NF-κB

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 in B cells.{{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 }} Later work by Alexander Poltorak and Bruno Lemaitre in mice and Drosophila fruit flies established Toll-like receptors as universally conserved activators of NF-κB signalling. These works ultimately contributed to awarding of the 2011 Nobel Prize in Physiology or Medicine to Bruce Beutler and Jules A. Hoffmann, who were the principal investigators of those studies.{{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 }}{{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 }}{{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}}

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-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 repeats. Whereas the generation of p52 from p100 is a tightly regulated process, p50 is produced from constitutive processing of p105.{{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 }}{{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 }} 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.{{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 }}{{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 }} 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).

NF-κB family members share structural homology with the retroviral oncoprotein v-Rel, resulting in their classification as NF-κB/Rel proteins.

There are five proteins in the mammalian NF-κB family:{{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 }}

The NF-κB/Rel proteins can be divided into two classes, which share general structural features:File:NF-kB proteins.png 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 repeats and has transrepression activity. In contrast, the C-terminus of class II proteins has a transactivation function. ]]

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 = | 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}}

In addition to mammals, NF-κB is found in a number of simple animals as well.{{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 }} These include cnidarians (such as sea anemones, coral and hydra), porifera (sponges), single-celled eukaryotes including Capsaspora owczarzaki and choanoflagellates, and insects (such as moths, mosquitoes and fruitflies). The sequencing of the genomes of the mosquitoes A. aegypti and A. gambiae, and the fruitfly 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 pathway (which evolved independently in insects and mammals) and by the Imd (immune deficiency) pathway.{{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 }}

File:3do7 NFkB relB DNA.png

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, STATs, and nuclear hormone receptors). 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 (ROS), tumor necrosis factor alpha (TNFα), interleukin 1-beta (IL-1β), bacterial lipopolysaccharides (LPS), isoproterenol, cocaine, endothelin-1 and ionizing radiation.(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 }}

NF-κB suppression of tumor necrosis factor cytotoxicity (apoptosis) is due to induction of antioxidant enzymes and sustained suppression of c-Jun N-terminal kinases (JNKs).{{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 }}

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.{{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 }}

Many bacterial products and stimulation of a wide variety of cell-surface receptors lead to NF-κB activation and fairly rapid changes in gene expression. The identification of Toll-like receptors (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.{{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 }} TLRs are key regulators of both innate and adaptive immune responses.{{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 }}

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 heterodimers with RelA, RelB, or c-Rel.{{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 }} In addition, p50 and p52 homodimers also bind to the nuclear protein Bcl-3, and such complexes can function as transcriptional activators.{{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 }}{{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 }}{{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 }}

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 repeats. By virtue of their ankyrin repeat domains, the IκB proteins mask the nuclear localization signals (NLS) of NF-κB proteins and keep them sequestered in an inactive state in the cytoplasm.{{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 }}

IκBs are a family of related proteins that have an N-terminal regulatory domain, followed by six or more ankyrin repeats and a PEST domain near their C terminus. Although the IκB family consists of IκBα, IκBβ, IκBε, and 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.{{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 }}.{{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 }} IκBδ degradation in response to developmental stimuli, such as those transduced through LTβR, potentiate NF-κB dimer activation in a NIK dependent non-canonical pathway.{{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 }}

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 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, which then leads them to be degraded by a cell structure called the proteasome.{{cn|date=November 2024}}

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.{{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 }} 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.{{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 }} 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.{{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 }} 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.{{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 }}

Concerning known protein inhibitors of NF-κB activity, one of them is IFRD1, which represses the activity of NF-κB p65 by enhancing the 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.{{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 }}{{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 }}

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.{{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 }}

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. RelB:p52 regulates the expression of homeostatic lymphokines, which instructs lymphoid organogenesis and lymphocyte trafficking in the secondary lymphoid organs.{{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 }} 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.{{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 }} Moreover, generation of the canonical and non-canonical dimers, viz RelA:p50 and RelB:p52, within the cellular milieu are mechanistically interlinked. 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.{{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 }} 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. {{cn|date=November 2024}}

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.{{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 }}{{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 }} 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.{{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 }}

NF-κB is a major transcription factor that regulates genes responsible for both the innate and adaptive immune response.{{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 | pmc = 11520635 }} Upon activation of either the T- or 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 ITAMs of the CD3 cytoplasmic tail. ZAP70 is then recruited to the phosphorylated ITAMs and helps recruit LAT and PLC-γ, which causes activation of 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.{{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 }}

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 plasticity, learning, and memory.{{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 }} In addition to stimuli that activate NF-κB in other tissues, NF-κB in the nervous system can be activated by Growth Factors (BDNF, NGF) and synaptic transmission such as glutamate. These activators of NF-κB in the nervous system all converge upon the IKK complex and the canonical pathway. {{cn|date=November 2024}}

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, fruit flies,{{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 }} and mice. NF-κB may regulate learning and memory in part by modulating synaptic plasticity, synapse function,{{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 }}{{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 }} as well as by regulating the growth of dendrites{{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 }} and dendritic spines.

