Tumor necrosis factor-alpha

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Crystal structure of TNFA
Tumor Necrosis Factor
Identifiers
Symbol	TNF TNFA
HUGO	11892
Entrez	7124
OMIM	191160
RefSeq	NM_000594
UniProt	P01375
PDB	1TNF
Other data
Locus	Chr. 6 p21.3

Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that all stimulate the acute phase reaction. TNF causes apoptotic cell death, cellular proliferation, differentiation, inflammation, tumorigenesis, and viral replication.

TNF's primary role is in the regulation of immune cells.

Dysregulation and, in particular, overproduction of TNF have been implicated in a variety of human diseases, as well as cancer. ^[1]

Contents 1 History and nomenclature 2 Gene 3 Structure 4 Physiology 5 Pharmacology 6 References 7 External links

[edit] History and nomenclature

TNF was isolated as a soluble factor released by host cells that caused necrosis of a transplanted tumor, "sarcoma Meth A".^[2] Although TNFα does cause the necrosis of some tumors, it may stimulate the growth of others. In that sense, the name is somewhat of a misnomer.

In 1984, the cDNA of TNF was cloned, the structural and functional homology to lymphotoxin (LT) was realized, and several years later, two membrane receptors, each capable of binding both cytokines, were identified. Subsequently, it was recognized that TNF is the prototypic member of a large cytokine family, the TNF family.

[edit] Gene

The human TNF gene (TNFA) was cloned in 1985.^[3] It maps to chromosome 6p21.3, spans about 3 kb and contains 4 exons. The last exon codes for more than 80% of the secreted protein.^[4] The 3' UTR of TNF alpha contains an ARE.

[edit] Structure

TNF is primarily produced as a 212 amino acid-long type II transmembrane protein arranged in stable homotrimers.^{[5] [6]} From this membrane-integrated form the soluble homotrimeric cytokine (sTNF) is released via proteolytic cleavage by the metalloprotease TNF alpha converting enzyme (TACE).^[7] The soluble 51 kDa trimeric sTNF tends to dissociate at concentrations below the nanomolar range, thereby losing its bioactivity.

The 17 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.

[edit] Physiology

TNF is mainly produced by macrophages, but also by a broad variety of other cell types including lymphoid cells, mast cells, endothelial cells, fibroblasts and neuronal tissue. Large amounts of sTNF are released in response to lipopolysaccharide, other bacterial products, IL1.

It has a number of actions on various organ systems, generally together with IL1 and IL6:

• On the hypothalamus:
  • Stimulating 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 signalling.
• It attracts neutrophils very potently, and helps them to stick to the endothelial cells for migration.
• On macrophages: stimulates phagocytosis, and production of IL1 oxidants and the inflammatory lipid prostaglandin E2 PGE₂.
• On other tissues: increasing insulin resistance.

A locally increasing concentration of TNF will cause the cardinal signs of Inflammation to occur: Heat, swelling, redness and pain.

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 tumor patients.

[edit] Pharmacology

TNF 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 and refractory asthma. These disorders are sometimes treated by inhibiting TNF with a monoclonal antibody such as infliximab (Remicade) or adalimumab (Humira), or with a circulating receptor fusion protein such as etanercept (Enbrel). Clinical trials regarding the effectiveness of these drugs on hidradenitis suppurativa are currently ongoing. A fourth anti-TNF biologic, certolizumab pegol, is expected to receive approval for human use in the near future.

Active tuberculosis may develop soon after the initiation of treatment with infliximab.^[8] Before prescribing the drug, physicians should screen patients for latent tuberculosis infection or disease. The anti-TNF monoclonal antibody biologics, Infliximab and adalimumab, and the fusion protein etanercept which are all currently FDA approved for human use, have label warnings which state that patients should be evaluated for latent TB infection and treatment should be initiated prior to starting therapy with these medications.

TNF or the effects of TNF are also inhibited by a number of natural compounds, including curcumin ^{[9] [10] [11] [12]} (an ingredient in turmeric) and catechins (in green tea).

[edit] References

[edit] External links

• MeSH Tumor+Necrosis+Factor-alpha