View source for NF-κB

{{short description|Family of transcription factor protein complexes}}
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[[File:NFKB mechanism of action.png|450px|thumb|'''Mechanism of NF-κB action'''.  The classic "canonical" NF-κB complex is a heterodimer of p50 and RelA,<ref name=":0">{{cite journal | vauthors = Biancalana M, Natan E, Lenardo MJ, Fersht AR | title = NF-κB Rel subunit exchange on a physiological timescale | journal = Protein Science | volume = 30 | issue = 9 | pages = 1818–1832 | date = September 2021 | pmid = 34089216 | pmc = 8376415 | doi = 10.1002/pro.4134 }}</ref> as shown.  NF-κB waits for activation in the cytosol, complexed with the inhibitory protein [[IκBα]].  Various extracellular signals can enter the cell via membrane receptors and activate the enzyme [[IκB kinase]] (IKK).  IKK, in turn, phosphorylates the IκBα protein, which results in [[ubiquitination]], dissociation of IκBα from NF-κB, and eventual degradation of IκBα by the [[proteasome]].  The activated NF-κB is then translocated into the nucleus where it binds to specific sequences of DNA called response elements (RE).  The DNA/NF-κB complex then recruits other proteins such as [[coactivator (genetics)|coactivators]] and [[RNA polymerase]], which transcribe downstream DNA into mRNA. In turn, mRNA is translated into protein, resulting in a change of cell function.<ref name="pmid17072321" /><ref name="pmid17303919" /><ref name="pmid17183360" /><ref name="Concetti_2018">{{cite journal | vauthors = Concetti J, Wilson CL | title = NFKB1 and Cancer: Friend or Foe? | journal = Cells | volume = 7 | issue = 9 | page = 133 | date = September 2018 | pmid = 30205516 | pmc = 6162711 | doi = 10.3390/cells7090133 | doi-access = free }}</ref>]]

'''Nuclear factor kappa-light-chain-enhancer of activated B cells''' ('''NF-κB''') is a family of transcription factor protein complexes that controls [[transcription (genetics)|transcription]] of [[DNA]], [[cytokine]] production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, [[cytokine]]s, [[free radical]]s, [[heavy metals]], [[ultraviolet irradiation]], oxidized [[LDL]], and bacterial or viral [[antigen]]s.<ref name="pmid17072321">{{cite journal | vauthors = Gilmore TD | title = Introduction to NF-kappaB: players, pathways, perspectives | journal = Oncogene | volume = 25 | issue = 51 | pages = 6680–6684 | date = October 2006 | pmid = 17072321 | doi = 10.1038/sj.onc.1209954 | doi-access = free }}</ref><ref name="pmid17303919">{{cite journal | vauthors = Brasier AR | title = The NF-kappaB regulatory network | journal = Cardiovascular Toxicology | volume = 6 | issue = 2 | pages = 111–130 | year = 2006 | pmid = 17303919 | doi = 10.1385/CT:6:2:111 | s2cid = 19755135 }}</ref><ref name="pmid17183360">{{cite journal | vauthors = Perkins ND | title = Integrating cell-signalling pathways with NF-kappaB and IKK function | journal = Nature Reviews. Molecular Cell Biology | volume = 8 | issue = 1 | pages = 49–62 | date = January 2007 | pmid = 17183360 | doi = 10.1038/nrm2083 | s2cid = 24589510 }}</ref><ref name="pmid10602459">{{cite journal | vauthors = Gilmore TD | title = The Rel/NF-kappaB signal transduction pathway: introduction | journal = Oncogene | volume = 18 | issue = 49 | pages = 6842–6844 | date = November 1999 | pmid = 10602459 | doi = 10.1038/sj.onc.1203237 | doi-access = free }}</ref><ref name="pmid12795416">{{cite journal | vauthors = Tian B, Brasier AR | title = Identification of a nuclear factor kappa B-dependent gene network | journal = Recent Progress in Hormone Research | volume = 58 | pages = 95–130 | year = 2003 | pmid = 12795416 | doi = 10.1210/rp.58.1.95 | doi-access = free }}</ref> NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and [[autoimmune diseases]], [[septic shock]], [[viral infection]], and improper immune development. NF-κB has also been implicated in processes of [[synaptic plasticity]] and memory.<ref name="Albensi_2000">{{cite journal | vauthors = Albensi BC, Mattson MP | title = Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity | journal = Synapse | volume = 35 | issue = 2 | pages = 151–159 | date = February 2000 | pmid = 10611641 | doi = 10.1002/(SICI)1098-2396(200002)35:2<151::AID-SYN8>3.0.CO;2-P | s2cid = 24215807 }}</ref><ref name="Meffert_2003">{{cite journal | vauthors = Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D | title = NF-kappa B functions in synaptic signaling and behavior | journal = Nature Neuroscience | volume = 6 | issue = 10 | pages = 1072–1078 | date = October 2003 | pmid = 12947408 | doi = 10.1038/nn1110 | s2cid = 43284934 | url = https://resolver.caltech.edu/CaltechAUTHORS:20150409-082723140 }}</ref><ref name="Levenson_2004">{{cite journal | vauthors = Levenson JM, Choi S, Lee SY, Cao YA, Ahn HJ, Worley KC, Pizzi M, Liou HC, Sweatt JD | title = A bioinformatics analysis of memory consolidation reveals involvement of the transcription factor c-rel | journal = The Journal of Neuroscience | volume = 24 | issue = 16 | pages = 3933–3943 | date = April 2004 | pmid = 15102909 | pmc = 6729420 | doi = 10.1523/JNEUROSCI.5646-03.2004 }}</ref><ref name="Freudenthal_1998">{{cite journal | vauthors = Freudenthal R, Locatelli F, Hermitte G, Maldonado H, Lafourcade C, Delorenzi A, Romano A | title = Kappa-B like DNA-binding activity is enhanced after spaced training that induces long-term memory in the crab Chasmagnathus | journal = Neuroscience Letters | volume = 242 | issue = 3 | pages = 143–146 | date = February 1998 | pmid = 9530926 | doi = 10.1016/S0304-3940(98)00059-7 | s2cid = 24577481 }}</ref><ref name="Merlo_2002">{{cite journal | vauthors = Merlo E, Freudenthal R, Romano A | title = The IkappaB kinase inhibitor sulfasalazine impairs long-term memory in the crab Chasmagnathus | journal = Neuroscience | volume = 112 | issue = 1 | pages = 161–172 | year = 2002 | pmid = 12044481 | doi = 10.1016/S0306-4522(02)00049-0 | s2cid = 1403544 }}</ref><ref name="Toxicol Ind Health">{{cite journal | vauthors = Park HJ, Youn HS | title = Mercury induces the expression of cyclooxygenase-2 and inducible nitric oxide synthase | journal = Toxicology and Industrial Health | volume = 29 | issue = 2 | pages = 169–174 | date = March 2013 | pmid = 22080037 | doi = 10.1177/0748233711427048 | s2cid = 25343140 }}</ref>

== Discovery ==
NF-κB was discovered by Ranjan Sen in the lab of Nobel laureate [[David Baltimore]] via its interaction with an 11-base pair sequence in the [[immunoglobulin]] light-chain [[Enhancer (genetics)|enhancer]] in [[B cells]].<ref name="pmid3091258">{{cite journal | vauthors = Sen R, Baltimore D | title = Multiple nuclear factors interact with the immunoglobulin enhancer sequences | journal = Cell | volume = 46 | issue = 5 | pages = 705–716 | date = August 1986 | pmid = 3091258 | doi = 10.1016/0092-8674(86)90346-6 | s2cid = 37832531 }}</ref> Later work by Alexander Poltorak and [[Bruno Lemaitre]] in mice and [[Drosophila melanogaster|''Drosophila'']] fruit flies established [[Toll-like receptor]]s as universally conserved activators of NF-κB signalling. These works ultimately contributed to awarding of the Nobel Prize to [[Bruce Beutler]] and [[Jules A. Hoffmann]], who were the principal investigators of those studies.<ref>{{cite journal | vauthors = Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B | title = Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene | journal = Science | volume = 282 | issue = 5396 | pages = 2085–2088 | date = December 1998 | pmid = 9851930 | doi = 10.1126/science.282.5396.2085 }}</ref><ref>{{cite journal | vauthors = Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA | title = The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults | journal = Cell | volume = 86 | issue = 6 | pages = 973–983 | date = September 1996 | pmid = 8808632 | doi = 10.1016/s0092-8674(00)80172-5 | s2cid = 10736743 | doi-access = free }}</ref><ref>{{Cite web |title=The Nobel Prize in Physiology or Medicine 2011 |url=https://www.nobelprize.org/prizes/medicine/2011/summary/ |access-date=2022-07-14 |website=NobelPrize.org |language=en-US}}</ref>

== Structure ==
All proteins of the NF-κB family share a [[Rel homology domain]] in their [[N-terminus]].  A subfamily of NF-κB proteins, including RelA, RelB, and c-Rel, have a [[transactivation]] domain in their [[C-terminus|C-termini]].  In contrast, the NF-κB1 and NF-κB2 proteins are synthesized as large precursors, p105 and p100, which undergo processing to generate the mature p50 and p52 subunits, respectively.  The processing of p105 and p100 is mediated by the [[ubiquitin]]/[[proteasome]] pathway and involves selective degradation of their C-terminal region containing [[ankyrin repeat]]s.  Whereas the generation of p52 from p100 is a tightly regulated process, p50 is produced from constitutive processing of p105.<ref name="pmid10837071">{{cite journal | vauthors = Karin M, Ben-Neriah Y | title = Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity | journal = Annual Review of Immunology | volume = 18 | pages = 621–663 | year = 2000 | pmid = 10837071 | doi = 10.1146/annurev.immunol.18.1.621 }}</ref><ref name="pmid11520989">{{cite journal | vauthors = Senftleben U, Cao Y, Xiao G, Greten FR, Krähn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M | title = Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway | journal = Science | volume = 293 | issue = 5534 | pages = 1495–1499 | date = August 2001 | pmid = 11520989 | doi = 10.1126/science.1062677 | s2cid = 83308790 | bibcode = 2001Sci...293.1495S }}</ref> The p50 and p52 proteins have no intrinsic ability to activate transcription and thus have been proposed to act as transcriptional repressors when binding κB elements as homodimers.<ref name="pmid8496683">{{cite journal | vauthors = Plaksin D, Baeuerle PA, Eisenbach L | title = KBF1 (p50 NF-kappa B homodimer) acts as a repressor of H-2Kb gene expression in metastatic tumor cells | journal = The Journal of Experimental Medicine | volume = 177 | issue = 6 | pages = 1651–1662 | date = June 1993 | pmid = 8496683 | pmc = 2191052 | doi = 10.1084/jem.177.6.1651 }}</ref><ref name="pmid15642694">{{cite journal | vauthors = Guan H, Hou S, Ricciardi RP | title = DNA binding of repressor nuclear factor-kappaB p50/p50 depends on phosphorylation of Ser337 by the protein kinase A catalytic subunit | journal = The Journal of Biological Chemistry | volume = 280 | issue = 11 | pages = 9957–9962 | date = March 2005 | pmid = 15642694 | doi = 10.1074/jbc.m412180200 | doi-access = free }}</ref> Indeed, this confounds the interpretation of p105-knockout studies, where the genetic manipulation is removing an IκB (full-length p105) and a likely repressor (p50 homodimers) in addition to a transcriptional activator (the RelA-p50 heterodimer).

