NF-κB: a key role in inflammatory diseases

Abstract

NF-κB in defense and diseaseActivation of the NF-κB/Rel transcription family, by nuclear translocation of cytoplasmic complexes, plays a central role in inflammation through its ability to induce transcription of proinflammatory genes (1).This pathway is activated upon appropriate cellular stimulation, most often by signals related to pathogens or stress.Here we will discuss the specificity of various NF-κB proteins, their role in inflammatory disease, the regulation of NF-κB activity by IκB proteins and IκB kinase (IKK), and the development of therapeutic strategies aimed at inhibition of NF-κB. Functions of individual NF-κB proteins in immune cellsThe NF-κB/Rel family includes NF-κB1 (p50/p105), NF-κB2 (p52/p100), p65 (RelA), RelB, and c-Rel (2).Most members of this family (RelB being one exception) can homodimerize, as well as form heterodimers with each other.The most prevalent activated form of NF-κB is a heterodimer consisting of a p50 or p52 subunit and p65, which contains transactivation domains necessary for gene induction.Studies in knockout mice have shown distinct functions for different members of the NF-κB/Rel family.Various NF-κB proteins play a pivotal role in defense of the host against certain pathogens.Furthermore, lack of RelA leads to embryonic lethality and liver degeneration in knockout mice, whereas mice lacking p50 or RelB are immunodeficient but otherwise develop normally to adulthood.B cells from p50 knockout mice show abnormal mitogen responses and antibody production.RelB plays a role in the development and differentiation of dendritic cells, and a mutation disrupting relB impairs antigen presentation.Other NF-κB proteins, including C-Rel and p52, are also essential for normal immune function.Of interest, unlike either of the corresponding single knockout mice, p50/p52 double knockout mice exhibit impaired development of osteoclasts and B cells (3).The expression of NF-κB proteins can provide siteand event-specificity in response to a particular stimulus.For instance, IL-1-induced collagenase expression in synoviocytes is primarily activated by p50 homodimers that bind to a critical NF-κB-like binding site (4).Both p50 and p65 play a role in constitutive IL-6 pro-duction in rheumatoid arthritis (RA) synovial fibroblasts (5), whereas p65 activation by thrombin regulates ICAM-1 expression in endothelial cells (6).p50 and p65 heterodimers are intimately involved in activation of inflammatory genes by IL-1 or TNF-α in human monocytes, and these effects are blocked by the anti-inflammatory cytokine IL-10 (7).Additional specificity is provided by the expression patterns of other regulatory molecules, including surface receptors to proinflammatory cytokines as well as the hierarchy of IKK and IκB isotypes in each cell lineage (see below).These differences, along with multiple variations in NF-κB-like binding sites that interact with certain NF-κB hetero-and homodimers, permit cells to respond to the external environment at the appropriate time with the correct genes.

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Affiliated Institutions

• Amsterdam UMC Location University of Amsterdam NL

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