Tumor necrosis factor
Encyclopedia
Tumor necrosis factor is a cytokine
involved in systemic inflammation
and is a member of a group of cytokines that stimulate the acute phase reaction. It is produced chiefly by activated macrophages, although it can be produced by other cell types as well.
The primary role of TNF is in the regulation of immune cells. TNF, being an endogenous pyrogen, is able to induce fever, to induce apoptotic
cell death, to induce sepsis (through IL1 & IL6 production), to induce cachexia
, induce inflammation
, and to inhibit tumorigenesis and viral replication
. Dysregulation of TNF production has been implicated in a variety of human disease
s, including Alzheimer's disease
, cancer
, major depression, and inflammatory bowel disease
(IBD). While still controversial, studies of depression and IBD are currently being linked by TNF levels. Recombinant TNF is used as an immunostimulant under the INN
tasonermin. Tumor necrosis factor-α can be produced ectopically in the setting of malignancy and parallels parathyroid hormone both in causing secondary hypercalcemia and in the cancers with which excessive production is associated.
in vivo
was recognized by the physician William B. Coley. In 1968, Dr. Gale A Granger from the University of California, Irvine
, reported a cytotoxic factor produced by lymphocytes and named it lymphotoxin (LT). Credit for this discovery is shared by Dr. Nancy H. Ruddle from Yale University
, who reported the same activity in a series of back-to-back articles published in the same month. Subsequently in 1975 Dr. Lloyd J. Old from Memorial Sloan-Kettering Cancer Center
, New York, reported another cytotoxic factor produced by macrophages, and named it tumor necrosis factor (TNF). Both factors were described based on their ability to kill mouse fibrosarcoma
L-929 cells.
When the cDNAs encoding LT and TNF were cloned in 1984, they were revealed to be similar. The binding of TNF to its receptor and its displacement by LT confirmed the functional homology
between the two factors. The sequential and functional homology of TNF and LT led to the renaming of TNF as TNFα and LT as TNFβ. In 1985, Bruce A. Beutler
and Anthony Cerami
discovered that a hormone that induces cachexia
and previously-named cachectin was actually TNF. These investigators then identified TNF as a mediator of lethal endotoxin
poisoning. Kevin J. Tracey
and Cerami discovered the key mediator role of TNF in lethal septic shock
, and identified the therapeutic effects of monoclonal anti-TNF antibodies..
(TNFA) was cloned in 1985. It maps to chromosome
6p21.3, spans about 3 kilobases and contains 4 exon
s. The last exon codes for more than 80% of the secreted protein. The 3' UTR of TNF alpha contains an AU-rich element
(ARE).
-long type II transmembrane protein
arranged in stable homotrimers. From this membrane-integrated form the soluble homotrimeric cytokine (sTNF) is released via proteolytic cleavage by the metalloprotease TNF alpha converting enzyme (TACE, also called ADAM17
). The soluble 51 kDa trimeric sTNF tends to dissociate at concentrations below the nanomolar range, thereby losing its bioactivity.
The 17-kilodalton (kDa) TNF protomers (185-amino acid-long) are composed of two antiparallel β-pleated sheet
s with antiparallel β-strand
s, forming a 'jelly roll' β-structure, typical for the TNF family, but also found in viral capsid proteins.
, and respond to the membrane-bound form of the TNF homotrimer. As most information regarding TNF signaling is derived from TNF-R1, the role of TNF-R2 is likely underestimated.
Upon contact with their ligand
, TNF receptors also form trimers, their tips fitting into the grooves formed between TNF monomers. This binding causes a conformational change to occur in the receptor, leading to the dissociation of the inhibitory protein SODD from the intracellular death domain. This dissociation enables the adaptor protein
TRADD
to bind to the death domain, serving as a platform for subsequent protein binding. Following TRADD binding, three pathways can be initiated.
The myriad and often-conflicting effects mediated by the above pathways indicate the existence of extensive cross-talk. For instance, NF-κB enhances the transcription of C-FLIP, Bcl-2
, and cIAP1
/ cIAP2, inhibitory proteins that interfere with death signaling. On the other hand, activated caspases cleave several components of the NF-κB pathway, including RIP, IKK, and the subunits of NF-κB itself. Other factors, such as cell type, concurrent stimulation of other cytokines, or the amount of reactive oxygen species
(ROS) can shift the balance in favor of one pathway or another. Such complicated signaling ensures that, whenever TNF is released, various cells with vastly diverse functions and conditions can all respond appropriately to inflammation
.
cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue
, fibroblasts, and neuron
al tissue. Large amounts of TNF are released in response to lipopolysaccharide
, other bacteria
l products, and Interleukin-1 (IL-1). In the skin, mast cells appear to be the predominant source of pre-formed TNF, which can be released upon inflammatory stimulus (e.g., LPS).