== Members ==
NF-κB family members share structural [[Homology (biology)|homology]] with the retroviral [[oncogene|oncoprotein]] v-Rel, resulting in their classification as NF-κB/Rel proteins.<ref name="pmid17072321" />

There are five proteins in the mammalian NF-κB family:<ref name="pmid8224837">{{cite journal | vauthors = Nabel GJ, Verma IM | title = Proposed NF-kappa B/I kappa B family nomenclature | journal = Genes & Development | volume = 7 | issue = 11 | pages = 2063 | date = November 1993 | pmid = 8224837 | doi = 10.1101/gad.7.11.2063 | doi-access = free }}</ref>
{| class="wikitable"  style="text-align:center"
! Class
! Protein
! Aliases
! Gene
|-
| rowspan="2" style="width:100px" | I
| style="width:100px" | NF-κB1
| style="width:100px" | p105 → p50
| style="width:100px" | ''[[NFKB1]]''
|-
| NF-κB2
| p100 → p52
| ''[[NFKB2]]''
|-
| rowspan="3" | II
| RelA
| p65
| ''[[RELA]]''
|-
| RelB
|
| ''[[RELB]]''
|-
| c-Rel
|
| ''[[REL]]''
|}

The NF-κB/Rel proteins can be divided into two classes, which share general structural features:<ref name=":0" />[[File:NF-kB proteins.png|none|thumb|900x900px|'''Schematic diagram of NF-κB protein structure'''.<ref name=":0" />  There are two structural classes of NF-κB proteins: class I (top) and class II (bottom).  Both classes of proteins contain a [[N-terminus|N-terminal]] [[DNA-binding domain]] (DBD), which also serves as a dimerization interface to other NF-κB transcription factors and, in addition, binds to the inhibitory [[IκBα]] protein.  The [[C-terminus]] of class I proteins contains a number of [[ankyrin repeat]]s and has [[repressor|transrepression]] activity.  In contrast, the C-terminus of class II proteins has a [[transactivation]] function.<ref name="pmid17072321" /><ref name="pmid17303919" /><ref name="pmid17183360" /><ref name="Concetti_2018" /> ]]

Below are the five human NF-κB family members:
{{infobox protein|align=left
| Name = [[NFKB1]] | caption = Top view of the crystallographic structure ({{PDB|1SVC}}) of a homodimer of the [[NFKB1]] protein (green and magenta) bound to DNA (brown). | image = 1SVC.png | width =  | HGNCid = 7794 | Symbol = [[NFKB1]] | AltSymbols =  | EntrezGene = 4790 | OMIM = 164011 | RefSeq = NM_003998 | UniProt = P19838 | PDB =  | ECnumber =  | Chromosome = 4 | Arm = q | Band = 24 | LocusSupplementaryData = }}
{{infobox protein|align=left|clear=none
| Name = [[RELA]] | caption =  Side view of the crystallographic structure ({{PDB|2RAM}}) of a homodimer of the RELA protein (green and magenta) bound to DNA (brown). | image = 2RAM.png | width =  | HGNCid = 9955 | Symbol = [[RELA]] | AltSymbols = <!-- NFKB3 --> | EntrezGene = 5970 | OMIM = 164014 | RefSeq = NM_021975 | UniProt = Q04206 | PDB =  | ECnumber =  | Chromosome = 11 | Arm = q | Band = 13 | LocusSupplementaryData =  }}
{{infobox protein|align=left|clear=none
| Name = [[NFKB2]] | caption =  | image =  | width =  | HGNCid = 7795 | Symbol = [[NFKB2]] | AltSymbols =  | EntrezGene = 4791 | OMIM = 164012 | RefSeq = NM_002502 | UniProt = Q00653 | PDB =  | ECnumber =  | Chromosome = 10 | Arm = q | Band = 24 | LocusSupplementaryData = }}
{{infobox protein|align=left|clear=none
| Name = [[RELB]] | caption =  | image =  | width =  | HGNCid = 9956 | Symbol = [[RELB]] | AltSymbols = | EntrezGene = 5971 | OMIM = 604758 | RefSeq = NM_006509 | UniProt = Q01201 | PDB =  | ECnumber =  | Chromosome = 19 | Arm = q | Band = 13.2 | LocusSupplementaryData = -19q13 }}
{{infobox protein|align=left|clear=none
| Name = [[REL]] | caption =  | image =  | width =  | HGNCid = 9954 | Symbol = [[REL]] | AltSymbols =  | EntrezGene = 5966 | OMIM = 164910 | RefSeq = NM_002908 | UniProt = Q04864 | PDB =  | ECnumber =  | Chromosome = 2 | Arm = p | Band = 13 | LocusSupplementaryData = -p12 }}
{{clear left}}

== Species distribution and evolution ==
In addition to mammals, NF-κB is found in a number of simple animals as well.<ref name="pmid9597130">{{cite journal | vauthors = Ghosh S, May MJ, Kopp EB | title = NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses | journal = Annual Review of Immunology | volume = 16 | pages = 225–260 | year = 1998 | pmid = 9597130 | doi = 10.1146/annurev.immunol.16.1.225 }}</ref>  These include [[cnidaria]]ns (such as [[sea anemone]]s, [[coral]] and [[hydra (genus)|hydra]]), [[sponge|porifera]] (sponges), single-celled eukaryotes including ''[[Capsaspora owczarzaki]]'' and choanoflagellates, and [[insect]]s (such as [[moth]]s, [[mosquito]]es and [[Drosophila melanogaster|fruitflies]]).  The sequencing of the genomes of the mosquitoes [[Aedes aegypti|''A. aegypti'']] and [[Anopheles gambiae|''A. gambiae'']], and the fruitfly [[Drosophila melanogaster|''D. melanogaster'']] has allowed comparative genetic and evolutionary studies on NF-κB.  In those insect species, activation of NF-κB is triggered by the [[Toll-like receptor|Toll pathway]] (which evolved independently in insects and mammals) and by the Imd (immune deficiency) pathway.<ref name="pmid17588928">{{cite journal | vauthors = Waterhouse RM, Kriventseva EV, Meister S, Xi Z, Alvarez KS, Bartholomay LC, Barillas-Mury C, Bian G, Blandin S, Christensen BM, Dong Y, Jiang H, Kanost MR, Koutsos AC, Levashina EA, Li J, Ligoxygakis P, Maccallum RM, Mayhew GF, Mendes A, Michel K, Osta MA, Paskewitz S, Shin SW, Vlachou D, Wang L, Wei W, Zheng L, Zou Z, Severson DW, Raikhel AS, Kafatos FC, Dimopoulos G, Zdobnov EM, Christophides GK | title = Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes | journal = Science | volume = 316 | issue = 5832 | pages = 1738–1743 | date = June 2007 | pmid = 17588928 | pmc = 2042107 | doi = 10.1126/science.1139862 | bibcode = 2007Sci...316.1738W }}</ref>

== Signaling ==

=== Effect of activation ===
[[File:3do7 NFkB relB DNA.png|thumb|NF-κB (green) heterodimerizes with RelB (cyan) to form a ternary complex with DNA (orange) that promotes gene transcription.<ref name="pmid19098713">{{PDB|3do7}}; {{cite journal | vauthors = Fusco AJ, Huang DB, Miller D, Wang VY, Vu D, Ghosh G | title = NF-kappaB p52:RelB heterodimer recognizes two classes of kappaB sites with two distinct modes | journal = EMBO Reports | volume = 10 | issue = 2 | pages = 152–159 | date = February 2009 | pmid = 19098713 | pmc = 2637311 | doi = 10.1038/embor.2008.227 }}</ref>]]

NF-κB is crucial in regulating cellular responses because it belongs to the category of "rapid-acting" primary transcription factors, i.e., transcription factors that are present in cells in an inactive state and do not require new protein synthesis in order to become activated (other members of this family include transcription factors such as [[c-Jun]], [[STAT protein|STATs]], and [[nuclear hormone receptor]]s).  This allows NF-κB to be a first responder to harmful cellular stimuli. Known inducers of NF-κB activity are highly variable and include reactive oxygen species ([[reactive oxygen species|ROS]]), tumor necrosis factor alpha ([[tumor necrosis factor-alpha|TNFα]]), interleukin 1-beta ([[IL1B|IL-1β]]), bacterial lipopolysaccharides ([[lipopolysaccharide|LPS]]), [[isoprenaline|isoproterenol]], [[cocaine]], [[endothelin-1]] and [[ionizing radiation]].<ref name="inducers">(a) {{cite journal | vauthors = Chandel NS, Trzyna WC, McClintock DS, Schumacker PT | title = Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin | journal = Journal of Immunology | volume = 165 | issue = 2 | pages = 1013–1021 | date = July 2000 | pmid = 10878378 | doi = 10.4049/jimmunol.165.2.1013 | doi-access = free }}; (b) {{cite journal | vauthors = Fitzgerald DC, Meade KG, McEvoy AN, Lillis L, Murphy EP, MacHugh DE, Baird AW | title = Tumour necrosis factor-alpha (TNF-alpha) increases nuclear factor kappaB (NFkappaB) activity in and interleukin-8 (IL-8) release from bovine mammary epithelial cells | journal = Veterinary Immunology and Immunopathology | volume = 116 | issue = 1–2 | pages = 59–68 | date = March 2007 | pmid = 17276517 | doi = 10.1016/j.vetimm.2006.12.008 }}; (c) {{cite journal | vauthors = Renard P, Zachary MD, Bougelet C, Mirault ME, Haegeman G, Remacle J, Raes M | title = Effects of antioxidant enzyme modulations on interleukin-1-induced nuclear factor kappa B activation | journal = Biochemical Pharmacology | volume = 53 | issue = 2 | pages = 149–160 | date = January 1997 | pmid = 9037247 | doi = 10.1016/S0006-2952(96)00645-4 }}; (d) {{cite journal | vauthors = Qin H, Wilson CA, Lee SJ, Zhao X, Benveniste EN | title = LPS induces CD40 gene expression through the activation of NF-kappaB and STAT-1alpha in macrophages and microglia | journal = Blood | volume = 106 | issue = 9 | pages = 3114–3122 | date = November 2005 | pmid = 16020513 | pmc = 1895321 | doi = 10.1182/blood-2005-02-0759 }}; (e) {{cite journal | vauthors = Takemoto Y, Yoshiyama M, Takeuchi K, Omura T, Komatsu R, Izumi Y, Kim S, Yoshikawa J | title = Increased JNK, AP-1 and NF-kappa B DNA binding activities in isoproterenol-induced cardiac remodeling | journal = Journal of Molecular and Cellular Cardiology | volume = 31 | issue = 11 | pages = 2017–2030 | date = November 1999 | pmid = 10591028 | doi = 10.1006/jmcc.1999.1033 }}; (f) {{cite journal | vauthors = Hargrave BY, Tiangco DA, Lattanzio FA, Beebe SJ | title = Cocaine, not morphine, causes the generation of reactive oxygen species and activation of NF-kappaB in transiently cotransfected heart cells | journal = Cardiovascular Toxicology | volume = 3 | issue = 2 | pages = 141–151 | year = 2003 | pmid = 14501032 | doi = 10.1385/CT:3:2:141 | s2cid = 35240781 }}; (g) {{cite journal | vauthors = Neuhofer W, Pittrow D | title = Role of endothelin and endothelin receptor antagonists in renal disease | journal = European Journal of Clinical Investigation | volume = 36 | issue = Supplementary 3 | pages = 78–88 | date = September 2006 | pmid = 16919017 | doi = 10.1111/j.1365-2362.2006.01689.x | s2cid = 30687039 }}; (h) {{cite journal | vauthors = Basu S, Rosenzweig KR, Youmell M, Price BD | title = The DNA-dependent protein kinase participates in the activation of NF kappa B following DNA damage | journal = Biochemical and Biophysical Research Communications | volume = 247 | issue = 1 | pages = 79–83 | date = June 1998 | pmid = 9636658 | doi = 10.1006/bbrc.1998.8741 }}</ref>

