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PMID: 10862795 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Distinct roles for the NF-kappaB1 (p50) and c-Rel transcription factors in inflammatory arthritis.

The Journal of clinical investigation ·Vol. 105 ·No. 12 ·2000-06-00 ·Pages 1799-806

Campbell IK, Gerondakis S, O'Donnell K, Wicks IP

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-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.

MeSH Terms
Acute Disease Animals Arthritis, Experimental/genetics,pathology,physiopathology Chronic Disease Collagen/immunology Crosses, Genetic Genes, rel Inflammation Joints/pathology Mice Mice, Inbred C57BL Mice, Knockout NF-kappa B/deficiency,genetics,metabolism NF-kappa B p50 Subunit Proto-Oncogene Proteins c-rel/deficiency,metabolism Transcription Factors/metabolism
Chemicals
NF-kappa B NF-kappa B p50 Subunit Proto-Oncogene Proteins c-rel Transcription Factors Collagen
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Campbell I K
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 S
O'Donnell K
Wicks I P
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI8298
Published
2000-06-00
Pages
1799-806
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC378503
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI8298 PMC Full Text View journal details
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