It has a number of actions on various organ systems, generally together with IL-1 and Interleukin-6 (IL-6):
A local increase in concentration of TNF will cause the cardinal signs of Inflammation to occur: heat, swelling, redness, pain and loss of function.
Whereas high concentrations of TNF induce shock-like symptoms, the prolonged exposure to low concentrations of TNF can result in cachexia
, a wasting syndrome. This can be found, for example, in cancer
patients.
Said et al. showed that TNF-alpha causes an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1 levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.
, ankylosing spondylitis
, inflammatory bowel disease
, psoriasis
, hidradenitis suppurativa
and refractory asthma
. These disorders are sometimes treated by using a TNF inhibitor
. This inhibition can be achieved with a monoclonal antibody such as infliximab
(Remicade), adalimumab
(Humira) or certolizumab pegol
(Cimzia), or with a circulating receptor fusion protein
such as etanercept
(Enbrel).
with TNFRSF1A
.
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
involved in systemic inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and is a member of a group of cytokines that stimulate the acute phase reaction. It is produced chiefly by activated macrophages, although it can be produced by other cell types as well.
The primary role of TNF is in the regulation of immune cells. TNF, being an endogenous pyrogen, is able to induce fever, to induce apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
cell death, to induce sepsis (through IL1 & IL6 production), to induce cachexia
Cachexia
Cachexia or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight...
, induce inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, and to inhibit tumorigenesis and viral replication
Viral replication
Viral replication is the term used by virologists to describe the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. From the perspective of the virus, the purpose of viral replication is...
. Dysregulation of TNF production has been implicated in a variety of human disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
s, including Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, major depression, and inflammatory bowel disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
(IBD). While still controversial, studies of depression and IBD are currently being linked by TNF levels. Recombinant TNF is used as an immunostimulant under the INN
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
tasonermin. Tumor necrosis factor-α can be produced ectopically in the setting of malignancy and parallels parathyroid hormone both in causing secondary hypercalcemia and in the cancers with which excessive production is associated.
Discovery
The theory of an anti-tumoral response of the immune systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
was recognized by the physician William B. Coley. In 1968, Dr. Gale A Granger from the University of California, Irvine
University of California, Irvine
The University of California, Irvine , founded in 1965, is one of the ten campuses of the University of California, located in Irvine, California, USA...
, reported a cytotoxic factor produced by lymphocytes and named it lymphotoxin (LT). Credit for this discovery is shared by Dr. Nancy H. Ruddle from Yale University
Yale University
Yale University is a private, Ivy League university located in New Haven, Connecticut, United States. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States...
, who reported the same activity in a series of back-to-back articles published in the same month. Subsequently in 1975 Dr. Lloyd J. Old from Memorial Sloan-Kettering Cancer Center
Memorial Sloan-Kettering Cancer Center
Memorial Sloan–Kettering Cancer Center is a cancer treatment and research institution founded in 1884 as the New York Cancer Hospital...
, New York, reported another cytotoxic factor produced by macrophages, and named it tumor necrosis factor (TNF). Both factors were described based on their ability to kill mouse fibrosarcoma
Fibrosarcoma
Fibrosarcoma is a malignant tumor derived from fibrous connective tissue and characterized by immature proliferating fibroblasts or undifferentiated anaplastic spindle cells.Usually in males ages 30 to 40. Originates in fibrous tissues of the bone. Invades long or flat bones such as femur, tibia,...
L-929 cells.
When the cDNAs encoding LT and TNF were cloned in 1984, they were revealed to be similar. The binding of TNF to its receptor and its displacement by LT confirmed the functional homology
Homology (chemistry)
In chemistry, homology refers to the appearance of homologues. A homologue is a compound belonging to a series of compounds differing from each other by a repeating unit, such as a methylene group, a peptide residue, etcetera....
between the two factors. The sequential and functional homology of TNF and LT led to the renaming of TNF as TNFα and LT as TNFβ. In 1985, Bruce A. Beutler
Bruce A. Beutler
Bruce Alan Beutler is an American immunologist and geneticist. Together with Jules A. Hoffmann, they received one-half of the 2011 Nobel Prize in Physiology or Medicine, for "their discoveries concerning the activation of innate immunity" Bruce Alan Beutler (born December 29, 1957) is an American...
