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There are five proteins in the mammalian NF-κB family:[17]

Class Protein Aliases Gene
I NF-κB1 p105 → p50 NFKB1
NF-κB2 p100 → p52 NFKB2
II RelA p65 RELA
c-Rel REL

Below are the five human NF-κB family members:

Top view of the crystallographic structure (PDB: 1SVC​) of a homodimer of the NFKB1 protein (green and magenta) bound to DNA (brown).
Symbol NFKB1
Entrez 4790
HUGO 7794
OMIM 164011
RefSeq NM_003998
UniProt P19838
Other data
Locus Chr. 4 q24
Side view of the crystallographic structure (PDB: 2RAM​) of a homodimer of the RELA protein (green and magenta) bound to DNA (brown).
Symbol RELA
Entrez 5970
HUGO 9955
OMIM 164014
RefSeq NM_021975
UniProt Q04206
Other data
Locus Chr. 11 q13
Symbol NFKB2
Entrez 4791
HUGO 7795
OMIM 164012
RefSeq NM_002502
UniProt Q00653
Other data
Locus Chr. 10 q24
Symbol RELB
Entrez 5971
HUGO 9956
OMIM 604758
RefSeq NM_006509
UniProt Q01201
Other data
Locus Chr. 19 q13.2-19q13
Symbol REL
Entrez 5966
HUGO 9954
OMIM 164910
RefSeq NM_002908
UniProt Q04864
Other data
Locus Chr. 2 p13-p12

Species distribution and evolution[edit]



Effect of Activation[edit]



Receptor activator of NF-κB (RANK), which is a type of TNFR, is a central activator of NF-κB. Osteoprotegerin (OPG), which is a decoy receptor homolog for RANK ligand (RANKL), inhibits RANK by binding to RANKL, and, thus, osteoprotegerin is tightly involved in regulating NF-κB activation.[22]






Activation process (canonical/classical)[edit]



Inhibitors of NF-κB activity[edit]


Non-canonical/alternate pathway[edit]

A select set of cell-differentiating or developmental stimuli, such as lymphotoxin β-receptor (LTβR), BAFF or RANKL, activate the non-canonical NF-κB pathway to induce NF-κB/RelB:p52 dimer in the nucleus. In this pathway, activation of the NF-κB inducing kinase (NIK) upon receptor ligation led to the phosphorylation and subsequent proteasomal processing of the NF-κB2 precursor protein p100 into mature p52 subunit in an IKK1/IKKa dependent manner. Then p52 dimerizes with RelB to appear as a nuclear RelB:p52 DNA binding activity and regulate a distinct class of genes.[38] In contrast to the canonical signaling that relies upon NEMO-IKK2 mediated degradation of IκBα, -β, -ε, the non-canonical signaling critically depends on NIK mediated processing of p100 into p52. Given their distinct regulations, these two pathways were thought to be independent of each other. However, recent analyses revealed that synthesis of the constituents of the non-canonical pathway, viz RelB and p52, is controlled by the canonical IKK2-IκB-RelA:p50 signaling.[39] Moreover, generation of the canonical and non-canonical dimers, viz RelA:p50 and RelB:p52, within the cellular milieu are also mechanistically interlinked.[39] These analyses suggest that an integrated NF-κB system network underlies activation of both RelA and RelB containing dimer and that a malfunctioning canonical pathway will lead to an aberrant cellular response also through the non-canonical pathway.

In immunity[edit]


In the nervous system[edit]


Recently there has been a great deal of interest in the role of NF-κB in the nervous system. Current studies suggest that NF-κB is important for learning and memory in multiple organisms including crabs,[9][10] fruit flies,[42] and mice.[7][8] NF-κB may regulate learning and memory in part by modulating synaptic plasticity,[6][43] synapse function,[42][44][45] as well as by regulating the growth of dendrites[46] and dendritic spines.[45]

Genes that have NF-κB binding sites are shown to have increased expression following learning,[8] suggesting that the transcriptional targets of NF-κB in the nervous system are important for plasticity. Many NF-κB target genes that may be important for plasticity and learning include growth factors (BDNF, NGF)[47] cytokines (TNF-alpha, TNFR)[48] and kinases (PKAc).[43]


Clinical significance[edit]

Overview of signal transduction pathways involved in apoptosis.


NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die via apoptosis. Normal cells can die when removed from the tissue they belong to, or when their genome cannot operate in harmony with tissue function: these events depend on feedback regulation of NF-κB, and fail in cancer.[55]

Defects in NF-κB results in increased susceptibility to apoptosis leading to increased cell death. This is because NF-κB regulates anti-apoptotic genes especially the TRAF1 and TRAF2 and therefore abrogates the activities of the caspase family of enzymes, which are central to most apoptotic processes.[56]




Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, atherosclerosis[59] and others. It is important to note though, that elevation of some NF-κB activators, such as osteoprotegerin (OPG), are associated with elevated mortality, especially from cardiovascular diseases.[60][61] Elevated NF-κB has also been associated with schizophrenia.[62] Recently, NF-κB activation has been suggested as a possible molecular mechanism for the catabolic effects of cigarette smoke in skeletal muscle and sarcopenia.[63] Research has shown that during inflammation the function of a cell depends on signals it activates in response to contact with adjacent cells and to combinations of hormones, especially cytokines that act on it through specific receptors.[64] A cells’ phenotype within a tissue develops through mutual stimulation of feedback signals that coordinate its function with other cells; this is especially evident during reprogramming of cell function when a tissue is exposed to inflammation, because cells alter their phenotype, and gradually express combinations of genes that prepare the tissue for regeneration after the cause of inflammation is removed.[64][65] Particularly important are feedback responses that develop between tissue resident cells, and circulating cells of the immune system.[65] Fidelity of feedback responses between diverse cell types and the immune system depends on the integrity of mechanisms that limit the range of genes activated by NF-κB, allowing only expression of genes which contribute to an effective immune response and subsequently, a complete restoration of tissue function after resolution of inflammation.[65] In cancer, mechanisms that regulate gene expression in response to inflammatory stimuli are altered to the point that a cell ceases to link its survival with the mechanisms that coordinate its phenotype and its function with the rest of the tissue.[55] This is often evident in severely compromised regulation of NF-κB activity, which allows cancer cells to express abnormal cohorts of NF-κB target genes.[66] This results in not only the cancer cells functioning abnormally: cells of surrounding tissue alter their function and cease to support the organism exclusively. Additionally, several types of cells in the microenvironment of cancer may change their phenotypes to support cancer growth.[67][68][69] Inflammation, therefore, is a process that tests the fidelity of tissue components because the process that leads to tissue regeneration requires coordination of gene expression between diverse cell types.[64][70]


NEMO deficiency syndrome is a rare genetic condition relating to a fault in IKBKG that in turn activates NF-kB. It mostly affects males and has a highly variable set of symptoms and prognoses.[71]


NF-κB is one of several induced transcriptional targets of ΔFosB which facilitates the development and maintenance of an addiction to a stimulus.[72][73][74] In the caudate putamen, NF-κB induction is associated with increases in locomotion, whereas in the nucleus accumbens, NF-κB induction enhances the positive reinforcing effect of a drug through reward sensitization.[73]

Neural and behavioral effects of validated ΔFosB transcriptional targets[73][75]
Neural effects Behavioral effects
c-Fos Molecular switch enabling the chronic
induction of ΔFosB[note 1]
[note 2]
 • Downregulation of κ-opioid feedback loop  • Increased drug reward
NF-κB  • Expansion of NAcc dendritic processes
 • NF-κB inflammatory response in the NAcc
 • NF-κB inflammatory response in the CP
 • Increased drug reward
 • Increased drug reward
 • Locomotor sensitization
GluR2  • Decreased sensitivity to glutamate  • Increased drug reward
Cdk5  • GluR1 synaptic protein phosphorylation
 • Expansion of NAcc dendritic processes
Decreased drug reward
(net effect)

Non-drug inhibitors[edit]

Many natural products (including anti-oxidants) that have been promoted to have anti-cancer and anti-inflammatory activity have also been shown to inhibit NF-κB. There is a controversial US patent (US patent 6,410,516)[76] that applies to the discovery and use of agents that can block NF-κB for therapeutic purposes. This patent is involved in several lawsuits, including Ariad v. Lilly. Recent work by Karin,[77] Ben-Neriah[78] and others has highlighted the importance of the connection between NF-κB, inflammation, and cancer, and underscored the value of therapies that regulate the activity of NF-κB.[79]


The circumsporozoite protein of Plasmodium falciparum has been shown to be an inhibitor of NF-κB.[81]

As a drug target[edit]


The discovery that activation of NF-κB nuclear translocation can be separated from the elevation of oxidant stress[84] gives a promising avenue of development for strategies targeting NF-κB inhibition.

A new drug called denosumab acts to raise bone mineral density and reduce fracture rates in many patient sub-groups by inhibiting RANKL. RANKL acts through its receptor RANK, which in turn promotes NF-κB,[85] RANKL normally works by enabling the differentiation of osteoclasts from monocytes.

Disulfiram, olmesartan and dithiocarbamates can inhibit the nuclear factor-κB (NF-κB) signaling cascade.[86] Effort to develop direct NF-kB inhibitor has emerged with compounds such as (-)-DHMEQ, PBS-1086, IT-603 and IT-901.[87][88][89] (-)-DHMEQ and PBS-1086 are irreversible binder to NF-KB while IT-603 and IT-901 are reversible binder. DHMEQ covalently binds to Cys 38 of p65.[90]

Anatabine's antiinflammatory effects are claimed to result from modulation of NF-κB activity.[91] However the studies purporting its benefit use abnormally high doses in the millimolar range (similar to the extracellular potassium concentration), which are unlikely to be achieved in humans.

See also[edit]


  1. ^ In other words, c-Fos repression allows ΔFosB to accumulate within nucleus accumbens medium spiny neurons more rapidly because it is selectively induced in this state.[74]
  2. ^ ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;[73][75] this table entry reflects only a decrease.


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