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. 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.
The activated form of NF-κB is a heterodimer. Its is usually formed from:
but the activated form in some processes is also associated with other proteins:
- Subunit rel
- Subunit relB
- Subunit v-rel
- Subunit p52
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.
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.
Multiple stimuli are known to do this. They include:
- Immune stimuli
- Protein C activators
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.
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.
- 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.
- Vitamin D may have indirect inhibitory effects through the nuclear vitamin D receptor
- ↑ Bubici C, Papa S, Pham CG, Zazzeroni F, Franzoso G. The NF-kappaB-mediated control of ROS and JNK signaling. Histology and histopathology 2006;21(1):69-80.
- ↑ a b c d Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. The New England journal of medicine 1997;336(15):1066-71.
- ↑ Szeto FL, Sun J, Kong J, Duan Y, Liao A, Madara JL, et al. Involvement of the vitamin D receptor in the regulation of NF-kappaB activity in fibroblasts. The Journal of steroid biochemistry and molecular biology 2007;103(3-5):563-6. (Direct link – subscription may be required.)