and Anthony Cerami
Anthony Cerami
-Biography:Anthony Cerami is a member of the National Academy of Sciences and the Institute of Medicine. He is the founder and Chairman of the Board of Warren Pharmaceuticals, and the founder and chairman of the Board and CEO of Araim Pharmaceuticals. He received a Ph.D...
discovered that a hormone that induces cachexia
Cachexia
Cachexia or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight...
and previously-named cachectin was actually TNF. These investigators then identified TNF as a mediator of lethal endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
poisoning. Kevin J. Tracey
Kevin J. Tracey
Kevin J. Tracey, a scientist and inventor, was born in Fort Wayne, Indiana on 10 December 1957. He is President of the Feinstein Institute for Medical Research and Professor and President of the Elmezzi Graduate School of Molecular Medicine in Manhasset, New York.-Education:Kevin J. Tracey...
and Cerami discovered the key mediator role of TNF in lethal septic shock
Septic shock
Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...
, and identified the therapeutic effects of monoclonal anti-TNF antibodies..
Gene
The human TNF geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(TNFA) was cloned in 1985. It maps to chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
6p21.3, spans about 3 kilobases and contains 4 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s. The last exon codes for more than 80% of the secreted protein. The 3' UTR of TNF alpha contains an AU-rich element
AU-rich element
AU-rich elements are one of the most common types of regulatory elements found in mRNAs. They are involved in the control of gene expression. They are the most common determinant of RNA stability in mammalian cells....
(ARE).
Structure
TNF is primarily produced as a 212-amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
-long type II transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
arranged in stable homotrimers. From this membrane-integrated form the soluble homotrimeric cytokine (sTNF) is released via proteolytic cleavage by the metalloprotease TNF alpha converting enzyme (TACE, also called ADAM17
ADAM17
ADAM metallopeptidase domain 17 , also called TACE , is a 70-kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases.- Chemical characteristics :...
). The soluble 51 kDa trimeric sTNF tends to dissociate at concentrations below the nanomolar range, thereby losing its bioactivity.
The 17-kilodalton (kDa) TNF protomers (185-amino acid-long) are composed of two antiparallel β-pleated sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
s with antiparallel β-strand
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
s, forming a 'jelly roll' β-structure, typical for the TNF family, but also found in viral capsid proteins.
Cell signaling
TNF can bind two receptors, TNF-R1 (TNF receptor type 1; CD120a; p55/60) and TNF-R2 (TNF receptor type 2; CD120b; p75/80). TNF-R1 is expressed in most tissues, and can be fully activated by both the membrane-bound and soluble trimeric forms of TNF, whereas TNF-R2 is found only in cells of the immune systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, and respond to the membrane-bound form of the TNF homotrimer. As most information regarding TNF signaling is derived from TNF-R1, the role of TNF-R2 is likely underestimated.
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
, TNF receptors also form trimers, their tips fitting into the grooves formed between TNF monomers. This binding causes a conformational change to occur in the receptor, leading to the dissociation of the inhibitory protein SODD from the intracellular death domain. This dissociation enables the adaptor protein
Adaptor protein
Signal transducing adaptor proteins are proteins which are accessory to main proteins in a signal transduction pathway. These proteins tend to lack any intrinsic enzymatic activity themselves but instead mediate specific protein–protein interactions that drive the formation of protein complexes...
TRADD
TRADD
Tumor necrosis factor receptor type 1-associated DEATH domain protein is a protein that in humans is encoded by the TRADD gene.TRADD is an adaptor protein.- Function :...
to bind to the death domain, serving as a platform for subsequent protein binding. Following TRADD binding, three pathways can be initiated.
- Activation of NF-κB: TRADD recruits TRAF2TRAF2TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.-Interactions:TRAF2 has been shown to interact with BCL10, CD30, CFLAR, IKK2, MAP3K7IP2, CD137, Caveolin 1, CD27, TNFRSF13B, TANK-binding kinase 1, TRAF1, CD40, UBE2N, MAP3K14, MAP4K2, CASP8AP2, HIVEP3,...
and RIP. TRAF2TRAF2TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.-Interactions:TRAF2 has been shown to interact with BCL10, CD30, CFLAR, IKK2, MAP3K7IP2, CD137, Caveolin 1, CD27, TNFRSF13B, TANK-binding kinase 1, TRAF1, CD40, UBE2N, MAP3K14, MAP4K2, CASP8AP2, HIVEP3,...
in turn recruits the multicomponent protein kinaseKinaseIn chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
IKKIκB kinaseThe IκB kinase is an enzyme complex that is involved in propagating the cellular response to inflammation.The IκB kinase enzyme complex is part of the upstream NF-κB signal transduction cascade...
