Tumor necrosis factor
From Wikipedia, the free encyclopedia
- For "tumor necrosis factor-beta", see lymphotoxin.
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| Crystal structure of tumor necrosis factor alpha | |
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tumor necrosis factor
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| Identifiers | |
| Symbol(s) | TNF TNFA |
| Entrez | 7124 |
| OMIM | 191160 |
| RefSeq | NM_000594 |
| UniProt | P01375 |
| PDB | 1TNF |
| Other data | |
| Locus | Chr. 6 p21.3 |
In medicine, tumor necrosis factor alpha (TNFα, cachexin or cachectin) is an important cytokine involved in systemic inflammation and the acute phase response.
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[edit] History and nomenclature
TNFα was isolated in 1975 by Carswell et al as a soluble factor released by host cells that caused necrosis of a transplanted tumor, "sarcoma Meth A". 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.
[edit] Structure
TNFα is a member of a group of other cytokines that all stimulate the acute phase reaction. It is a 185 amino acid glycoprotein peptide hormone, cleaved from a 212 amino acid-long propeptide on the surface of macrophages. Some cells secrete shorter or longer isoforms. Genetically it maps to chromosome 6p21.3 in humans.
[edit] Physiology
TNFα is released by white blood cells, endothelium and several other tissues in the course of damage, e.g. by infection. Its release is stimulated by several other mediators, such as interleukin 1 and bacterial endotoxin. It has a number of actions on various organ systems, generally together with interleukins 1 and 6:
- On the hypothalamus:
- Stimulating of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH).
- Suppressing appetite (hence its name "cachexin" - cachexia is severe weight loss in illness).
- Fever.
- On the liver: stimulating the acute phase response, leading to an increase in C-reactive protein and a number of other mediators.
- It attracts neutrophils very potently, and helps them to stick to the endothelial cells for migration.
- On macrophages: stimulates phagocytosis, and production of IL-1 oxidants and the inflammatory lipid prostaglandin E2 (PGE2).
- On other tissues: increasing insulin resistance.
A locally increasing concentration of TNFα will cause the cardinal signs of Inflammation to occur: Heat, swelling, redness and pain.
[edit] Pharmacology
TNFα 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 TNFα 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. 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 (2,3,4,5) (an ingredient in turmeric) and catechins (in green tea).
[edit] References
- (1) Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 1975;72:3666-70. PMID 1103152.
- (2) Crit Care Med. 2006 Jul;34(7):1874-82.
- (3) Int J Radiat Oncol Biol Phys. 2006 Jul 1;65(3):890-8
- (4) J Vet Med A Physiol Pathol Clin Med. 2006 Feb;53(1):49-54.
- (5) Phytomedicine. 2005 Jun;12(6-7):445-52
- (6) Tuberculosis Associated with Infliximab, a Tumor Necrosis Factor {alpha}–Neutralizing Agent
Keane J., Gershon S., Wise R. P., Mirabile-Levens E., Kasznica J., Schwieterman W. D., Siegel J. N., Braun M. M. N Engl J Med 2001; 345:1098-1104, Oct 11, 2001.
