Distinct roles for the NF-kappaB1 (p50) and c-Rel transcription factors in inflammatory arthritis.
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-kappaB transcription factors. Although an attractive target for therapeutic intervention in inflammatory diseases, Rel/NF-kappaB is involved in normal physiology, thus global inhibition could be harmful. An alternate approach is to identify and target the Rel/NF-kappaB 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-kappaB subunits play distinct roles in the pathogenesis of inflammatory arthritis and may provide a rationale for more specific therapeutic blockade of Rel/NF-kappaB in RA.
Campbell
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Reid Rheumatology Laboratory, Division of Autoimmunity and Transplantation, and. Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Gerondakis
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O'Donnell
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Wicks
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D000208:Acute Disease; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002908:Chronic Disease; D003094:Collagen / Q000276:immunology; D003433:Crosses, Genetic; D020573:Genes, rel; D007249:Inflammation; D007596:Joints / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel; D014157:Transcription Factors; D003094:Collagen