The NF-κB dimers can then translocate to the nucleus and activate the transcription and/or repression of genes. Phosphorylated IκB becomes ubiquitinated and is then targeted for degradation by the proteasome. induces the activation of the IκB kinase (IKK) complex to phosphorylate members of the IκB family. In the most canonical example, p50/relA dimers are held in the cytoplasm by IκBα. These dimers are held by cytoplasmic inhibitors until their release via signal-mediated degradation of those inhibitors. 3 NF-κB is comprised of a family of five DNA-binding proteins relA (p65), relB, c-rel, p50 (derived from the p105 precursor), and p52 (derived from the p100 precursor), which can mix and match to form a large number of dimeric transcription factors. This is not surprising as NF-κB plays a central role in the mediation of inflammation and the immune response. NF-κB has long been appreciated as a central player in many of the processes underlying the progression of RA. Fibroblast-like synoviocytes as well as other cells secrete MMPs and RANKL which activate osteoclasts, leading ultimately to the bone malformations that characterize late stage RA. 2 In addition to secreting autoantibodies, B cells are extremely efficient antigen presenting cells and so act to continue activating T cells. Anti-CCP antibodies are currently of great interest as they are both quite predictive of disease and mark a specific subset of RA. B cells secrete autoantibodies such as rheumatoid factor and anti-cyclic citrullinated protein (anti-CCP) antibodies. IL-17, in turn, promotes neutrophil migration and activation. Programmed by IL-23, T cells differentiate into Th17 cells which secrete IL-17. Macrophages are considered one of the major contributors of cytokines to this process, producing TNFα, IL-1, and IL-6 in large quantities. Inflammatory cytokines program the cells comprising pannus to assume their pathological character. The cytokine network plays a major role in disease progression. Osteoblasts respond by rebuilding the bone however, as patterning information has become corrupted, the process leads to the progressive malformation of the joint and crippling of the patient. Osteoclasts become activated and begin to mobilize hydroxyapatite thus removing bone from the joint. These molecules work together to degrade cartilage and extracellular matrix and expose bone cells to the inflammatory environment. Rheumatoid arthritis (RA) is a chronic autoimmune disease of the joints in which synovial cells proliferate and intermix with infiltrating immune cells to form a pathological tissue termed “pannus.” 1 A complex network of cytokines including TNFα, IL-1, IL-6, IL-17, and others is produced leading to a state of inflammation and the secretion of reactive compounds and destructive enzymes such as matrix metalloproteinases (MMPs) and collagenases.
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