, enabling the serine-threonine kinaseKinaseIn chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
RIP to activate it. An inhibitory protein, IκBα, that normally binds to NF-κB and inhibits its translocation, is phosphorylated by IKK and subsequently degraded, releasing NF-κB. NF-κB is a heterodimeric transcription factorTranscription factorIn molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
that translocates to the nucleusCell nucleusIn cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
and mediates the transcription of a vast array of proteins involved in cell survival and proliferation, inflammatory response, and anti-apoptotic factors.
- Activation of the MAPK pathways: Of the three major MAPK cascades, TNF induces a strong activation of the stressStress (medicine)Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
-related JNK group, evokes moderate response of the p38-MAPK, and is responsible for minimal activation of the classical ERKExtracellular signal-regulated kinasesIn molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
s. TRAF2/Rac activates the JNK-inducing upstream kinases of MLK2MAP3K10Mitogen-activated protein kinase kinase kinase 10 is an enzyme that in humans is encoded by the MAP3K10 gene.-Interactions:MAP3K10 has been shown to interact with NEUROD1, Huntingtin, MAPK8IP1, KIF3A, CDC42 and MAPK8IP2.-Further reading:...
/MLK3MAP3K11Mitogen-activated protein kinase kinase kinase 11 is an enzyme that in humans is encoded by the MAP3K11 gene.-Interactions:MAP3K11 has been shown to interact with MAPK8IP1, CDC42, SH3RF1, MAPK8IP2 and AKT1.-Further reading:...
, TAK1MAP3K7Mitogen-activated protein kinase kinase kinase 7 is an enzyme that in humans is encoded by the MAP3K7 gene.-Interactions:MAP3K7 has been shown to interact with Mothers against decapentaplegic homolog 6, MAP3K7IP2, MAP3K7IP1, MAP3K7IP3, ASK1, PPM1B, TRAF6, MAP2K6 and CHUK.-Further reading:...
, MEKK1 and ASK1ASK1Apoptosis signal-regulating kinase 1 also known as mitogen-activated protein kinase kinase kinase 5 is a member of MAP kinase kinase kinase family and as such a part of mitogen-activated protein kinase pathway...
(either directly or through GCKs and Trx, respectively), and these kinases phosphorylate MKK7, which then activates JNK. JNK translocates to the nucleus and activates transcription factors such as c-JunC-junc-Jun is the name of a gene and protein that, in combination with c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the c-jun gene. It is activated through double phosphorylation by the...
and ATF2. The JNK pathway is involved in cell differentiation, proliferation, and is generally pro-apoptotic.
- Induction of death signaling: Like all death-domain-containing members of the TNFR superfamily, TNF-R1 is involved in death signaling. However, TNF-induced cell death plays only a minor role compared to its overwhelming functions in the inflammatory process. Its death-inducing capability is weak compared to other family members (such as FasFasFas can mean the following:* Fas receptor, an important cell surface receptor protein of the TNF receptor family known also as CD95, that induces apoptosis on binding Fas ligand.* Fes, Morocco, the third largest city in Morocco, as an alternate spelling...
), and often masked by the anti-apoptotic effects of NF-κB. Nevertheless, TRADD binds FADDFADDFas-Associated protein with Death Domain is an adaptor molecule that bridges the Fas-receptor, and other death receptors, to caspase-8 through its death domain to form the death-inducing signaling complex during apoptosis. -Signalling:...
, which then recruits the cysteine proteaseCysteine proteaseProteases are enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic dyad. The first step is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a...
caspase-8. A high concentration of caspaseCaspaseCaspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
-8 induces its autoproteolytic activation and subsequent cleaving of effector caspases, leading to cell apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
The myriad and often-conflicting effects mediated by the above pathways indicate the existence of extensive cross-talk. For instance, NF-κB enhances the transcription of C-FLIP, Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
, and cIAP1
BIRC2
Baculoviral IAP repeat-containing protein 2 is a protein that in humans is encoded by the BIRC2 gene.-Interactions:...
/ cIAP2, inhibitory proteins that interfere with death signaling. On the other hand, activated caspases cleave several components of the NF-κB pathway, including RIP, IKK, and the subunits of NF-κB itself. Other factors, such as cell type, concurrent stimulation of other cytokines, or the amount of reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
(ROS) can shift the balance in favor of one pathway or another. Such complicated signaling ensures that, whenever TNF is released, various cells with vastly diverse functions and conditions can all respond appropriately to inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
.
