NF-kappa B is usually activated by signal-induced, ubiquitin-mediated degradation of its inhibitor, I kappa B. This process is initiated by phosphorylation of I kappa B by the I kappa B kinase (IKK) complex, predominantly by the IKK beta catalytic subunit, and requires the regulatory subunit IKK gamma (NEMO). Another activation pathway, with no known physiological inducers, involves ubiquitin-mediated processing of the NF-kappa B2 inhibitory protein p100 and is dependent on phosphorylation of p100 by IKK alpha. We show here that B cell-activating factor (BAFF) activates this second pathway and that this requires the BAFF receptor (BAFF-R), the NF-kappa B-inducing kinase (NIK) and protein synthesis, but not NEMO. This NEMO-independent cascade is physiologically relevant for the survival and, hence, progression of maturing splenic B cells.

The evolutionarily conserved nuclear factor-kappaB family of transcription factors is known to have a crucial role in rapid responses to stress and pathogens, inducing transcription of many genes that are essential for host defence. Now, studies of mice that are deficient in nuclear factor-kappaB-family members (or deficient in the activation of these factors) reveal that nuclear factor-kappaB is extensively involved in the development of T cells and B cells. And, as we review here, although these factors have several roles, their primary cell-autonomous function is to ensure lymphocyte survival at various developmental stages. This function is subverted in numerous diseases and can lead, for example, to survival of self-reactive lymphocytes or tumour cells.

Nuclear factor-κB (NF-κB) is an inducible transcription factor controlled by two principal signaling cascades, each activated by a set of signal ligands: the classical/canonical NF-κB activation pathway and the alternative/noncanonical pathway. The former pathway proceeds via phosphorylation and degradation of inhibitor of NF-κB (IκB) and leads most commonly to activation of the heterodimer RelA/NF-κB1(p50). The latter pathway proceeds via phosphorylation and proteolytic processing of NF-κB2 (p100) and leads to activation, most commonly, of the heterodimer RelB/NF-κB2 (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-κB 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-κB activation in autoimmunity, focusing particularly on RA. We discuss the involvement of NF-κB 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-α, 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-κB signaling pathways in RA are also discussed. IntroductionNuclear factor-κ κB Detailed reviews of nuclear factor-κB (NF-κB) function and regulation are available in the recent literature [1][2][3][4][5]. Briefly, NF-κB is a family of inducible dimeric transcription factors including five members ( Figure 1): Rel (c-Rel), RelA (p65), RelB, NF-κB1 (p50/p105) and NF-κB2 (p52/p100). It recognizes a common consensus DNA sequence and regulates a large number of target genes, particularly those involved in the immune system and defense against pathogens, but also genes concerned with inflammation, injury, stress, and the acute phase response. In unstimulated cells, homodimers or heterodimers of NF-κB family members are bound to ankyrinrich regions of inhibitor of NF-κB (IκB) inhibitory proteins (the closely related IκBα, IκBβ, and IκBε). This binding serves to retain the dimers in the cytoplasm, which are hence unable to initiate transcription of target genes. The NF-κB1/p105 and NF-κB2/p100 precursor proteins, which encode p50 and p52 in their amino-terminal halves, also behave like IκBs, with ankyrin repeats in their carboxyl-terminal halves being analogous to those of the smaller IκBs (Figure 1). The IκBs and NF-κB2/p100 are important targets of inducible regulatory pathways that mobilize active NF-κB to the nucleus [1][2][3][4][5][6]. ...