NF-κB suppression of [[tumor necrosis factor]] cytotoxicity (apoptosis) is due to induction of [[Antioxidant#Enzyme systems|antioxidant enzymes]] and sustained suppression of [[c-Jun N-terminal kinases]] (JNKs).<ref name="pmid16456579">{{cite journal | vauthors = Papa S, Bubici C, Zazzeroni F, Pham CG, Kuntzen C, Knabb JR, Dean K, Franzoso G | title = The NF-kappaB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease | journal = Cell Death and Differentiation | volume = 13 | issue = 5 | pages = 712–729 | date = May 2006 | pmid = 16456579 | doi = 10.1038/sj.cdd.4401865 | doi-access = free }}</ref>

Receptor activator of NF-κB ([[RANK]]),  which is a type of [[Tumor necrosis factor receptor|TNFR]], is a central activator of NF-κB. [[Osteoprotegerin]] (OPG), which is a [[Decoy#Decoy receptor|decoy receptor]] [[homolog]] for RANK ligand ([[RANKL]]), inhibits RANK by binding to RANKL, and, thus, osteoprotegerin is tightly involved in regulating NF-κB activation.<ref name="pmid17530461">{{cite journal | vauthors = Baud'huin M, Lamoureux F, Duplomb L, Rédini F, Heymann D | title = RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases | journal = Cellular and Molecular Life Sciences | volume = 64 | issue = 18 | pages = 2334–2350 | date = September 2007 | pmid = 17530461 | doi = 10.1007/s00018-007-7104-0 | s2cid = 32179220 | pmc = 11149428 }}</ref>

Many bacterial products and stimulation of a wide variety of cell-surface [[Receptor (biochemistry)|receptors]] lead to NF-κB activation and fairly rapid changes in gene expression.<ref name="pmid17072321" /> The identification of [[Toll-like receptor]]s (TLRs) as specific pattern recognition molecules and the finding that stimulation of TLRs leads to activation of NF-κB improved our understanding of how different pathogens activate NF-κB. For example, studies have identified TLR4 as the receptor for the LPS component of [[Gram-negative bacteria]].<ref name="pmid16930560">{{cite journal | vauthors = Doyle SL, O'Neill LA | title = Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity | journal = Biochemical Pharmacology | volume = 72 | issue = 9 | pages = 1102–1113 | date = October 2006 | pmid = 16930560 | doi = 10.1016/j.bcp.2006.07.010 }}</ref> TLRs are key regulators of both innate and adaptive immune responses.<ref name="pmid17072327">{{cite journal | vauthors = Hayden MS, West AP, Ghosh S | title = NF-kappaB and the immune response | journal = Oncogene | volume = 25 | issue = 51 | pages = 6758–6780 | date = October 2006 | pmid = 17072327 | doi = 10.1038/sj.onc.1209943 | doi-access = free }}</ref>

Unlike RelA, RelB, and c-Rel, the p50 and p52 NF-κB subunits do not contain [[transactivation]] domains in their C terminal halves.  Nevertheless, the p50 and p52 NF-κB members play critical roles in modulating the specificity of NF-κB function.  Although homodimers of p50 and p52 are, in general, repressors of κB site transcription, both p50 and p52 participate in target gene transactivation by forming [[Protein dimer|heterodimers]] with RelA, RelB, or c-Rel.<ref name="pmid12360211">{{cite journal | vauthors = Li Q, Verma IM | title = NF-kappaB regulation in the immune system | journal = Nature Reviews. Immunology | volume = 2 | issue = 10 | pages = 725–734 | date = October 2002 | pmid = 12360211 | doi = 10.1038/nri910 | s2cid = 6962119 }}</ref>  In addition, p50 and p52 homodimers also bind to the nuclear protein [[BCL3|Bcl-3]], and such complexes can function as transcriptional activators.<ref name="pmid8330739">{{cite journal | vauthors = Fujita T, Nolan GP, Liou HC, Scott ML, Baltimore D | title = The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that activates through NF-kappa B p50 homodimers | journal = Genes & Development | volume = 7 | issue = 7B | pages = 1354–1363 | date = July 1993 | pmid = 8330739 | doi = 10.1101/gad.7.7b.1354 | doi-access = free }}</ref><ref name="pmid1406939">{{cite journal | vauthors = Franzoso G, Bours V, Park S, Tomita-Yamaguchi M, Kelly K, Siebenlist U | title = The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-kappa B-mediated inhibition | journal = Nature | volume = 359 | issue = 6393 | pages = 339–342 | date = September 1992 | pmid = 1406939 | doi = 10.1038/359339a0 | s2cid = 4322739 | bibcode = 1992Natur.359..339F | url = https://zenodo.org/record/1233131 }}</ref><ref name="pmid8453667">{{cite journal | vauthors = Bours V, Franzoso G, Azarenko V, Park S, Kanno T, Brown K, Siebenlist U | title = The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers | journal = Cell | volume = 72 | issue = 5 | pages = 729–739 | date = March 1993 | pmid = 8453667 | doi = 10.1016/0092-8674(93)90401-B | doi-access = free }}</ref>

=== Inhibition ===
In unstimulated cells, the NF-κB dimers are sequestered in the [[cytoplasm]] by a family of inhibitors, called IκBs (Inhibitor of κB), which are proteins that contain multiple copies of a sequence called [[ankyrin repeat]]s.  By virtue of their ankyrin repeat domains, the IκB proteins mask the [[nuclear localization signal]]s (NLS) of NF-κB proteins and keep them sequestered in an inactive state in the cytoplasm.<ref name="pmid9865693">{{cite journal | vauthors = Jacobs MD, Harrison SC | title = Structure of an IkappaBalpha/NF-kappaB complex | journal = Cell | volume = 95 | issue = 6 | pages = 749–758 | date = December 1998 | pmid = 9865693 | doi = 10.1016/S0092-8674(00)81698-0 | s2cid = 7003353 | doi-access = free }}</ref>

'''IκBs''' are a family of related proteins that have an N-terminal regulatory domain, followed by six or more ankyrin repeats and a [[PEST sequence|PEST domain]] near their C terminus.  Although the IκB family consists of [[IκBα]], [[NFKBIB|IκBβ]], [[NFKBIE|IκBε]], and [[BCL3|Bcl-3]], the best-studied and major IκB protein is IκBα.  Due to the presence of ankyrin repeats in their C-terminal halves, p105 and p100 also function as IκB proteins. The c-terminal half of p100, that is often referred to as IκBδ, also functions as an inhibitor.<ref name="PMID 17254973">{{cite journal | vauthors = Basak S, Kim H, Kearns JD, Tergaonkar V, O'Dea E, Werner SL, Benedict CA, Ware CF, Ghosh G, Verma IM, Hoffmann A | title = A fourth IkappaB protein within the NF-kappaB signaling module | journal = Cell | volume = 128 | issue = 2 | pages = 369–381 | date = January 2007 | pmid = 17254973 | pmc = 1831796 | doi = 10.1016/j.cell.2006.12.033 }}.</ref><ref name="pmid7898917">{{cite journal | vauthors = Dobrzanski P, Ryseck RP, Bravo R | title = Specific inhibition of RelB/p52 transcriptional activity by the C-terminal domain of p100 | journal = Oncogene | volume = 10 | issue = 5 | pages = 1003–1007 | date = March 1995 | pmid = 7898917 }}</ref>  IκBδ degradation in response to developmental stimuli, such as those transduced through [[lymphotoxin beta receptor|LTβR]], potentiate NF-κB dimer activation in a NIK dependent non-canonical pathway.<ref name="PMID 17254973" /><ref name="pmid16195333">{{cite journal | vauthors = Lo JC, Basak S, James ES, Quiambo RS, Kinsella MC, Alegre ML, Weih F, Franzoso G, Hoffmann A, Fu YX | title = Coordination between NF-kappaB family members p50 and p52 is essential for mediating LTbetaR signals in the development and organization of secondary lymphoid tissues | journal = Blood | volume = 107 | issue = 3 | pages = 1048–1055 | date = February 2006 | pmid = 16195333 | pmc = 1895903 | doi = 10.1182/blood-2005-06-2452 }}</ref>

=== Activation process (canonical/classical) ===
Activation of the NF-κB is initiated by the signal-induced degradation of IκB proteins.  This occurs primarily via activation of a kinase called the [[IκB kinase]] (IKK).  IKK is composed of a heterodimer of the catalytic IKKα and IKKβ subunits and a "master" regulatory protein termed [[IKBKG|NEMO]] (NF-κB essential modulator) or IKKγ. When activated by signals, usually coming from the outside of the cell, the IκB kinase phosphorylates two serine residues located in an IκB regulatory domain.  When phosphorylated on these serines (e.g., serines 32 and 36 in human IκBα), the IκB proteins are modified by a process called [[Ubiquitination#Ubiquitylation|ubiquitination]], which then leads them to be degraded by a cell structure called the [[proteasome]].

With the degradation of IκB, the NF-κB complex is then freed to enter the nucleus where it can 'turn on' the expression of specific genes that have DNA-binding sites for NF-κB nearby.  The activation of these genes by NF-κB then leads to the given physiological response, for example, an inflammatory or immune response, a cell survival response, or cellular proliferation. Translocation of NF-κB to nucleus can be detected immunocytochemically and measured by laser scanning cytometry.<ref name="pmid9822350">{{cite journal | vauthors = Deptala A, Bedner E, Gorczyca W, Darzynkiewicz Z | title = Activation of nuclear factor kappa B (NF-kappaB) assayed by laser scanning cytometry (LSC) | journal = Cytometry | volume = 33 | issue = 3 | pages = 376–382 | date = November 1998 | pmid = 9822350 | pmc = 3874872 | doi = 10.1002/(SICI)1097-0320(19981101)33:3<376::AID-CYTO13>3.0.CO;2-Q }}</ref> NF-κB turns on expression of its own repressor, IκBα.  The newly synthesized IκBα then re-inhibits NF-κB and, thus, forms an auto feedback loop, which results in oscillating levels of NF-κB activity.<ref name="pmid15499023">{{cite journal | vauthors = Nelson DE, Ihekwaba AE, Elliott M, Johnson JR, Gibney CA, Foreman BE, Nelson G, See V, Horton CA, Spiller DG, Edwards SW, McDowell HP, Unitt JF, Sullivan E, Grimley R, Benson N, Broomhead D, Kell DB, White MR | title = Oscillations in NF-kappaB signaling control the dynamics of gene expression | journal = Science | volume = 306 | issue = 5696 | pages = 704–708 | date = October 2004 | pmid = 15499023 | doi = 10.1126/science.1099962 | s2cid = 86055964 | bibcode = 2004Sci...306..704N }}</ref> In addition, several viruses, including the AIDS virus HIV, have binding sites for NF-κB that controls the expression of viral genes, which in turn contribute to viral replication or viral pathogenicity.  In the case of HIV-1, activation of NF-κB may, at least in part, be involved in activation of the virus from a latent, inactive state.<ref name="pmid11160127">{{cite journal | vauthors = Hiscott J, Kwon H, Génin P | title = Hostile takeovers: viral appropriation of the NF-kappaB pathway | journal = The Journal of Clinical Investigation | volume = 107 | issue = 2 | pages = 143–151 | date = January 2001 | pmid = 11160127 | pmc = 199181 | doi = 10.1172/JCI11918 }}</ref> YopP is a factor secreted by ''[[Yersinia pestis]]'', the causative agent of plague, that prevents the ubiquitination of IκB. This causes this pathogen to effectively inhibit the NF-κB pathway and thus block the immune response of a human infected with Yersinia.<ref name="pmid18201977">{{cite journal | vauthors = Adkins I, Schulz S, Borgmann S, Autenrieth IB, Gröbner S | title = Differential roles of Yersinia outer protein P-mediated inhibition of nuclear factor-kappa B in the induction of cell death in dendritic cells and macrophages | journal = Journal of Medical Microbiology | volume = 57 | issue = Pt 2 | pages = 139–144 | date = February 2008 | pmid = 18201977 | doi = 10.1099/jmm.0.47437-0 | doi-access = free }}</ref>

