Signalling, inflammation and arthritis: NF-kappaB and its relevance to arthritis and inflammation.
In the synovial cells of patients with RA, activation of the nuclear factor-kappaB (NF-kappaB) pathway results in the transactivation of a multitude of responsive genes that contribute to the inflammatory phenotype, including TNF-alpha from macrophages, matrix metalloproteinases from synovial fibroblasts and chemokines that recruit immune cells to the inflamed pannus. This is largely a consequence of activation of the 'canonical' NF-kappaB pathway that involves heterodimers of p50/p65. Whilst much information on the role of NF-kappaB in inflammation has been gleaned from genetic deficiency of the respective genes in mice, important differences exist in the signalling networks between human and murine immune cells and immortalized cell lines. Despite these differences at the molecular level, the importance of NF-kappaB in inflammation is undisputed and inhibition of the pathway is widely believed to have great potential as a therapeutic target in RA. Commercial effort has gone into developing inhibitors of NF-kappaB activation. However, inhibition of the NF-kappaB activation can result in an exacerbation of inflammation if TNF-alpha production by macrophages is not controlled. It will be important that such inhibitors are carefully monitored before their long-term use in chronic inflammatory conditions such as RA.
Simmonds
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RE
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, UK.
Foxwell
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BM
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018836:Inflammation Mediators; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase