The two NF-κB activation pathways and their role in innate and adaptive immunity

NF-κB and the immune response

“…Mice with a point mutation in nik (aly/aly mice) lack multiple secondary lymphoid organs (Miyawaki et al, 1994;Koike et al, 1996;Shinkura et al, 1999) and share several phenotypic similarities with lymphotoxin and IKKa single knockout animals (Mebius, 2003;Bonizzi and Karin, 2004). p52/RelB, which is activated downstream of NIK and IKKa, is thought to be the primary transcriptional mediator of several key organogenic factors including CXCL12, CXCL13, CCL19, CCL21 and MadCAM-1 (Yilmaz et al, 2003).…”

“…Although the role of NF-kB in cancer biology is becoming progressively better established, historically much of our current knowledge of NF-kB resulted from efforts directed at understanding the regulation and function of the immune response. In keeping with the critical role played by NF-kB in different areas of immunology, numerous excellent reviews have been published covering the role of NF-kB in Toll-like receptor (TLR) and antigen receptor (AgR) signaling, lymphoid organogenesis and hematopoiesis (Mebius, 2003;Bonizzi and Karin, 2004;Hayden and Ghosh, 2004;Lin and Wang, 2004;Siebenlist et al, 2005;Akira et al, 2006). This review will, therefore, attempt to provide a more comprehensive, if less detailed, review of the diverse functions of NF-kB in immunology, with the goal of illuminating how it is that so much in immunology seems to revolve around this family of transcription factors.…”

Monarch-1/PYPAF7 and other CATERPILLER (CLR, NOD, NLR) proteins with negative regulatory functions

“…These MAP3 kinases activate the IKK complex (composed of IKKα, β, and γ), which promotes the activation of RelA/p50 NF-κB dimers. This "canonical" pathway proceeds rapidly and leads to the production of inflammatory cytokines and chemokines including IL-6, TNF-α and IL-8 [22].…”

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

“…Stimulation of the NF-kB pathway leads to the rapid phosphorylation of IkBs and its subsequent degradation, resulting in NF-kB translocation into the nucleus. The phosphorylation of IkBa on serine residues 32 and 36 is initiated by an inhibitor of NF-kB kinase (IKK) complex which, at least in the canonical NF-kB activation pathway, includes a catalytic heterocomplex composed of IKK-1, IKK-2 and NEMO (Ghosh and Karin, 2002;Bonizzi and Karin, 2004;Greten and Karin, 2004). This pathway is activated in high-risk MDS and AML cells because chemical inhibition of IKK, knockdown of each of the components of the IKK complex (IKK1, IKK2, NEMO), inhibition of the proteasome (which is required for IkB degradation) or knockdown of p65 (the most abundant subunit of NF-kB) invariably interrupts anti-apoptotic NF-kB signaling and hence activates the apoptotic pathway (Campbell et al, 2004;Karin et al, 2004;Rajkumar et al, 2005).…”