=== Inhibitors of NF-κB activity ===
Concerning known protein inhibitors of NF-κB activity, one of them is [[IFRD1]], which represses the activity of NF-κB p65 by enhancing the [[Histone deacetylase|HDAC]]-mediated deacetylation of the p65 subunit at lysine 310, by favoring the recruitment of HDAC3 to p65. In fact IFRD1 forms trimolecular complexes with p65 and HDAC3.<ref name="pmid15743821">{{cite journal | vauthors = Micheli L, Leonardi L, Conti F, Buanne P, Canu N, Caruso M, Tirone F | title = PC4 coactivates MyoD by relieving the histone deacetylase 4-mediated inhibition of myocyte enhancer factor 2C | journal = Molecular and Cellular Biology | volume = 25 | issue = 6 | pages = 2242–2259 | date = March 2005 | pmid = 15743821 | pmc = 1061592 | doi = 10.1128/MCB.25.6.2242-2259.2005 }}</ref><ref name="pmid21127072">{{cite journal | vauthors = Micheli L, Leonardi L, Conti F, Maresca G, Colazingari S, Mattei E, Lira SA, Farioli-Vecchioli S, Caruso M, Tirone F | title = PC4/Tis7/IFRD1 stimulates skeletal muscle regeneration and is involved in myoblast differentiation as a regulator of MyoD and NF-kappaB | journal = The Journal of Biological Chemistry | volume = 286 | issue = 7 | pages = 5691–5707 | date = February 2011 | pmid = 21127072 | pmc = 3037682 | doi = 10.1074/jbc.M110.162842 | doi-access = free }}</ref>

The NAD{{+}}-dependent protein deacetylase and longevity factor [[SIRT1]] inhibits NF-κB gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310.<ref name="pmid15152190">{{cite journal | vauthors = Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW | title = Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase | journal = The EMBO Journal | volume = 23 | issue = 12 | pages = 2369–2380 | date = June 2004 | pmid = 15152190 | pmc = 423286 | doi = 10.1038/sj.emboj.7600244 }}</ref>

=== Non-canonical/alternate pathway ===
A select set of cell-differentiating or developmental stimuli, such as [[Lymphotoxin beta receptor|lymphotoxin β-receptor]] (LTβR), [[B-cell activating factor|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 [[MAP3K14|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. RelB:p52 regulates the expression of homeostatic lymphokines, which instructs lymphoid organogenesis and lymphocyte trafficking in the secondary lymphoid organs.<ref name="pmid15470505">{{cite journal | vauthors = Bonizzi G, Bebien M, Otero DC, Johnson-Vroom KE, Cao Y, Vu D, Jegga AG, Aronow BJ, Ghosh G, Rickert RC, Karin M | title = Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers | journal = The EMBO Journal | volume = 23 | issue = 21 | pages = 4202–4210 | date = October 2004 | pmid = 15470505 | pmc = 524385 | doi = 10.1038/sj.emboj.7600391 }}</ref>  In contrast to the canonical signaling that relies on NEMO-IKK2 mediated degradation of IκBα, -β, -ε, non-canonical signaling  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, it was found that syntheses of the constituents of the non-canonical pathway, viz RelB and p52, are controlled by  canonical IKK2-IκB-RelA:p50 signaling.<ref name="Basak_2008">{{cite journal | vauthors = Basak S, Shih VF, Hoffmann A | title = Generation and activation of multiple dimeric transcription factors within the NF-kappaB signaling system | journal = Molecular and Cellular Biology | volume = 28 | issue = 10 | pages = 3139–3150 | date = May 2008 | pmid = 18299388 | pmc = 2423155 | doi = 10.1128/MCB.01469-07 }}</ref> Moreover, generation of the canonical and non-canonical dimers, viz RelA:p50 and RelB:p52, within the cellular milieu are  mechanistically interlinked.<ref name="Basak_2008" /> 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. Most intriguingly, a recent study identified that TNF-induced canonical signalling subverts non-canonical RelB:p52 activity in the inflamed lymphoid tissues limiting lymphocyte ingress.<ref>{{cite journal | vauthors = Mukherjee T, Chatterjee B, Dhar A, Bais SS, Chawla M, Roy P, George A, Bal V, Rath S, Basak S | title = A TNF-p100 pathway subverts noncanonical NF-κB signaling in inflamed secondary lymphoid organs | journal = The EMBO Journal | volume = 36 | issue = 23 | pages = 3501–3516 | date = December 2017 | pmid = 29061763 | pmc = 5709727 | doi = 10.15252/embj.201796919 }}</ref> Mechanistically, TNF inactivated NIK in LTβR‐stimulated cells and induced the synthesis of ''Nfkb2'' mRNA encoding p100; these together potently accumulated unprocessed p100, which attenuated the RelB activity. A role of p100/''Nfkb2'' in dictating lymphocyte ingress in the inflamed lymphoid tissue may have broad physiological implications.

In addition to its traditional role in lymphoid organogenesis, the non-canonical NF-κB pathway also directly reinforces inflammatory immune responses to microbial pathogens by modulating canonical NF-κB signalling. It was shown that p100/''Nfkb2'' mediates stimulus-selective and cell-type-specific crosstalk between the two NF-κB pathways and that ''Nfkb2''-mediated crosstalk protects mice from gut pathogens.<ref>{{cite journal | vauthors = Banoth B, Chatterjee B, Vijayaragavan B, Prasad MV, Roy P, Basak S | title = Stimulus-selective crosstalk via the NF-κB signaling system reinforces innate immune response to alleviate gut infection | journal = eLife | volume = 4 | pages = e05648 | date = April 2015 | pmid = 25905673 | pmc = 4432492 | doi = 10.7554/eLife.05648 | veditors = Chakraborty AK | doi-access = free }}</ref><ref>{{cite journal | vauthors = Chatterjee B, Banoth B, Mukherjee T, Taye N, Vijayaragavan B, Chattopadhyay S, Gomes J, Basak S | title = Late-phase synthesis of IκBα insulates the TLR4-activated canonical NF-κB pathway from noncanonical NF-κB signaling in macrophages | journal = Science Signaling | volume = 9 | issue = 457 | pages = ra120 | date = December 2016 | pmid = 27923915 | pmc = 5260935 | doi = 10.1126/scisignal.aaf1129 }}</ref> On the other hand, a lack of p100-mediated regulations repositions RelB under the control of TNF-induced canonical signalling. In fact, mutational inactivation of p100/''Nfkb2'' in multiple myeloma enabled TNF to induce a long-lasting RelB activity, which imparted resistance in myeloma cells to chemotherapeutic drug.<ref>{{cite journal | vauthors = Roy P, Mukherjee T, Chatterjee B, Vijayaragavan B, Banoth B, Basak S | title = Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFκB pathway | journal = Oncogene | volume = 36 | issue = 10 | pages = 1417–1429 | date = March 2017 | pmid = 27641334 | pmc = 5346295 | doi = 10.1038/onc.2016.309 }}</ref>

=== In immunity ===
NF-κB is a major transcription factor that regulates genes responsible for both the [[innate immune system|innate]] and [[adaptive immune system|adaptive immune response]].<ref>{{cite journal | vauthors = Smith EM, Gregg M, Hashemi F, Schott L, Hughes TK | title = Corticotropin Releasing Factor (CRF) activation of NF-kappaB-directed transcription in leukocytes | journal = Cellular and Molecular Neurobiology | volume = 26 | issue = 4–6 | pages = 1021–1036 | date = 2006-07-01 | pmid = 16633893 | doi = 10.1007/s10571-006-9040-1 | s2cid = 22544468 }}</ref> Upon activation of either the [[T-cell receptor|T-]] or [[B-cell receptor#Antibody forms|B-cell receptor]], NF-κB becomes activated through distinct signaling components. Upon ligation of the T-cell receptor, protein kinase [[Lck]] is recruited and phosphorylates the [[Immunoreceptor tyrosine-based activation motif|ITAMs]] of the [[CD3 (immunology)|CD3]] cytoplasmic tail.  [[ZAP70]] is then recruited to the phosphorylated ITAMs and helps recruit [[Linker of Activated T cells|LAT]] and [[PLCG2|PLC-γ]], which causes activation of [[protein kinase C|PKC]].  Through a cascade of phosphorylation events, the kinase complex is activated and NF-κB is able to enter the nucleus to upregulate genes involved in T-cell development, maturation, and proliferation.<ref name="pmid11231305">{{cite journal | vauthors = Livolsi A, Busuttil V, Imbert V, Abraham RT, Peyron JF | title = Tyrosine phosphorylation-dependent activation of NF-kappa B. Requirement for p56 LCK and ZAP-70 protein tyrosine kinases | journal = European Journal of Biochemistry | volume = 268 | issue = 5 | pages = 1508–1515 | date = March 2001 | pmid = 11231305 | doi = 10.1046/j.1432-1327.2001.02028.x }}</ref>

=== In the nervous system ===
In addition to roles in mediating cell survival, studies by [[Mark Mattson]] and others have shown that NF-κB has diverse functions in the [[nervous system]] including roles in [[synaptic plasticity|plasticity]], learning, and memory.<ref name="pmid16397579">{{cite journal | vauthors = Mattson MP, Meffert MK | title = Roles for NF-kappaB in nerve cell survival, plasticity, and disease | journal = Cell Death and Differentiation | volume = 13 | issue = 5 | pages = 852–860 | date = May 2006 | pmid = 16397579 | doi = 10.1038/sj.cdd.4401837 | doi-access = free }}</ref> In addition to stimuli that activate NF-κB in other tissues, NF-κB in the nervous system can be activated by Growth Factors ([[BDNF]], [[Nerve growth factor|NGF]]) and synaptic transmission such as [[glutamic acid|glutamate]].<ref name="Meffert_2003" />  These activators of NF-κB in the nervous system all converge upon the IKK complex and the canonical pathway.

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,<ref name="Freudenthal_1998" /><ref name="Merlo_2002" /> fruit flies,<ref name="Heckscher_2007">{{cite journal | vauthors = Heckscher ES, Fetter RD, Marek KW, Albin SD, Davis GW | title = NF-kappaB, IkappaB, and IRAK control glutamate receptor density at the Drosophila NMJ | journal = Neuron | volume = 55 | issue = 6 | pages = 859–873 | date = September 2007 | pmid = 17880891 | pmc = 2701504 | doi = 10.1016/j.neuron.2007.08.005 }}</ref> and mice.<ref name="Meffert_2003" /><ref name="Levenson_2004" />  NF-κB may regulate learning and memory in part by modulating synaptic plasticity,<ref name="Albensi_2000" /><ref name="Kaltschmidt_2006" /> synapse function,<ref name="Heckscher_2007" /><ref name="pmid20720118">{{cite journal | vauthors = Wang J, Fu XQ, Lei WL, Wang T, Sheng AL, Luo ZG | title = Nuclear factor kappaB controls acetylcholine receptor clustering at the neuromuscular junction | journal = The Journal of Neuroscience | volume = 30 | issue = 33 | pages = 11104–11113 | date = August 2010 | pmid = 20720118 | pmc = 6633475 | doi = 10.1523/JNEUROSCI.2118-10.2010 }}</ref><ref name="Boersma_2011">{{cite journal | vauthors = Boersma MC, Dresselhaus EC, De Biase LM, Mihalas AB, Bergles DE, Meffert MK | title = A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis | journal = The Journal of Neuroscience | volume = 31 | issue = 14 | pages = 5414–5425 | date = April 2011 | pmid = 21471377 | pmc = 3113725 | doi = 10.1523/JNEUROSCI.2456-10.2011 }}</ref> as well as by regulating the growth of [[dendrites]]<ref name="Gutierrez_2005">{{cite journal | vauthors = Gutierrez H, Hale VA, Dolcet X, Davies A | title = NF-kappaB signalling regulates the growth of neural processes in the developing PNS and CNS | journal = Development | volume = 132 | issue = 7 | pages = 1713–1726 | date = April 2005 | pmid = 15743881 | doi = 10.1242/dev.01702 | doi-access = free }}</ref> and [[dendritic spine]]s.<ref name="Boersma_2011" />

Genes that have NF-κB binding sites are shown to have increased expression following learning,<ref name="Levenson_2004" /> 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)<ref name="pmid11885780">{{cite journal | vauthors = Zaheer A, Yorek MA, Lim R | title = Effects of glia maturation factor overexpression in primary astrocytes on MAP kinase activation, transcription factor activation, and neurotrophin secretion | journal = Neurochemical Research | volume = 26 | issue = 12 | pages = 1293–1299 | date = December 2001 | pmid = 11885780 | doi = 10.1023/A:1014241300179 | s2cid = 26418384 }}</ref> cytokines ([[TNF-alpha]], [[TNFR]])<ref name="pmid15197744">{{cite journal | vauthors = Qiu J, Hu X, Nesic O, Grafe MR, Rassin DK, Wood TG, Perez-Polo JR | title = Effects of NF-kappaB oligonucleotide "decoys" on gene expression in P7 rat hippocampus after hypoxia/ischemia | journal = Journal of Neuroscience Research | volume = 77 | issue = 1 | pages = 108–118 | date = July 2004 | pmid = 15197744 | doi = 10.1002/jnr.20156 | s2cid = 25522763 }}</ref> and kinases ([[Protein kinase A|PKAc]]).<ref name="Kaltschmidt_2006">{{cite journal | vauthors = Kaltschmidt B, Ndiaye D, Korte M, Pothion S, Arbibe L, Prüllage M, Pfeiffer J, Lindecke A, Staiger V, Israël A, Kaltschmidt C, Mémet S | title = NF-kappaB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling | journal = Molecular and Cellular Biology | volume = 26 | issue = 8 | pages = 2936–2946 | date = April 2006 | pmid = 16581769 | pmc = 1446931 | doi = 10.1128/MCB.26.8.2936-2946.2006 }}</ref>

Despite the functional evidence for a role for Rel-family transcription factors in the nervous system, it is still not clear that the neurological effects of NF-κB reflect transcriptional activation in neurons. Most manipulations and assays are performed in the mixed-cell environments found in vivo, in "neuronal" cell cultures that contain significant numbers of glia, or in tumor-derived "neuronal" cell lines.  When transfections or other manipulations have been targeted specifically at neurons, the endpoints measured are typically electrophysiology or other parameters far removed from gene transcription. Careful tests of NF-κB-dependent transcription in highly purified cultures of neurons generally show little to no NF-κB activity.<ref name="pmid23872390">{{cite journal | vauthors = Listwak SJ, Rathore P, Herkenham M | title = Minimal NF-κB activity in neurons | journal = Neuroscience | volume = 250 | pages = 282–299 | date = October 2013 | pmid = 23872390 | pmc = 3785079 | doi = 10.1016/j.neuroscience.2013.07.013 }}</ref><ref name="pmid11555675">{{cite journal | vauthors = Jarosinski KW, Whitney LW, Massa PT | title = Specific deficiency in nuclear factor-kappaB activation in neurons of the central nervous system | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 81 | issue = 9 | pages = 1275–1288 | date = September 2001 | pmid = 11555675 | doi = 10.1038/labinvest.3780341 | doi-access = free }}</ref>

Some of the reports of NF-κB in neurons appear to have been an artifact of antibody nonspecificity.<ref name="pmid21999414">{{cite journal | vauthors = Herkenham M, Rathore P, Brown P, Listwak SJ | title = Cautionary notes on the use of NF-κB p65 and p50 antibodies for CNS studies | journal = Journal of Neuroinflammation | volume = 8 | pages = 141 | date = October 2011 | pmid = 21999414 | pmc = 3210105 | doi = 10.1186/1742-2094-8-141 | doi-access = free }}</ref> Of course, artifacts of cell culture—e.g., removal of neurons from the influence of glia—could create spurious results as well. But this has been addressed in at least two co-culture approaches. Moerman et al.<ref name="pmid10216229">{{cite journal | vauthors = Moerman AM, Mao X, Lucas MM, Barger SW | title = Characterization of a neuronal kappaB-binding factor distinct from NF-kappaB | journal = Brain Research. Molecular Brain Research | volume = 67 | issue = 2 | pages = 303–315 | date = April 1999 | pmid = 10216229 | doi = 10.1016/s0169-328x(99)00091-1 }}</ref> used a coculture format whereby neurons and glia could be separated after treatment for [[electrophoretic mobility shift assay|EMSA]] analysis, and they found that the NF-κB induced by glutamatergic stimuli was restricted to glia (and, intriguingly, only glia that had been in the presence of neurons for 48&nbsp;hours). The same investigators explored the issue in another approach, utilizing neurons from an NF-κB reporter transgenic mouse cultured with wild-type glia; glutamatergic stimuli again failed to activate in neurons.<ref name="pmid19450264">{{cite journal | vauthors = Mao XR, Moerman-Herzog AM, Chen Y, Barger SW | title = Unique aspects of transcriptional regulation in neurons--nuances in NFkappaB and Sp1-related factors | journal = Journal of Neuroinflammation | volume = 6 | pages = 16 | date = May 2009 | pmid = 19450264 | pmc = 2693111 | doi = 10.1186/1742-2094-6-16 | doi-access = free }}</ref> Some of the DNA-binding activity noted under certain conditions (particularly that reported as constitutive) appears to result from Sp3 and Sp4 binding to a subset of κB enhancer sequences in neurons.<ref name="pmid17316402">{{cite journal | vauthors = Mao X, Yang SH, Simpkins JW, Barger SW | title = Glutamate receptor activation evokes calpain-mediated degradation of Sp3 and Sp4, the prominent Sp-family transcription factors in neurons | journal = Journal of Neurochemistry | volume = 100 | issue = 5 | pages = 1300–1314 | date = March 2007 | pmid = 17316402 | pmc = 1949346 | doi = 10.1111/j.1471-4159.2006.04297.x }}</ref> This activity is actually inhibited by glutamate and other conditions that elevate intraneuronal calcium. In the final analysis, the role of NF-κB in neurons remains opaque due to the difficulty of measuring transcription in cells that are simultaneously identified for type. Certainly, learning and memory could be influenced by transcriptional changes in astrocytes and other glial elements. And it should be considered that there could be mechanistic effects of NF-κB aside from direct transactivation of genes.

== Clinical significance ==
[[File:Signal transduction pathways.svg|thumb|Overview of signal transduction pathways involved in [[apoptosis]].]]

=== Cancers ===
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]]. In cancer, proteins that control NF-κB signaling are mutated or aberrantly expressed, leading to defective coordination between the malignant cell and the rest of the organism. This is evident both in metastasis, as well as in the inefficient eradication of the tumor by the immune system.<ref>{{cite journal | vauthors = Vlahopoulos SA | title = Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode | journal = Cancer Biology & Medicine | volume = 14 | issue = 3 | pages = 254–270 | date = August 2017 | pmid = 28884042 | pmc = 5570602 | doi = 10.20892/j.issn.2095-3941.2017.0029 }}</ref>

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.<ref name="Vlahopoulos SA 2015">{{cite journal | vauthors = Vlahopoulos SA, Cen O, Hengen N, Agan J, Moschovi M, Critselis E, Adamaki M, Bacopoulou F, Copland JA, Boldogh I, Karin M, Chrousos GP | title = Dynamic aberrant NF-κB spurs tumorigenesis: a new model encompassing the microenvironment | journal = Cytokine & Growth Factor Reviews | volume = 26 | issue = 4 | pages = 389–403 | date = August 2015 | pmid = 26119834 | pmc = 4526340 | doi = 10.1016/j.cytogfr.2015.06.001 }}</ref>

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.<ref name="pmid14504472">{{cite journal | vauthors = Sheikh MS, Huang Y | title = Death receptor activation complexes: it takes two to activate TNF receptor 1 | journal = Cell Cycle | volume = 2 | issue = 6 | pages = 550–552 | year = 2003 | pmid = 14504472 | doi = 10.4161/cc.2.6.566 | doi-access = free }}</ref>