Genes that have NF-κB binding sites are shown to have increased expression following learning, 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){{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 }} cytokines (TNF-alpha, TNFR){{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 }} and kinases (PKAc).{{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 }}

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.{{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 }}{{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 }}

Some of the reports of NF-κB in neurons appear to have been an artifact of antibody nonspecificity.{{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 }} 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.{{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 }} used a coculture format whereby neurons and glia could be separated after treatment for 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 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.{{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 }} 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.{{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 }} 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. {{cn|date=November 2024}}

File:Signal transduction pathways.svg.]]

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.{{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 }}

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.{{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 }}

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.{{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 }}

In tumor cells, NF-κB activity is enhanced, as for example, in 41% of nasopharyngeal carcinoma,{{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 }} colorectal cancer, prostate cancer and 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.{{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 }}{{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 }} Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents.{{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 }}{{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 }} Thus, NF-κB is the subject of much active research among pharmaceutical companies as a target for anti-cancer therapy.{{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 }}

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.{{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 }} 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. {{cn|date=November 2024}}

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{{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 }} and others. It is important to note though, that elevation of some NF-κB inhibitors, such as osteoprotegerin (OPG), are associated with elevated mortality, especially from cardiovascular diseases.{{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 }}{{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 }} Elevated NF-κB has also been associated with schizophrenia.{{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 }} Recently, NF-κB activation has been suggested as a possible molecular mechanism for the catabolic effects of cigarette smoke in skeletal muscle and sarcopenia.{{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 }} 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.{{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 }} 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.{{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 }} Particularly important are feedback responses that develop between tissue resident cells, and circulating cells of the immune system.

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. 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. 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.{{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 }} 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.{{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 }}{{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 }}{{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 }} 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.{{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 }}

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.[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

NF-κB is increasingly expressed with obesity and aging,{{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 }} resulting in reduced levels of the anti-inflammatory, pro-autophagy, anti-insulin resistance protein sirtuin 1. NF-κB increases the levels of the microRNA miR-34a, which inhibits nicotinamide adenine dinucleotide (NAD) synthesis by binding to its promoter region,{{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 }} resulting in lower levels of sirtuin 1.

NF-κB and interleukin 1 alpha mutually induce each other in senescent cells in a positive feedback loop causing the production of senescence-associated secretory phenotype (SASP) factors.{{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 }} NF-κB and the NAD-degrading enzyme CD38 also mutually induce each other.{{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 }}

NF-κB is a central component of the cellular response to damage.{{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 }} NF-κB is activated in a variety of cell types that undergo normal or accelerated aging. Genetic or pharmacologic inhibition of NF-κB activation can delay the onset of numerous aging related symptoms and pathologies. 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 damage DNA.

NF-κB is one of several induced transcriptional targets of ΔFosB which facilitates the development and maintenance of an addiction to a stimulus.{{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 }}{{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 = | s2cid = 19157711 }}{{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 }} 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.

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){{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}} 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,{{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 }} Ben-Neriah{{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 }} 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.{{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 }}

Extracts from a number of herbs and dietary plants are efficient inhibitors of NF-κB activation in vitro.{{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 }} Nobiletin, a flavonoid isolated from citrus peels, has been shown to inhibit the NF-κB signaling pathway in mice.{{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 }} The circumsporozoite protein of Plasmodium falciparum has been shown to be an inhibitor of NF-κB.{{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 }} Likewise, various withanolides of Withania somnifera (Ashwagandha) have been found to have inhibiting effects on NF-κB through inhibition of proteasome mediated ubiquitin degradation of IκBα.{{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 }}{{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 }}

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.{{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 }}{{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 }}

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.{{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 }}{{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 }}

The discovery that activation of NF-κB nuclear translocation can be separated from the elevation of oxidant stress{{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 }} 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,{{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 }}

RANKL normally works by enabling the differentiation of osteoclasts from monocytes.{{cite journal |vauthors =Chandrabalan S, Dang L, Hansen U, et al|title=A novel method to efficiently differentiate human osteoclasts from blood-derived monocytes |journal=Biological Procedures Online |date=2024 |volume=19 |issue=26 |page=7 |doi=10.1186/s12575-024-00233-6 |doi-access=free |pmid=38504200 |pmc=10949786 }}

Disulfiram, olmesartan and dithiocarbamates can inhibit the NF-κB signaling cascade.{{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 }} Effort to develop direct NF-κB inhibitor has emerged with compounds such as (-)-DHMEQ, PBS-1086, IT-603 and IT-901.{{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 }}{{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 }}{{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 }} (-)-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.{{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 }}

Anatabine's antiinflammatory effects are claimed to result from modulation of NF-κB activity.{{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 }} 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. {{cn|date=November 2024}}

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.{{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 | bibcode = 2015EnvTP..39..690K }}

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.{{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 }}

Research has shown that the N-acylethanolamine, palmitoylethanolamide is capable of PPAR-mediated inhibition of NF-κB.{{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 }}

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.{{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 }}

• IKK2
• RELA
• TNF receptor superfamily
• Imd pathway

{{reflist|group=note}}

{{Reflist|33em}}

{{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}}

Delta0

Category:Aging-related proteins

Category:Protein complexes

Category:Programmed cell death

Category:Transcription factors