The roles of the classical and alternative nuclear factor-kappaB pathways: potential implications for autoimmunity and rheumatoid arthritis.
Nuclear factor-kappaB (NF-kappaB) is an inducible transcription factor controlled by two principal signaling cascades, each activated by a set of signal ligands: the classical/canonical NF-kappaB activation pathway and the alternative/noncanonical pathway. The former pathway proceeds via phosphorylation and degradation of inhibitor of NF-kappaB (IkappaB) and leads most commonly to activation of the heterodimer RelA/NF-kappaB1(p50). The latter pathway proceeds via phosphorylation and proteolytic processing of NF-kappaB2 (p100) and leads to activation, most commonly, of the heterodimer RelB/NF-kappaB2 (p52). Both pathways play critical roles at multiple levels of the immune system in both health and disease, including the autoimmune inflammatory response. These roles include cell cycle progression, cell survival, adhesion, and inhibition of apoptosis. NF-kappaB is constitutively activated in many autoimmune diseases, including diabetes type 1, systemic lupus erythematosus, and rheumatoid arthritis (RA). In this review we survey recent developments in the involvement of the classical and alternative pathways of NF-kappaB activation in autoimmunity, focusing particularly on RA. We discuss the involvement of NF-kappaB in self-reactive T and B lymphocyte development, survival and proliferation, and the maintenance of chronic inflammation due to cytokines such as tumor necrosis factor-alpha, IL-1, IL-6, and IL-8. We discuss the roles played by IL-17 and T-helper-17 cells in the inflammatory process; in the activation, maturation, and proliferation of RA fibroblast-like synovial cells; and differentiation and activation of osteoclast bone-resorbing activity. The prospects of therapeutic intervention to block activation of the NF-kappaB signaling pathways in RA are also discussed.
Brown
Keith D
KD
Immune Activation Section, Laboratory of Immune Regulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1876, USA.
Claudio
Estefania
E
Siebenlist
Ulrich
U
D001172:Arthritis, Rheumatoid / Q000503:physiopathology*; D015551:Autoimmunity / Q000502:physiology*; D016207:Cytokines / Q000502:physiology; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology
D016207:Cytokines; D020381:Interleukin-17; D016328:NF-kappa B
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