Nuclear factor-kappaB

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Nuclear factor-kappaB (nuclear factor-κB, NF-κB, NF-kappaB) is an ubiquitous transcription factor of importance in immune and inflammatory responses as well as promoting cell survival[1]. It interacts with the c-Jun-N-terminal kinase (JNK) cascade and has antioxidant activity dependent upon upregulation of both ferritin heavy chain (FHC) and Mn++ superoxide dismutase (Mn-SOD). Its role in intracellular signaling processes is very complex.

Contents

Molecular biology

Structure

The activated form of NF-κB is a heterodimer. Its is usually formed from[2]:

  • Subunit p65 (also called relA) - coded by RELA gene
  • Subunit p50 - coded by NFKB1 gene

but the activated form in some processes is also associated with other proteins:

  • Subunit rel
  • Subunit relB
  • Subunit v-rel
  • Subunit p52

Function

As well as a transcriptional activator it may act as a repressor. For example NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators and the NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL-3 so it is all rather complicated.

Inactive cell

In the unactivated cell, cytoplasmic NF-κB is bound to inhibitory proteins IκBα and IκBβ. IκBα can be thought of as having acute pathway control mechanisms while IκBβ more slow, background level control mechanisms.

NF-κB activation

Multiple stimuli are known to do this. They include:[2]

Various inhibitory protein kinases (IκB kinases) exist which phosphorylate IκB, causing its rapid degradation by proteasomes. This releases NF-κB which in the nucleus binds to specific κB promoter sequences associated with target genes. The IκBα gene (MAD-3 gene) also has a κB recognition sequence, so NF-κB induces the synthesis of IκBα. This is then transported into the nucleus where it binds and inactivates activated NF-κB terminating the activated gene expression with the complex being cycled back to the cytoplasm. As the synthesis of IκBβ is not induced by NF-κB, cells which use IκBβ to regulate NF-κB are likely to have the respective stimulated transcription products produced for a more prolonged period.

NF-κB regulation

It is not the only transcription factor involved in the regulation of inflammatory and immune genes and frequently functions together with other transcription factors including activator protein 1 (AP-1) and the nuclear factor of interleukin-6. It acts on a wide range of genes for cytokines, enzymes involved in inflammation such as inducible nitric oxide synthase and cyclooxygenase-2, immune receptor molecules, and adhesion molecules such as intercellular adhesion molecule 1, vascular-cell adhesion molecule 1, and E-selectin[2].

Therapeutic interactions

  • Glucocorticoids act at multiple stages to dampen NF-κB activation. Activated glucocorticoid receptors may bind to activated NF-κB. They increase transcription of IκBα.
  • Aspirin and sodium salicylate at high concentrations inhibit activation of NF-κB
  • Interleukin-10 inhibits NF-κB, through its effect on IκBα
  • Gold salts inhibit the binding of NF-κB to DNA.[2]
  • Vitamin D may have indirect inhibitory effects through the nuclear vitamin D receptor[3]

References