Tumor necrosis factor (
TNF,
cachexin or
cachectin formerly known as
tumor necrosis factor-alpha) is a
cytokine involved in systemic
inflammation and is a member of a group of cytokines that stimulate the
acute phase reaction.
The primary role of TNF is in the regulation of immune cells. TNF is able to induce apoptotic cell death, to induce inflammation, and to inhibit tumorigenesis and viral replication. Dysregulation of TNF production has been implicated in a variety of human diseases, 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.
Discovery
The theory of an
anti-tumoral response of the
immune system 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 and year. 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.
Gene
The human TNF
gene (
TNFA) was cloned in 1985. It maps to
chromosome 6p21.3, spans about 3
kilobases and contains 4
exons. The last exon codes for more than 80% of the secreted protein. The 3' UTR of TNF alpha contains an
AU-rich element (ARE).
Structure
TNF is primarily produced as a 212-
amino acid-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 sheets with antiparallel β-strands, forming a 'jelly roll' β-structure, typical for the TNF family, but also found in viral capsid proteins.
Cell signaling
Two receptors,
TNF-R1 (
TNF receptor type 1; CD120a; p55/60) and
TNF-R2 (TNF receptor type 2; CD120b; p75/80), can be bound to by TNF. 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 system, 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.
Activation of NF-κB: TRADD recruits TRAF2 and RIP. TRAF2 in turn recruits the multicomponent protein kinase IKK, enabling the serine-threonine kinase 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 factor that translocates to the nucleus 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 stress-related JNK group, evokes moderate response of the p38-MAPK, and is responsible for minimal activation of the classical ERKs. TRAF2 activates the JNK-inducing upstream kinases of MEKK1 and ASK1 (either directly or through GCKs and Trx, respectively), and these two kinases phosphorylate MKK7, which then activates JNK. JNK translocates to the nucleus and activates transcription factors such as c-Jun 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 Fas), and often masked by the anti-apoptotic effects of NF-κB. Nevertheless, TRADD binds FADD, which then recruits the cysteine protease caspase-8. A high concentration of caspase-8 induces its autoproteolytic activation and subsequent cleaving of effector caspases, leading to cell apoptosis.
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.
Physiology
TNF was thought to be produced primarily by
macrophages, but it is produced also by a broad variety of cell types including
lymphoid cells,
mast cells,
endothelial cells,
cardiac myocytes,
adipose tissue,
fibroblasts, and
neuronal tissue. Large amounts of TNF are released in response to
lipopolysaccharide, other
bacterial 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) (Walsh, L.J.
et al. 1991, Proc Natl Acad Sci 88(10):p. 4220-4).
It has a number of actions on various organ systems, generally together with IL-1 and Interleukin-6 (IL-6):
On the hypothalamus:
* Stimulation of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH)
* Suppressing appetite
* Fever
On the liver: stimulating the acute phase response, leading to an increase in C-reactive protein and a number of other mediators. It also induces insulin resistance 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 prostaglandin E2 PGE2
On other tissues: increasing insulin resistance.
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.
Pharmacology
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,
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).
See also
Lymphotoxin (Tumor necrosis factor-beta)
Interactions
Tumor necrosis factor-alpha has been shown to
interact with
TNFRSF1A.
References
External links
Category:Cytokines
Category:Immunostimulants
