Signaling via the NFκB system

Abstract

The nuclear factor kappa B (NFκB) family of transcription factors is a key regulator of immune development, immune responses, inflammation, and cancer. The NFκB signaling system (defined by the interactions between NFκB dimers, IκB regulators, and IKK complexes) is responsive to a number of stimuli, and upon ligand-receptor engagement, distinct cellular outcomes, appropriate to the specific signal received, are set into motion. After almost three decades of study, many signaling mechanisms are well understood, rendering them amenable to mathematical modeling, which can reveal deeper insights about the regulatory design principles. While other reviews have focused on upstream, receptor proximal signaling (Hayden MS, Ghosh S. Signaling to NF-κB. Genes Dev 2004, 18:2195-2224; Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R. TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme. Cell Mol Life Sci 2008, 65:2964-2978), and advances through computational modeling (Basak S, Behar M, Hoffmann A. Lessons from mathematically modeling the NF-κB pathway. Immunol Rev 2012, 246:221-238; Williams R, Timmis J, Qwarnstrom E. Computational models of the NF-KB signalling pathway. Computation 2014, 2:131), in this review we aim to summarize the current understanding of the NFκB signaling system itself, the molecular mechanisms, and systems properties that are key to its diverse biological functions, and we discuss remaining questions in the field. WIREs Syst Biol Med 2016, 8:227-241. doi: 10.1002/wsbm.1331 For further resources related to this article, please visit the WIREs website.

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“…One of the pivotal inflammatory transcription factors is NFkB, a family of dimeric transcription factors expressed in CAFs (96) with a cardinal role in the regulation of immune responses, inflammation and cancer (98). We have mentioned briefly before that 1,25(OH) 2 D 3 inhibits NF-ĸB activation and signaling via its "messenger VDR" by acting on several components of the multifaceted NF-ĸB system (62,99).…”

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“…However, the mechanism by which neddlylation promotes inflammation remains unclear. NF-κB proteins are a family of dimeric transcription factors that mediate the expression of inflammatory cytokines (41); transcriptional mediators are pre-existing in the cytoplasm and are able to be rapidly activated by various extracellular stimuli, including microbial components and inflammatory cytokines, prior to entry into the nucleus to mediate an inflammatory response (42). The degradation of IκB proteins is the key to NF-κB activity (42).…”

“…NF-κB proteins are a family of dimeric transcription factors that mediate the expression of inflammatory cytokines (41); transcriptional mediators are pre-existing in the cytoplasm and are able to be rapidly activated by various extracellular stimuli, including microbial components and inflammatory cytokines, prior to entry into the nucleus to mediate an inflammatory response (42). The degradation of IκB proteins is the key to NF-κB activity (42). Impaired degradation of IκBα upon neddylation inhibition has been attributed to the inhibitory effects of MLN4924 on cytokine production in macrophages and dendritic cells (6,19,20,37).…”