In tumor cells, NF-κB activity is enhanced, as for example, in 41% of [[nasopharyngeal carcinoma]],<ref>{{cite journal | vauthors = Li YY, Chung GT, Lui VW, To KF, Ma BB, Chow C, Woo JK, Yip KY, Seo J, Hui EP, Mak MK, Rusan M, Chau NG, Or YY, Law MH, Law PP, Liu ZW, Ngan HL, Hau PM, Verhoeft KR, Poon PH, Yoo SK, Shin JY, Lee SD, Lun SW, Jia L, Chan AW, Chan JY, Lai PB, Fung CY, Hung ST, Wang L, Chang AM, Chiosea SI, Hedberg ML, Tsao SW, van Hasselt AC, Chan AT, Grandis JR, Hammerman PS, Lo KW | title = Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations | journal = Nature Communications | volume = 8 | pages = 14121 | date = January 2017 | pmid = 28098136 | pmc = 5253631 | doi = 10.1038/ncomms14121 | bibcode = 2017NatCo...814121L }}</ref> [[colorectal cancer]], [[prostate cancer]] and [[pancreatic cancer|pancreatic tumors]]. This is either due to mutations in genes encoding the NF-κB transcription factors themselves or in genes that control NF-κB activity (such as IκB genes); in addition, some tumor cells secrete factors that cause NF-κB to become active.<ref>{{cite journal | vauthors = Sun SC | title = Non-canonical NF-κB signaling pathway | journal = Cell Research | volume = 21 | issue = 1 | pages = 71–85 | date = January 2011 | pmid = 21173796 | pmc = 3193406 | doi = 10.1038/cr.2010.177 }}</ref><ref>{{cite journal | vauthors = Nouri M, Massah S, Caradec J, Lubik AA, Li N, Truong S, Lee AR, Fazli L, Ramnarine VR, Lovnicki JM, Moore J, Wang M, Foo J, Gleave ME, Hollier BG, Nelson C, Collins C, Dong X, Buttyan R | title = Transient Sox9 Expression Facilitates Resistance to Androgen-Targeted Therapy in Prostate Cancer | journal = Clinical Cancer Research | volume = 26 | issue = 7 | pages = 1678–1689 | date = April 2020 | pmid = 31919137 | doi = 10.1158/1078-0432.CCR-19-0098 | doi-access = free }}</ref>  Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents.<ref>{{cite journal | vauthors = Taniguchi K, Karin M | title = NF-κB, inflammation, immunity and cancer: coming of age | journal = Nature Reviews. Immunology | volume = 18 | issue = 5 | pages = 309–324 | date = May 2018 | pmid = 29379212 | doi = 10.1038/nri.2017.142 | s2cid = 3701398 }}</ref><ref>{{cite journal | vauthors = Sun L, Mathews LA, Cabarcas SM, Zhang X, Yang A, Zhang Y, Young MR, Klarmann KD, Keller JR, Farrar WL | title = Epigenetic regulation of SOX9 by the NF-κB signaling pathway in pancreatic cancer stem cells | journal = Stem Cells | volume = 31 | issue = 8 | pages = 1454–1466 | date = August 2013 | pmid = 23592398 | pmc = 3775871 | doi = 10.1002/stem.1394 }}</ref>  Thus, NF-κB is the subject of much active research among pharmaceutical companies as a target for anti-cancer therapy.<ref name="pmid17355113">{{cite journal | vauthors = Escárcega RO, Fuentes-Alexandro S, García-Carrasco M, Gatica A, Zamora A | title = The transcription factor nuclear factor-kappa B and cancer | journal = Clinical Oncology | volume = 19 | issue = 2 | pages = 154–161 | date = March 2007 | pmid = 17355113 | doi = 10.1016/j.clon.2006.11.013 }}</ref>

However, even though convincing experimental data have identified NF-κB as a critical promoter of tumorigenesis, which creates a solid rationale for the development of antitumor therapy that is based upon suppression of NF-κB activity, caution should be exercised when considering anti-NF-κB activity as a broad therapeutic strategy in cancer treatment as data has also shown that NF-κB activity enhances tumor cell sensitivity to apoptosis and senescence. In addition, it has been shown that canonical NF-κB is a Fas transcription activator and the alternative NF-κB is a Fas transcription repressor.<ref name="pmid22669972">{{cite journal | vauthors = Liu F, Bardhan K, Yang D, Thangaraju M, Ganapathy V, Waller JL, Liles GB, Lee JR, Liu K | title = NF-κB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression | journal = The Journal of Biological Chemistry | volume = 287 | issue = 30 | pages = 25530–25540 | date = July 2012 | pmid = 22669972 | pmc = 3408167 | doi = 10.1074/jbc.M112.356279 | doi-access = free }}</ref> Therefore, NF-κB promotes Fas-mediated apoptosis in cancer cells, and thus inhibition of NF-κB may suppress Fas-mediated apoptosis to impair host immune cell-mediated tumor suppression.

=== Inflammation ===
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<ref>{{cite journal | vauthors = Monaco C, Andreakos E, Kiriakidis S, Mauri C, Bicknell C, Foxwell B, Cheshire N, Paleolog E, Feldmann M | title = Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 15 | pages = 5634–5639 | date = April 2004 | pmid = 15064395 | pmc = 397455 | doi = 10.1073/pnas.0401060101 | doi-access = free | bibcode = 2004PNAS..101.5634M }}</ref> 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]].<ref name="pmid20447527">{{cite journal | vauthors = Venuraju SM, Yerramasu A, Corder R, Lahiri A | title = Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity | journal = Journal of the American College of Cardiology | volume = 55 | issue = 19 | pages = 2049–2061 | date = May 2010 | pmid = 20447527 | doi = 10.1016/j.jacc.2010.03.013 | doi-access = free }}</ref><ref name="pmid20448212">{{cite journal | vauthors = Lieb W, Gona P, Larson MG, Massaro JM, Lipinska I, Keaney JF, Rong J, Corey D, Hoffmann U, Fox CS, Vasan RS, Benjamin EJ, O'Donnell CJ, Kathiresan S | title = Biomarkers of the osteoprotegerin pathway: clinical correlates, subclinical disease, incident cardiovascular disease, and mortality | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 30 | issue = 9 | pages = 1849–1854 | date = September 2010 | pmid = 20448212 | pmc = 3039214 | doi = 10.1161/ATVBAHA.109.199661 }}</ref> Elevated NF-κB has also been associated with [[schizophrenia]].<ref name="pmid19058794">{{cite journal | vauthors = Song XQ, Lv LX, Li WQ, Hao YH, Zhao JP | title = The interaction of nuclear factor-kappa B and cytokines is associated with schizophrenia | journal = Biological Psychiatry | volume = 65 | issue = 6 | pages = 481–488 | date = March 2009 | pmid = 19058794 | doi = 10.1016/j.biopsych.2008.10.018 | s2cid = 10836374 }}</ref> Recently, NF-κB activation has been suggested as a possible molecular mechanism for the catabolic effects of cigarette smoke in skeletal muscle and [[sarcopenia]].<ref name="pmid23835952">{{cite book | vauthors = Kaisari S, Rom O, Aizenbud D, Reznick AZ | title = Neurobiology of Respiration | chapter = Involvement of NF-κB and Muscle Specific E3 Ubiquitin Ligase MuRF1 in Cigarette Smoke-Induced Catabolism in C2 Myotubes | series = Advances in Experimental Medicine and Biology | volume = 788 | pages = 7–17 | year = 2013 | pmid = 23835952 | doi = 10.1007/978-94-007-6627-3_2 | isbn = 978-94-007-6626-6 }}</ref> 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.<ref name="ReferenceA">{{cite journal | vauthors = Hajishengallis G, Chavakis T | title = Endogenous modulators of inflammatory cell recruitment | journal = Trends in Immunology | volume = 34 | issue = 1 | pages = 1–6 | date = January 2013 | pmid = 22951309 | pmc = 3703146 | doi = 10.1016/j.it.2012.08.003 }}</ref> A cell's 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.<ref name="ReferenceA" /><ref name="ReferenceB">{{cite journal | vauthors = Vidal PM, Lemmens E, Dooley D, Hendrix S | title = The role of "anti-inflammatory" cytokines in axon regeneration | journal = Cytokine & Growth Factor Reviews | volume = 24 | issue = 1 | pages = 1–12 | date = February 2013 | pmid = 22985997 | doi = 10.1016/j.cytogfr.2012.08.008 }}</ref> Particularly important are feedback responses that develop between tissue resident cells, and circulating cells of the immune system.<ref name="ReferenceB" />

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.<ref name="ReferenceB" />  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.<ref name="Vlahopoulos SA 2015" /> 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.<ref>{{cite journal | vauthors = Grivennikov SI, Karin M | title = Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer | journal = Cytokine & Growth Factor Reviews | volume = 21 | issue = 1 | pages = 11–19 | date = February 2010 | pmid = 20018552 | pmc = 2834864 | doi = 10.1016/j.cytogfr.2009.11.005 }}</ref> 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.<ref>{{cite journal | vauthors = Bonavita E, Galdiero MR, Jaillon S, Mantovani A | title = Phagocytes as Corrupted Policemen in Cancer-Related Inflammation | journal = Advances in Cancer Research | volume = 128 | pages = 141–171 | year = 2015 | pmid = 26216632 | doi = 10.1016/bs.acr.2015.04.013 | isbn = 978-0-12-802316-7 }}</ref><ref>{{cite journal | vauthors = Sionov RV, Fridlender ZG, Granot Z | title = The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment | journal = Cancer Microenvironment | volume = 8 | issue = 3 | pages = 125–158 | date = December 2015 | pmid = 24895166 | pmc = 4714999 | doi = 10.1007/s12307-014-0147-5 }}</ref><ref>{{cite journal | vauthors = Kong X, Li L, Li Z, Xie K | title = Targeted destruction of the orchestration of the pancreatic stroma and tumor cells in pancreatic cancer cases: molecular basis for therapeutic implications | journal = Cytokine & Growth Factor Reviews | volume = 23 | issue = 6 | pages = 343–356 | date = December 2012 | pmid = 22749856 | pmc = 3505269 | doi = 10.1016/j.cytogfr.2012.06.006 }}</ref> 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.<ref name="ReferenceA" /><ref>{{cite journal | vauthors = Mecollari V, Nieuwenhuis B, Verhaagen J | title = A perspective on the role of class III semaphorin signaling in central nervous system trauma | journal = Frontiers in Cellular Neuroscience | volume = 8 | pages = 328 | year = 2014 | pmid = 25386118 | pmc = 4209881 | doi = 10.3389/fncel.2014.00328 | doi-access = free }}</ref>

=== NEMO ===
[[NEMO deficiency syndrome]] is a rare genetic condition relating to a fault in [[IKBKG]] that in turn activates NF-κB.  It mostly affects males and has a highly variable set of symptoms and prognoses.<ref name="NEMO deficiency syndrome">[https://www.gosh.nhs.uk/conditions-and-treatments/conditions-we-treat/nemo-deficiency-syndrome/ NEMO deficiency syndrome information] NEMO deficiency syndrome information], [[Great Ormond Street Hospital for Children]]</ref>

=== Aging and obesity ===
NF-κB is increasingly expressed with [[obesity]] and aging,<ref name="pmid23770291">{{cite journal | vauthors = Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A | title = Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders | journal = Cellular Signalling | volume = 25 | issue = 10 | pages = 1939–1948 | date = October 2013 | pmid = 23770291 | doi = 10.1016/j.cellsig.2013.06.007 }}</ref> resulting in reduced levels of the anti-inflammatory, pro-[[autophagy]], anti-[[insulin resistance]] protein [[sirtuin 1]]. NF-κB increases the levels of the [[microRNA]] [[MIR34A|miR-34a]], which inhibits [[nicotinamide adenine dinucleotide]] (NAD) synthesis by binding to its [[Promoter (genetics)|promoter]] region,<ref name="pmid32485811">{{cite journal | vauthors = de Gregorio E, Colell A, Morales A, Marí M | title = Relevance of SIRT1-NF-κB Axis as Therapeutic Target to Ameliorate Inflammation in Liver Disease | journal = International Journal of Molecular Sciences | volume = 21 | issue = 11 | pages = 3858 | date = May 2020 | pmid = 32485811 | pmc = 7312021 | doi = 10.3390/ijms21113858 | doi-access = free }}</ref> resulting in lower levels of sirtuin 1.

