Tumor necrosis factor
|Tumor necrosis factor|
|Belt model according to PDB 1TNF|
Existing structural data : 1a8m , 1tnf , 2az5 , 2tun , 4tsv , 5tsw
|Properties of human protein|
|Mass / length primary structure||233/157 AS (membrane / soluble)|
|Secondary to quaternary structure||Homotrimer; Membrane shape: single pass type II membrane protein|
|Precursor||233 AS; 25.6 kDa|
|Isoforms||Soluble form from membrane protein by proteolysis|
|Gene names||TNF ; DIF; TNF-alpha; TNFA; TNFSF2|
|Gene locus||Chr 6: 31.58 - 31.58 Mb||Chr 17: 35.2 - 35.2 Mb|
Tumor necrosis factor (short: TNF , or still in common: tumor necrosis factor-α for short: TNF-α , or out of date: cachectin , or scientifically: tumor necrosis factor ligand superfamily member 2 for short TNFSF2 ) is a multifunctional signal substance ( cytokine ) of the immune system , which in local and systemic inflammation is involved. TNF is mainly released by macrophages . Its main function is to regulate the activity of various immune cells. TNF can stimulate cell death ( apoptosis ), cell proliferation , cell differentiation and the release of other cytokines. It triggers a fever and is involved in the development of cachexia in certain diseases. It also has effects on lipid metabolism, coagulation, insulin resistance and endothelial function.
Together with lymphotoxin-α (syn: TNF-β), TNF is one of the longest known representatives of the TNF / TNFR superfamily , a cytokine system that has important functions in the immune response and in the organogenesis of the lymphatic system in particular .
Genetics, education, protein structure
The human gene for TNF was sequenced in 1985; it is encoded on chromosome 6 gene locus p21.3, is approx. 3 kB long and comprises four exons . TNF is initially translated as a 233 amino acid long, 26 kDa type 2 transmembrane protein , which arranges itself in stable homotrimers (groups of three). Of this membrane-bound TNF-preform by proteolytic cleavage by the metalloprotease TNF-α converting enzyme (TACE = T NF α C onverting E nzyme ) the active sTNF-soluble, 51 kDa trimeric released.
TNF is mainly produced and released by macrophages , but also by a large number of other cells such as lymphocytes , mast cells , endothelial cells , heart muscle cells, fibroblasts and neuronal tissue. Large amounts of sTNF are released in response to lipopolysaccharides , other bacterial products, and interleukin-1β . The formation is stimulated via toll-like receptors and the MAP kinase pathway as well as NF-κB .
The soluble tumor necrosis factor sTNF acts on two receptors, which it shares with lymphotoxin-α (TNF-β): 1. TNF-R1 and 2. TNF-R2 . It is believed that most of the TNF activity is mediated via the TNF-R1.
Both receptors activate the nuclear transcription factor NF-κB via TRAF2 and various other intermediate steps (see picture) , which leads to cell activation, cell differentiation, cytokine production and inhibition of programmed cell death ( apoptosis ).
The TNF-R1 can also (in the absence of TRAF2 ) form an intracellular apoptosis-inducing complex that triggers apoptosis by activating specific caspases .
The regulation of all these steps is extremely complex. Overall, TNF is an extremely versatile cytokine with a large number of functions in different contexts. The TNF shares many of its functions with interleukin-1β and interleukin-6 . TNF causes the following in the various organ systems:
- In the hypothalamus :
- Increased release of CRH and stimulation of the hypothalamus-pituitary-adrenal axis.
- Appetite suppression .
- Causing, but also limiting, a fever reaction (there are contradicting data in the literature).
- In the liver : formation of acute phase proteins such as B. the CRP .
- In macrophages : stimulation of phagocytosis . Macrophages infected with Mycobacterium tuberculosis require constant release of TNF in order to lock the bacteria in the phagosome. This latent state of infection can last for decades. When TNF disappears, the disease breaks out.
- TNF promotes migration on neutrophils .
- In all tissues: It leads to increased insulin resistance and an increase in the activity of cyclooxygenase-2 .
A locally increased concentration of TNF leads to the classic symptoms of inflammation: heat, swelling, redness and pain. High systemic TNF concentrations lead to shock symptoms .
The possibilities of using tumor necrosis factors therapeutically are mainly limited by the short half-life of these substances. TNF-α inhibiting drugs are mainly used in rheumatism therapy. Active ingredients are, for example, Etanercept , Infliximab , Adalimumab , Golimumab or Certolizumab .
- Rahman MM, McFadden G: Modulation of tumor necrosis factor by microbial pathogens . In: PLoS Pathog . . 2, No. 2, February 2006, p. E4. doi : 10.1371 / journal.ppat.0020004 . PMID 16518473 . PMC 1383482 (free full text).
- Harris J, Keane J: How tumor necrosis factor blockers interfere with tuberculosis immunity . In: Clin. Exp. Immunol. . 161, No. 1, July 2010, pp. 1-9. doi : 10.1111 / j.1365-2249.2010.04146.x . PMID 20491796 .
- Tumor necrosis factor. In: Online Mendelian Inheritance in Man . (English)
- HSA-7124 in the Kyoto Encyclopedia of Genes and Genomes
- UniProt P01375
- ↑ Hehlgans, T. and pepper, K. (2005): The intriguing biology of the tumor necrosis factor / tumor necrosis factor receptor superfamily: players, rules and the games . Immunology 115: 1-20. PMID 15819693
- ↑ TOLL-like receptor signaling pathway on the Kyoto Encyclopedia of Genes and Genomes (KEGG) .
- ↑ a b Masmudur M. Rahman, Grant McFadden: Modulation of Tumor Necrosis Factor by Microbial Pathogens . In: PLoS Pathogens . tape 2 , no. 2 , 2006, doi : 10.1371 / journal.ppat.0020004 .
- ↑ Flynn JL, Goldstein MM, Chan J, et al. : Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice . In: Immunity . 2, No. 6, June 1995, pp. 561-72. PMID 7540941 .
- ↑ Gardam MA, Keystone EC, Menzies R, et al. : Anti-tumor necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management . In: Lancet Infect Dis . 3, No. 3, March 2003, pp. 148-55. PMID 12614731 .
- ↑ Keane J, Gershon S, Wise RP, et al. : Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent . In: N. Engl. J. Med. . 345, No. 15, October 2001, pp. 1098-104. PMID 11596589 .
- ↑ Mohan AK, Coté TR, Block JA, Manadan AM, Siegel JN, Braun MM: Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor . In: Clin. Infect. Dis. . 39, No. 3, August 2004, pp. 295-9. doi : 10.1086 / 421494 . PMID 15306993 .