A single NFκB system for both canonical and non-canonical signaling

Abstract

Two distinct nuclear factor κB (NFκB) signaling pathways have been described; the canonical pathway that mediates inflammatory responses, and the non-canonical pathway that is involved in immune cell differentiation and maturation and secondary lymphoid organogenesis. The former is dependent on the IκB kinase adaptor molecule NEMO, the latter is independent of it. Here, we review the molecular mechanisms of regulation in each signaling axis and attempt to relate the apparent regulatory logic to the physiological function. Further, we review the recent evidence for extensive cross-regulation between these two signaling axes and summarize them in a wiring diagram. These observations suggest that NEMO-dependent and -independent signaling should be viewed within the context of a single NFκB signaling system, which mediates signaling from both inflammatory and organogenic stimuli in an integrated manner. As in other regulatory biological systems, a systems approach including mathematical models that include quantitative and kinetic information will be necessary to characterize the network properties that mediate physiological function, and that may break down to cause or contribute to pathology.

Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

“…1). Basal RelB expression may finally determine the strength and kinetics of noncanonical NF-κB signaling (36). The results from the present study, although obtained mostly with the human GEN pDC line, also likely apply to primary pDCs, given that GEN cells share many of the functional attributes of primary pDCs, including TLR-induced IDO expression (37,38).…”

Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation

“…Other reports concur with our findings that NF-κB inhibition prevents apoptosis and islet damage when islets are exposed to cytokines, using a degradation-resistant IκBα transgenic mouse and islet model [37,44]. Since NF-κB activation is involved in a broad range of biological processes, including cell survival, stress responses and maturation of various cell types, the present data is inadequate to confirm that NF-κB inhibition alone is sufficient to protect islets from cytokine-induced apoptosis [45]. Oxygen free radicals (such as those produced from cytokine-stimulated iNOS) play a role in cytokine-mediated damage [46].…”

A Role for the NF-κB Pathway in Cell Protection from Complement-Dependent Cytotoxicity

“…Alternatively, the canonical and noncanonical NF-kB signaling pathways may cross-regulate each other and act as a single NF-kB signaling system in promotion of complement resistance (reviewed in Refs. 24,40). It is also conceivable that IKKa supports activity of IKKb in the conventional signaling pathway by facilitating assembly of the holo-IKK complex.…”

“…Through canonical and noncanonical signaling pathways, NF-kB proteins regulate inflammatory and developmental processes, respectively. Upon activation of the IkB kinases IKKa or IKKb, they phosphorylate IkBs and target them to ubiquitination and proteasomal degradation, thus enabling translocation of the NF-kB homo-and heterodimers into the nucleus and activation of genes responsible for inflammation and survival (21)(22)(23)(24)(25).…”