NF-κB and [[IL1A|interleukin 1 alpha]] mutually induce each other in [[Cellular senescence|senescent cells]] in a [[positive feedback]] loop causing the production of [[senescence-associated secretory phenotype]] (SASP) factors.<ref name="pmid28371119">{{cite journal | vauthors = Wang R, Yu Z, Sunchu B, Shoaf J, Dang I, Zhao S, Caples K, Bradley L, Beaver LM, Ho E, Löhr CV, Perez VI | title = Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism | journal = Aging Cell | volume = 16 | issue = 3 | pages = 564–574 | date = June 2017 | pmid = 28371119 | pmc = 5418203 | doi = 10.1111/acel.12587 }}</ref> NF-κB and the NAD-degrading enzyme [[CD38]] also mutually induce each other.<ref name="pmid32774895">{{cite journal | vauthors = Yarbro JR, Emmons RS, Pence BD | title = Macrophage Immunometabolism and Inflammaging: Roles of Mitochondrial Dysfunction, Cellular Senescence, CD38, and NAD | journal = Immunometabolism | volume = 2 | issue = 3 | pages = e200026 | date = June 2020 | pmid = 32774895 | pmc = 7409778 | doi = 10.20900/immunometab20200026 }}</ref>

NF-κB is a central component of the cellular response to damage.<ref name = Tilstra2012>{{cite journal |vauthors=Tilstra JS, Robinson AR, Wang J, Gregg SQ, Clauson CL, Reay DP, Nasto LA, St Croix CM, Usas A, Vo N, Huard J, Clemens PR, Stolz DB, Guttridge DC, Watkins SC, Garinis GA, Wang Y, Niedernhofer LJ, Robbins PD |title=NF-κB inhibition delays DNA damage-induced senescence and aging in mice |journal=J Clin Invest |volume=122 |issue=7 |pages=2601–12 |date=July 2012 |pmid=22706308 |pmc=3386805 |doi=10.1172/JCI45785 }}</ref>  NF-κB is activated in a variety of cell types that undergo normal or accelerated [[ageing|aging]].<ref name = Tilstra2012/> Genetic or pharmacologic inhibition of NF-κB activation can delay the onset of numerous aging related symptoms and pathologies.<ref name = Tilstra2012/> This effect may be explained, in part, by the finding that reduction of NF-κB reduces the production of mitochondria-derived [[reactive oxygen species]] that can [[DNA damage (naturally occurring)|damage DNA]].<ref name = Tilstra2012/>

=== Addiction ===
NF-κB is one of several induced transcriptional targets of [[ΔFosB]] which facilitates the development and maintenance of an [[addiction]] to a stimulus.<ref name="Nestler">{{cite journal | vauthors = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 11 | pages = 623–637 | date = October 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 }}</ref><ref name="What the ΔFosB?">{{cite journal | vauthors = Ruffle JK | title = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | journal = The American Journal of Drug and Alcohol Abuse | volume = 40 | issue = 6 | pages = 428–437 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | quote = <!-- NFkB activation Another target of ΔFosB is the induction of nuclear factor-kB (NFkB) (100,101). NFkB is a transcription factor implicated in the expression of various parts of the inflammatory response, including cytokines and cell adhesion molecules. Chronic cocaine administration was shown to stimulate NFkB induction in the NAc and caudate-putamen (100,102). Similarly, morphine-dependent NFkB activation has been reported (although this was not investigated with regards to an association with ΔFosB) (103). Correlating induction with behavioral change, NFkB expression in the NAc is thought responsible for mediation of the positive reinforcement of the drug, whilst in the caudate-putamen being associated with changes of movement (100) (Table 1). NFkB has also been linked to the observed dendritic branching in chronic drug exposure&nbsp;...<br />Table 1. Correlating cellular and molecular effects of ΔFosB targets with behavioral changes following chronic cocaine exposure. --> | s2cid = 19157711 }}</ref><ref name="Cellular basis">{{cite journal | vauthors = Nestler EJ | title = Cellular basis of memory for addiction | journal = Dialogues in Clinical Neuroscience | volume = 15 | issue = 4 | pages = 431–443 | date = December 2013 | pmid = 24459410 | pmc = 3898681 | doi = 10.31887/DCNS.2013.15.4/enestler }}</ref> In the [[caudate putamen]], NF-κB induction is associated with increases in locomotion, whereas in the [[nucleus accumbens]], NF-κB induction enhances the [[positive reinforcement|positive reinforcing]] effect of a drug through [[reward sensitization]].<ref name="What the ΔFosB?" />
{| class="wikitable" style="margin:1em auto; text-align:center"
|+Neural and behavioral effects of validated ΔFosB transcriptional targets<ref name="What the ΔFosB?" /><ref name="pmid18640924">{{cite journal | vauthors = Nestler EJ | title = Review. Transcriptional mechanisms of addiction: role of DeltaFosB | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 363 | issue = 1507 | pages = 3245–3255 | date = October 2008 | pmid = 18640924 | pmc = 2607320 | doi = 10.1098/rstb.2008.0067 | quote = <!-- Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below.&nbsp;... <br />Examples of validated targets for ΔFosB in nucleus accumbens&nbsp;... GluR2&nbsp;... dynorphin&nbsp;... Cdk5&nbsp;... NFκB&nbsp;... c-Fos --> }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320/table/tbl3/ Table 3]</ref>
! scope="col" | Target<br />gene
! scope="col" | Target<br />[[gene expression|expression]]
! scope="col" | Neural effects
! scope="col" | Behavioral effects
|-
| scope="row" style="height: 40px"| [[c-Fos]]     || ↓ || Molecular switch enabling the chronic<br /> induction of ΔFosB{{#tag:ref|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.<ref name="Cellular basis" />|group="note"}} || –
|-
| scope="row" style="height: 40px"| [[dynorphin]] || ↓<br />{{#tag:ref|ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;<ref name="What the ΔFosB?" /><ref name="pmid18640924" /> this table entry reflects only a decrease. |group="note"}} || style="text-align:left" | {{bull}}Downregulation of [[κ-opioid receptor|κ-opioid]] feedback loop || style="text-align:left" | {{bull}} Decreased drug aversion
|-
| scope="row" style="height: 40px"| NF-κB      || ↑ || style="text-align:left" | {{bull}}Expansion of [[Nucleus accumbens|NAcc]] dendritic processes<br />{{bull}}NF-κB inflammatory response in the {{abbr|NAcc|nucleus accumbens}}<br />{{bull}}NF-κB inflammatory response in the {{abbr|CP|caudate putamen}}|| style="text-align:left" | {{bull}}Increased drug reward<br />{{bull}}Increased drug reward<br />{{bull}}[[Stereotypy|Locomotor sensitization]]
|-
| scope="row" style="height: 40px"| [[GluR2]]     || ↑ || style="text-align:left" | {{bull}}Decreased [[sensitization|sensitivity]] to [[glutamate]] || style="text-align:left" | {{bull}}Increased drug reward
|-
| scope="row" style="height: 40px"| [[Cdk5]]      || ↑ || style="text-align:left" | {{bull}}[[GluR1]] synaptic protein phosphorylation <br />{{bull}}Expansion of {{abbr|NAcc|nucleus accumbens}} dendritic processes || Decreased drug reward<br /><small>(net effect)</small>
|}

== Non-drug inhibitors ==
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)<ref name="US6410516">{{cite patent | country = US | number = 6410516 | gdate = 25 June 2002 | inventor = Baltimore D, Sen R, Sharp PA, Singh H, Staudt L, Lebowitz JH, Baldwin Jr AS, Clerc RG, Corcoran LM, Baeuerle PA, Lenardo MJ, Fan CM, Maniatis TP | assign1 = Harvard College, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology | title = Nuclear factors associated with transcriptional regulation}}</ref> 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,<ref name="pmid18301380">{{cite journal | vauthors = Karin M | title = The IkappaB kinase – a bridge between inflammation and cancer | journal = Cell Research | volume = 18 | issue = 3 | pages = 334–342 | date = March 2008 | pmid = 18301380 | doi = 10.1038/cr.2008.30 | doi-access = free }}</ref> Ben-Neriah<ref name="pmid16530406">{{cite journal | vauthors = Pikarsky E, Ben-Neriah Y | title = NF-kappaB inhibition: a double-edged sword in cancer? | journal = European Journal of Cancer | volume = 42 | issue = 6 | pages = 779–784 | date = April 2006 | pmid = 16530406 | doi = 10.1016/j.ejca.2006.01.011 }}</ref> 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.<ref name="pmid18593019">{{cite book | vauthors = Mantovani A, Marchesi F, Portal C, Allavena P, Sica A | title = Targeted Therapies in Cancer | chapter = Linking Inflammation Reactions to Cancer: Novel Targets for Therapeutic Strategies | series = Advances in Experimental Medicine and Biology | volume = 610 | pages = 112–127 | year = 2008 | pmid = 18593019 | doi = 10.1007/978-0-387-73898-7_9 | isbn = 978-0-387-73897-0 }}</ref>

Extracts from a number of herbs and dietary plants are efficient inhibitors of NF-κB activation in vitro.<ref name="pmid20424131">{{cite journal | vauthors = Paur I, Balstad TR, Kolberg M, Pedersen MK, Austenaa LM, Jacobs DR, Blomhoff R | title = Extract of oregano, coffee, thyme, clove, and walnuts inhibits NF-kappaB in monocytes and in transgenic reporter mice | journal = Cancer Prevention Research | volume = 3 | issue = 5 | pages = 653–663 | date = May 2010 | pmid = 20424131 | doi = 10.1158/1940-6207.CAPR-09-0089 | doi-access = free }}</ref> [[Nobiletin]], a flavonoid isolated from citrus peels, has been shown to inhibit the NF-κB signaling pathway in mice.<ref name="pmid31214026">{{cite journal | vauthors = Lin Z, Wu D, Huang L, Jiang C, Pan T, Kang X, Pan J | title = Nobiletin Inhibits IL-1β-Induced Inflammation in Chondrocytes ''via'' Suppression of NF-κB Signaling and Attenuates Osteoarthritis in Mice | journal = Frontiers in Pharmacology | volume = 10 | pages = 570 | year = 2019 | pmid = 31214026 | pmc = 6554687 | doi = 10.3389/fphar.2019.00570 | doi-access = free }}</ref> The circumsporozoite protein of ''[[Plasmodium falciparum]]'' has been shown to be an inhibitor of NF-κB.<ref name="Ding_2012">{{cite journal | vauthors = Ding Y, Huang X, Liu T, Fu Y, Tan Z, Zheng H, Zhou T, Dai J, Xu W | title = The Plasmodium circumsporozoite protein, a novel NF-κB inhibitor, suppresses the growth of SW480 | journal = Pathology & Oncology Research | volume = 18 | issue = 4 | pages = 895–902 | date = October 2012 | pmid = 22678765 | doi = 10.1007/s12253-012-9519-7 | s2cid = 15823271 }}</ref> Likewise, various [[withanolide]]s of [[Withania somnifera]] (Ashwagandha) have been found to have inhibiting effects on NF-κB through inhibition of proteasome mediated [[ubiquitin]] degradation of IκBα.<ref>{{cite book | vauthors = White PT, Subramanian C, Motiwala HF, Cohen MS | title = Anti-inflammatory Nutraceuticals and Chronic Diseases | chapter = Natural Withanolides in the Treatment of Chronic Diseases | series = Advances in Experimental Medicine and Biology | volume = 928 | pages = 329–373 | date = 2016 | pmid = 27671823 | pmc = 7121644 | doi = 10.1007/978-3-319-41334-1_14 | publisher = Springer International Publishing | isbn = 978-3-319-41332-7 | veditors = Gupta SC, Prasad S, Aggarwal BB }}</ref><ref>{{Cite journal | vauthors = Wei Z, Li T, Kuang H, Su H, Wang Q  |date=2020-02-11 |title=Pharmacological Effects of Withanolides |url=https://biomedres.us/fulltexts/BJSTR.MS.ID.004218.php |journal=Biomedical Journal of Scientific & Technical Research |language=English |volume=25 |issue=3 |pages=19243–19248 |doi=10.26717/BJSTR.2020.25.004218 |issn=2574-1241|doi-access=free }}</ref>

