NF-kB (nuclear factor-kappa B) is a protein complex that plays a critical role in regulating the immune response, inflammation, cell proliferation, and cell survival.
It is found in the cytoplasm of cells.
It is typically inactive when bound to inhibitory proteins called IkBs (inhibitors of NF-kB).
Various stimuli: pro-inflammatory cytokines, pathogens, and stress signals, can activate NF-kB by triggering the degradation of IkBs.
NF-kB translocates into the cell nucleus and binds to specific DNA sequences, thereby regulating the expression of genes involved in immune and inflammatory responses.
This process can lead to the production of cytokines, chemokines, and cell adhesion molecules, among other proteins that coordinate the immune response.
NF-kB is implicated in numerous diseases, including inflammatory conditions, autoimmune disorders, and cancer.
NF-kB activity alteration is a therapeutic target in these diseases.
NF-κB is found in almost all cell types.
It is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.
NF-κB plays a key role in regulating the immune response to infection.
The incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection.
In its improper immune development, NF-κB has also been implicated in processes of synaptic plasticity and memory.
UV radiation activates the transcription factor, NF-κB, which is the first step in inflammation.
NF-κB activation results in the increase of proinflammatory cytokines: interleukin 1 (IL-1), IL-6 vascular endothelial growth factor, and tumor necrosis factor (TNF-α).
This then attracts neutrophils which lead to an increase in oxidative damage through the generation of free radicals.
NF-κB complex is a heterodimer of p50 and RelA
In its inactivated state, NF-κB is located in the cytosol complexed with the inhibitory protein IκBα.
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 coactivators and RNA polymerase, which transcribe downstream DNA into mRNA.
In turn, mRNA is translated into protein, resulting in a change of cell function.
NF-κB is important in regulating cellular responses because it belongs to the category of rapid-acting primary transcription factors, that are in an inactive state and do not require new protein synthesis in order to become activated.
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.
NF-κB suppression of tumor necrosis factor cytotoxicity, or apoptosis, is due to induction of antioxidant enzymes and sustained suppression of c-Jun N-terminal kinases (JNKs).
Receptor activator of NF-κB (RANK), is a central activator of NF-κB.
Osteoprotegerin (OPG), which is a decoy receptor homolog inhibits RANK by binding to RANKL, and, thus, osteoprotegerin is tightly involved in regulating NF-κB activation.
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 stimulation of TLRs leads to activation of NF-κB.
TLRs are key regulators of both innate and adaptive immune responses.
In unstimulated cells, the NF-κB dimers are sequestered in the cytoplasm by a family of inhibitors, called IκBs (Inhibitor of κB).
IκBs are proteins that contain multiple copies of a sequence called ankyrin repeats, which mask the nuclear localization signals (NLS) of NF-κB proteins and keep them sequestered in an inactive state in the cytoplasm.
Activation of the NF-κB is initiated by the signal-induced degradation of IκB proteins, occuring primarily via activation of a kinase called the IκB kinase (IKK).
IκB proteins are modified by a process called ubiquitination, which then leads them to be degraded by a cell structure called the proteasome.
With the degradation of IκB, the NF-κB complex enters the nucleus where it allows 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 physiological response, for example, an inflammatory or immune response, a cell survival response, or cellular proliferation.
The translocation of NF-κB to the nucleus can be detected immunocytochemically and measured by laser scanning cytometry.
There is an auto feedback loop, resulting in oscillating levels of NF-κB activity.
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.
Activation of NF-κB may, at least in part, be involved in activation of the HIV-1 virus from a latent, inactive state.
Yersinia pestis, the causative agent of plague secretes YopP that prevents the ubiquitination of IκB, and effectively inhibits the NF-κB pathway and thus blocks the immune response of a human infected with Yersinia.
NF-κB is a major transcription factor that regulates genes responsible for both the innate and adaptive immune response.
Upon activation of either the T- or B-cell receptor, NF-κB becomes activated through distinct signaling components.
Through a cascade of phosphorylation events, the protein kinase complex is activated and NF-κB is able to enter the nucleus to upregulate genes involved in T-cell development, maturation, and proliferation.
NF-κB functions in the nervous system include roles in plasticity, learning, and memory.
NF-κB in the nervous system can be activated by Growth Factors (BDNF, NGF) and synaptic transmission such as glutamate.
NF-κB helps regulate learning and memory by modulating synaptic plasticity, synapse functions, and by regulating the growth of dendrites and dendritic spines.
NF-κB binding sites in genes have increased expression following learning, suggesting transcriptional targets of NF-κB in the nervous system are important for neuroplasticity.
However purified cultures of neurons generally show little to no NF-κB activity.
Many different types of tumors have misregulated NF-κB.
Activated NF-κB turns on the expression of genes that keep the cell proliferating and protects the cell from apoptosis.
NF-κB signaling leads to defective coordination between the malignant cell and the rest of the organism.
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,
Defects in NF-κB results in increased susceptibility to apoptosis leading to increased cell death.
This is because NF-κB regulates anti-apoptotic genes which are central to most apoptotic processes.
In tumor cells, NF-κB activity is enhanced, in 41% of nasopharyngeal carcinoma, colorectal cancer, prostate cancer and pancreatic tumors.
Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents.
NF-κB activity enhances tumor cell sensitivity to apoptosis and senescence.
NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, atherosclerosis and others.
Elevation of some NF-κB activators, such as osteoprotegerin (OPG), are associated with elevated mortality, especially from cardiovascular diseases.
Elevated NF-κB has also been associated with schizophrenia.
Compromised regulation of NF-κB activity, which allows cancer cells to express abnormal cohorts of NF-κB target genes.
NF-κB is increasingly expressed with obesity and aging.
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.
NF-κB is one oa transcriptional targets of ΔFosB which facilitates the development and maintenance of an addiction to a stimulus.
In the caudate putamen, NF-κB induction is associated with increases in motor function.
In the nucleus accumbens, NF-κB induction enhances the positive reinforcing effect of a drug through reward sensitization.
Extracts from a number of herbs and dietary plants are efficient inhibitors of NF-κB activation.
Aberrant activation of NF-κB is frequently observed in many cancers.
Suppression of NF-κB limits the proliferation of cancer cells.
NF-κB is a key player in the inflammatory response.
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.
The drug denosumab acts to raise bone mineral density and reduce fracture rates in many patient sub-groups by inhibiting RANKL.
RANKL/RANK promotes enabling the differentiation of osteoclasts from monocytes.
Disulfiram, olmesartan and dithiocarbamates can inhibit the nuclear factor-κB (NF-κB) signaling cascade.