Physiology
TNF was thought to be produced primarily by macrophages, but it is produced also by a broad variety of cell types including lymphoidLymphoid
Lymphoid is a term used to describe lymph or the lymphatic system.In the context of lymphoid leukemia, it refers specifically to lymphocytes Lymphoid leukemias and lymphomas are now considered to be tumors of the same type of cell lineage. They are called "leukemia" when in the blood or marrow and...
cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
, fibroblasts, and neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
al tissue. Large amounts of TNF are released in response to lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
, other bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
l products, and Interleukin-1 (IL-1). In the skin, mast cells appear to be the predominant source of pre-formed TNF, which can be released upon inflammatory stimulus (e.g., LPS).
It has a number of actions on various organ systems, generally together with IL-1 and Interleukin-6 (IL-6):
- On the hypothalamusHypothalamusThe Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
:- Stimulation of the hypothalamic-pituitary-adrenal axisHypothalamic-pituitary-adrenal axisThe hypothalamic-pituitary-adrenal axis , also known as thelimbic-hypothalamic-pituitary-adrenal axis and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland ,...
by stimulating the release of corticotropin releasing hormone (CRH) - Suppressing appetiteAppetiteThe appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
- FeverFeverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
- Stimulation of the hypothalamic-pituitary-adrenal axis
- On the liverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
: stimulating the acute phase response, leading to an increase in C-reactive proteinC-reactive proteinC-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
and a number of other mediators. It also induces insulin resistanceInsulin resistanceInsulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
by promoting serine-phosphorylation of insulin receptor substrate-1 (IRS-1), which impairs insulin signaling - It is a potent chemoattractant for neutrophils, and promotes the expression of adhesion molecules on endothelial cells, helping neutrophils migrate.
- On macrophages: stimulates phagocytosis, and production of IL-1 oxidants and the inflammatory lipid prostaglandinProstaglandinA prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
E2 PGE2 - On other tissues: increasing insulin resistanceInsulin resistanceInsulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
.
A local increase in concentration of TNF will cause the cardinal signs of Inflammation to occur: heat, swelling, redness, pain and loss of function.
Whereas high concentrations of TNF induce shock-like symptoms, the prolonged exposure to low concentrations of TNF can result in cachexia
Cachexia
Cachexia or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight...
, a wasting syndrome. This can be found, for example, in cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
patients.
Said et al. showed that TNF-alpha causes an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1 levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.
Pharmacology
Tumor necrosis factor promotes the inflammatory response, which, in turn, causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritisRheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, ankylosing spondylitis
Ankylosing spondylitis
Ankylosing spondylitis , previously known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strümpell disease is a chronic inflammatory disease of the axial skeleton with variable involvement of peripheral joints and nonarticular structures...
, inflammatory bowel disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
, psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, hidradenitis suppurativa
Hidradenitis suppurativa
Hidradenitis suppurativa is a skin disease that most commonly affects areas bearing apocrine sweat glands or sebaceous glands, such as the underarms, breasts, inner thighs, groin and buttocks.-Overview:...
and refractory asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
. These disorders are sometimes treated by using a TNF inhibitor
TNF inhibitor
Tumor necrosis factor promotes the inflammatory response, which in turn causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, hidradenitis suppurativa and refractory asthma. These disorders are...
. This inhibition can be achieved with a monoclonal antibody such as infliximab
Infliximab
Infliximab is a monoclonal antibody against tumour necrosis factor alpha . It is used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc...
(Remicade), adalimumab
Adalimumab
Adalimumab is the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States. Like infliximab and etanercept, adalimumab binds to TNFα, preventing it from activating TNF receptors; adalimumab was constructed from a fully human monoclonal antibody, while infliximab...
(Humira) or certolizumab pegol
Certolizumab pegol
Certolizumab pegol is a therapeutic monoclonal antibody produced by UCB for the treatment of Crohn's disease and rheumatoid arthritis.-Method of action:...
(Cimzia), or with a circulating receptor fusion protein
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
such as etanercept
Etanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...
(Enbrel).
Interactions
Tumor necrosis factor-alpha has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with TNFRSF1A
TNFRSF1A
Tumor necrosis factor receptor superfamily member 1A is a protein that in humans is encoded by the TNFRSF1A gene. The protein encoded by this gene is a member of the Tumor necrosis factor receptor superfamily, which also contains TNFRSF1B. This protein is one of the major receptors for the tumor...
.