== As a drug target ==
Aberrant activation of NF-κB is frequently observed in many cancers.  Moreover, suppression of NF-κB limits the proliferation of cancer cells.  In addition,  NF-κB is a key player in the inflammatory response.  Hence methods of inhibiting NF-κB signaling has potential therapeutic application in cancer and inflammatory diseases.<ref name="pmid12040437">{{cite journal | vauthors = Garg A, Aggarwal BB | title = Nuclear transcription factor-kappaB as a target for cancer drug development | journal = Leukemia | volume = 16 | issue = 6 | pages = 1053–1068 | date = June 2002 | pmid = 12040437 | doi = 10.1038/sj.leu.2402482 | doi-access = free }}</ref><ref name="pmid18156302">{{cite journal | vauthors = Sethi G, Sung B, Aggarwal BB | title = Nuclear factor-kappaB activation: from bench to bedside | journal = Experimental Biology and Medicine | volume = 233 | issue = 1 | pages = 21–31 | date = January 2008 | pmid = 18156302 | doi = 10.3181/0707-MR-196 | s2cid = 86359181 }}</ref>

Both the canonical and non-canonical NF-κB pathways require proteasomal degradation of regulatory pathway components for NF-κB signalling to occur. The [[proteosome]] inhibitor [[Bortezomib]] broadly blocks this activity and is approved for treatment of NF-κB driven [[Mantle Cell Lymphoma]] and [[Multiple Myeloma]].<ref>{{cite journal | vauthors = Curran MP, McKeage K | title = Bortezomib: a review of its use in patients with multiple myeloma | journal = Drugs | volume = 69 | issue = 7 | pages = 859–888 | date = 2009 | pmid = 19441872 | doi = 10.2165/00003495-200969070-00006 }}</ref><ref>{{cite journal | vauthors = Raedler L | title = Velcade (Bortezomib) Receives 2 New FDA Indications: For Retreatment of Patients with Multiple Myeloma and for First-Line Treatment of Patients with Mantle-Cell Lymphoma | journal = American Health & Drug Benefits | volume = 8 | issue = Spec Feature | pages = 135–140 | date = March 2015 | pmid = 26629279 | pmc = 4665054 }}</ref>

The discovery that activation of NF-κB nuclear translocation can be separated from the elevation of oxidant stress<ref name="pmid10477716">{{cite journal | vauthors = Vlahopoulos S, Boldogh I, Casola A, Brasier AR | title = Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation | journal = Blood | volume = 94 | issue = 6 | pages = 1878–1889 | date = September 1999 | pmid = 10477716 | doi = 10.1182/blood.V94.6.1878.418k03_1878_1889 | s2cid = 25974629 }}</ref> gives a promising avenue of development for strategies targeting NF-κB inhibition.

The drug [[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,<ref name="pmid18301800">{{cite journal | vauthors = Hamdy NA | title = Denosumab: RANKL inhibition in the management of bone loss | journal = Drugs of Today | volume = 44 | issue = 1 | pages = 7–21 | date = January 2008 | pmid = 18301800 | doi = 10.1358/dot.2008.44.1.1178467 }}</ref>
RANKL normally works by enabling the differentiation of osteoclasts from monocytes.

[[Disulfiram]], [[olmesartan]] and [[dithiocarbamate]]s can inhibit the NF-κB signaling cascade.<ref name="pmid17979756">{{cite journal | vauthors = Cvek B, Dvorak Z | title = Targeting of nuclear factor-kappaB and proteasome by dithiocarbamate complexes with metals | journal = Current Pharmaceutical Design | volume = 13 | issue = 30 | pages = 3155–3167 | year = 2007 | pmid = 17979756 | doi = 10.2174/138161207782110390 }}</ref> Effort to develop direct NF-κB inhibitor has emerged with compounds such as (-)-DHMEQ, PBS-1086, IT-603 and IT-901.<ref name="pmid25843712">{{cite journal | vauthors = Blakely CM, Pazarentzos E, Olivas V, Asthana S, Yan JJ, Tan I, Hrustanovic G, Chan E, Lin L, Neel DS, Newton W, Bobb KL, Fouts TR, Meshulam J, Gubens MA, Jablons DM, Johnson JR, Bandyopadhyay S, Krogan NJ, Bivona TG | title = NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer | journal = Cell Reports | volume = 11 | issue = 1 | pages = 98–110 | date = April 2015 | pmid = 25843712 | pmc = 4394036 | doi = 10.1016/j.celrep.2015.03.012 }}</ref><ref name="pmid22806876">{{cite journal | vauthors = Fabre C, Mimura N, Bobb K, Kong SY, Gorgun G, Cirstea D, Hu Y, Minami J, Ohguchi H, Zhang J, Meshulam J, Carrasco RD, Tai YT, Richardson PG, Hideshima T, Anderson KC | title = Dual inhibition of canonical and noncanonical NF-κB pathways demonstrates significant antitumor activities in multiple myeloma | journal = Clinical Cancer Research | volume = 18 | issue = 17 | pages = 4669–4681 | date = September 2012 | pmid = 22806876 | pmc = 4456190 | doi = 10.1158/1078-0432.CCR-12-0779 }}</ref><ref name="pmid26744524">{{cite journal | vauthors = Shono Y, Tuckett AZ, Liou HC, Doubrovina E, Derenzini E, Ouk S, Tsai JJ, Smith OM, Levy ER, Kreines FM, Ziegler CG, Scallion MI, Doubrovin M, Heller G, Younes A, O'Reilly RJ, van den Brink MR, Zakrzewski JL | title = Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB-Controlled Oxidative Stress Responses | journal = Cancer Research | volume = 76 | issue = 2 | pages = 377–389 | date = January 2016 | pmid = 26744524 | pmc = 4715937 | doi = 10.1158/0008-5472.CAN-14-2814 }}</ref> (-)-DHMEQ and PBS-1086 are irreversible binder to NF-κB while IT-603 and IT-901 are reversible binder. DHMEQ covalently binds to Cys 38 of p65.<ref name="pmid18729348">{{cite journal | vauthors = Yamamoto M, Horie R, Takeiri M, Kozawa I, Umezawa K | title = Inactivation of NF-kappaB components by covalent binding of (-)-dehydroxymethylepoxyquinomicin to specific cysteine residues | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 18 | pages = 5780–5788 | date = September 2008 | pmid = 18729348 | doi = 10.1021/jm8006245 }}</ref>

[[Anatabine]]'s antiinflammatory effects are claimed to result from modulation of NF-κB activity.<ref name="urlRoskamp Institute | Role of RCP006 as an anti-inflammatory agent">{{cite web | url = http://www.rfdn.org/inflammaging3.html | title = Role of RCP006 as an anti-inflammatory agent | publisher = Roskamp Institute | access-date = 2011-09-06 | archive-date = 2011-10-23 | archive-url = https://web.archive.org/web/20111023123801/http://rfdn.org/inflammaging3.html | url-status = dead }}</ref>  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.

BAY 11-7082 has also been identified as a drug that can inhibit the NF-κB signaling cascade. It is capable of preventing the phosphorylation of IKK-α in an irreversible manner such that there is down regulation of NF-κB activation.<ref>{{cite journal | vauthors = Kolati SR, Kasala ER, Bodduluru LN, Mahareddy JR, Uppulapu SK, Gogoi R, Barua CC, Lahkar M | title = BAY 11-7082 ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated oxidative stress and renal inflammation via NF-κB pathway | journal = Environmental Toxicology and Pharmacology | volume = 39 | issue = 2 | pages = 690–699 | date = March 2015 | pmid = 25704036 | doi = 10.1016/j.etap.2015.01.019 }}</ref>

It has been shown that administration of BAY 11-7082 rescued renal functionality in diabetic-induced Sprague-Dawley rats by suppressing NF-κB regulated oxidative stress.<ref name="Suppression of NF-κB and NF-κB regu">{{cite journal | vauthors = Kumar A, Negi G, Sharma SS | title = Suppression of NF-κB and NF-κB regulated oxidative stress and neuroinflammation by BAY 11-7082 (IκB phosphorylation inhibitor) in experimental diabetic neuropathy | journal = Biochimie | volume = 94 | issue = 5 | pages = 1158–1165 | date = May 2012 | pmid = 22342224 | doi = 10.1016/j.biochi.2012.01.023 }}</ref>

Research has shown that the N-acylethanolamine, [[palmitoylethanolamide]] is capable of PPAR-mediated inhibition of NF-κB.<ref>{{cite journal | vauthors = Dana N, Vaseghi G, Haghjooy Javanmard S | title = Crosstalk between Peroxisome Proliferator-Activated Receptors and Toll-Like Receptors: A Systematic Review | journal = Advanced Pharmaceutical Bulletin | volume = 9 | issue = 1 | pages = 12–21 | date = February 2019 | pmid = 31011554 | pmc = 6468223 | doi = 10.15171/apb.2019.003 }}</ref>

The [[biological target]] of [[iguratimod]], a drug marketed to treat rheumatoid arthritis in Japan and China, was unknown as of 2015, but the primary mechanism of action appeared to be preventing NF-κB activation.<ref name=Tanaka2015>{{cite journal | vauthors = Tanaka K, Yamaguchi T, Hara M | title = Iguratimod for the treatment of rheumatoid arthritis in Japan | journal = Expert Review of Clinical Immunology | volume = 11 | issue = 5 | pages = 565–573 | date = May 2015 | pmid = 25797025 | doi = 10.1586/1744666X.2015.1027151 | s2cid = 25134255 }}</ref>

== See also ==
* [[IKK2]]
* [[RELA]]
* [[TNF receptor superfamily]]
* [[Imd pathway]]

== Notes ==
{{reflist|group=note}}

== References ==
{{Reflist|33em}}

== External links ==
{{Scholia|topic}}
* {{MeshName|NF-kappa+B}}
* {{cite book |author=Sankar Ghosh |title=Handbook of Transcription Factor NF-κB |publisher=CRC |location=Boca Raton |year=2006 |isbn=978-0-8493-2794-0 }}
* {{cite web | url = http://bu.edu/nf-kb/ |title = The Rel/NF-κB Signal Transduction Pathway | access-date = 2007-12-02 | author =  Thomas D Gilmore | publisher = [[Boston University]]}}

{{Addiction}}
{{Transcription factors|g4}}

{{DEFAULTSORT:NF-KB}}
[[Category:Addiction|Delta0]]
[[Category:Aging-related proteins]]
[[Category:Protein complexes]]
[[Category:Programmed cell death]]
[[Category:Transcription factors]]