Tumor necrosis factor

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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
Identifier
Gene names TNF  ; DIF; TNF-alpha; TNFA; TNFSF2
External IDs
Occurrence
Homology family TNF
Parent taxon Theria
Orthologue
human House mouse
Entrez 7124 21926
Ensemble ENSG00000204490 ENSMUSG00000024401
UniProt P01375 P06804
Refseq (mRNA) NM_000594 NM_001278601
Refseq (protein) NP_000585 NP_001265530
Gene locus Chr 6: 31.58 - 31.58 Mb Chr 17: 35.2 - 35.2 Mb
PubMed search 7124 21926

Tumor necrosis factor (short: TNF , or still in common: tumor necrosis factor-α for short: TNF-α , or out of date: cachectin , or scientifically: tumor necrosis factor ligand superfamily member 2 for short TNFSF2 ) is a multifunctional signal substance ( cytokine ) of the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 .

Functions

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 ).

Tumor necrosis factor receptors 1 and 2 and subsequent signal cascades in the cell. Source .

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:

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 .

pharmacology

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 .

literature

Web links

Individual evidence

  1. ↑ 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
  2. ↑ TOLL-like receptor signaling pathway on the Kyoto Encyclopedia of Genes and Genomes (KEGG) .
  3. ↑ 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 .
  4. ↑ 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 .
  5. ↑ 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 .
  6. ↑ 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 .
  7. ↑ 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 .