapeutic intervention in inflammatory diseases, Rel/NF-κB is involved in normal physiology, thus global inhibition could be harmful. An alternate approach is to identify and target the Rel/NF-κB subunits critical for components of disease. To assess this, mice with null mutations in c-rel or nfkb1 were used to examine directly the roles of c-Rel and p50 in models of acute and chronic inflammatory arthritis. We found c-Rel–deficient mice were resistant to collagen-induced arthritis but had a normal response in an acute, destructive arthritis model (methylated BSA/IL-1 induced arthritis) suggesting c-Rel is required for systemic but not local joint disease. In contrast, p50-deficient mice were refractory to induction of both the chronic and acute arthritis models, showing this subunit is essential for local joint inflammation and destruction. Our data suggest Rel/NF-κB subunits play distinct roles in the pathogenesis of inflammatory arthritis and may provide a rationale for more specific therapeutic blockade of Rel/NF-κB in RA.

Authors

Ian K. Campbell, Steve Gerondakis, Kristy O’Donnell, Ian P. Wicks

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Figure 1

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Clinical and histological assessment of CIA in c-rel–/– versus WT mice. ...
Clinical and histological assessment of CIA in c-rel–/– versus WT mice. The incidence of arthritis (shown as cumulative percentage) (a) and mean clinical scores (± SEM) (c) of c-rel–/– (open circles, n = 35) and WT (filled circles, n = 37) mice are shown with time after primary immunization with CII. Data are pooled from three experiments. For statistical analysis see Table 1. At 60 days after primary immunization with CII, mice were sacrificed, their hind limbs removed, and the paws processed for histology (see Methods). Frontal sections of the interphalangeal joints of WT (b) and c-rel–/– (d) mice are shown. WT mouse joints frequently showed severe pathology with pannus invading into the subchondral bone (arrow). The majority of c-rel–/– mouse joints examined appeared normal, with intact articular cartilage (C) and no inflammatory cells in the joint space (J) or synovium (arrowhead). B, bone; M, bone marrow. Hematoxylin and eosin stained. ×200.