Key Points
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Nuclear factor-κB (NF-κB) has a crucial and complex function in orchestrating multiple aspects of inflammation. Increasing knowledge of the complexity within the NF-κB signalling pathways is revealing some of the mechanisms that are used by the NF-κB family to appropriately regulate gene expression during an inflammatory response.
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IKK (inhibitor of NF-κB (IκB) kinase), which is a key component in the initiation of the NF-κB pathway through the induction of IκB degradation, exerts additional effects on the NF-κB transcriptional programmes. These include negative regulatory effects brought about by targeting of NF-κB proteins for degradation and positive effects brought about by selectively augmenting co-activator recruitment to facilitate the transcription of NF-κB-dependent genes.
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Certain members of the IκB protein family have now been shown to selectively up-regulate the transcription of specific NF-κB target genes by providing transactivating activity to the otherwise repressive p50 and p52 NF-κB homodimers. IκB proteins can also influence NF-κB transcriptional programmes by affecting the formation, stability and responsiveness of the NF-κB complexes.
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NF-κB transcriptional specificity can be shaped by crosstalk with other signalling pathways, for example the p38 mitogen-activating protein kinase (MAPK) pathway. The newly described Akirins also function selectively in NF-κB transcriptional responses, although the mechanism of action of these proteins remains unknown.
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Several new models of the termination of NF-κB transcriptional responses have been proposed. Nuclear degradation of NF-κB subunits, dissociation of co-activators and sub-nuclear relocalization of NF-κB complexes have been implicated in the process of shutting off NF-κB.
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Components of the NF-κB pathway can both positively and negatively influence gene expression, and NF-κB activation can facilitate and regulate inflammatory processes. Approaches to target NF-κB in inflammatory disease must, therefore, take into account the varied contributions of the NF-κB transcription-factor family in various signalling pathways.
Abstract
Research on the biological function of nuclear factor-κB (NF-κB), a key mediator of inducible transcription in the immune system, has traditionally focused on its role in the initiation of innate and adaptive immune responses. These studies have largely concentrated on the mechanisms of signalling that lead to NF-κB activation and on the positive role of NF-κB in both physiological immunity and pathological inflammation. More recently, there has been growing interest in the mechanisms that directly regulate the NF-κB transcriptional programmes. As a result, several new NF-κB regulatory components have been identified and some of the known components have been assigned new roles. In this Review, we discuss these new insights into the regulation of NF-κB.
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Acknowledgements
The work in the author's laboratory is supported by grants from the National Institutes of Health (NIH) (AI033443, AI066109, AI059440 and AI068977). M.S.H. was also supported by an NIH National Institute of General Medical Science (NIGMS) Medical Scientist Training Program (MSTP) grant GM07205.
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Glossary
- LPS tolerance
-
A transient state of hyporesponsiveness to subsequent stimulation with the Toll-like receptor (TLR) ligand LPS following previous exposure to TLR ligands.
- Transcriptional co-activator
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A protein complex that associates with the ligand-binding domain of peroxisome-proliferator-activated receptors (PPARs) and other transcription factors. Transcriptional co-activators reorganize chromatin templates and recruit the basal transcriptional machinery to the promoter region.
- Transcriptional co-repressor
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A protein complex (including N-CoR and SMRT) that recruits histone-deacetylase complexes to reverse the actions of histone acetyltransferases and that inhibits gene transcription when associated with nuclear hormone receptors.
- Notch
-
A transmembrane receptor that is involved in the pathway for direct cell–cell signalling through its association with a transmembrane ligand of the Delta or Serrate/Jagged family on a neighbouring cell. Notch receptors regulate cell-fate choice in the development of many cell lineages, and so are vital in the regulation of embryonic differentiation due to development.
- p53
-
A transcription factor that is activated by many genotoxic insults and that induces cellular senescence or apoptosis. The gene that encodes p53 is frequently mutated or functionally inactivated in cancer cells.
- RNA interference
-
The use of double-stranded RNAs (dsRNAs) with sequences that precisely match a given gene in order to knock down the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript. The two most common forms of dsRNAs that are used for gene silencing are small — usually 21-base-pairs long — interfering RNAs and plasmid-delivered short hairpin RNAs.
- PML nuclear body
-
A type of nuclear speckle of unknown function that contains several proteins, including the promyelocytic leukaemia (PML) protein.
- Small ubiquitin-like modifier (SUMO) E3 ligase
-
An enzyme that catalyses the conjugation of SUMO to a protein substrate.
- LPS-induced shock
-
A clinical condition that is induced by hyper-reactivity of the innate immune system to bacterial LPS. It is mediated by the pro-inflammatory cytokines interleukin-1 and tumour-necrosis factor, both of which are produced in high amounts following sustained activation of Toll-like receptor 4 by LPS.
- Ischaemia–reperfusion injury
-
An injury in which the tissue first suffers from hypoxia as a result of severely decreased, mediates or completely arrested, blood flow. Restoration of normal blood flow then triggers inflammation, which exacerbates tissue damage.
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Ghosh, S., Hayden, M. New regulators of NF-κB in inflammation. Nat Rev Immunol 8, 837–848 (2008). https://doi.org/10.1038/nri2423
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DOI: https://doi.org/10.1038/nri2423
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