Tumor necrosis factor alpha

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Tumor necrosis factor
TNFa Crystal Structure.rsh.png
PDB rendering based on 1TNF.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols TNF ; DIF; TNF-alpha; TNFA; TNFSF2
External IDs OMIM191160 MGI104798 HomoloGene496 ChEMBL: 1825 GeneCards: TNF Gene
RNA expression pattern
PBB GE TNF 207113 s at.png
More reference expression data
Species Human Mouse
Entrez 7124 21926
Ensembl ENSG00000204490 ENSMUSG00000024401
UniProt P01375 P06804
RefSeq (mRNA) NM_000594 NM_001278601
RefSeq (protein) NP_000585 NP_001265530
Location (UCSC) Chr 6:
31.54 – 31.55 Mb
Chr 17:
35.2 – 35.2 Mb
PubMed search [1] [2]

Tumor necrosis factor (TNF, cachexin, or cachectin, and formerly known as tumor necrosis factor alpha or TNFα) is an adipokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction. It is produced chiefly by activated macrophages, although it can be produced by many other cell types such as CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons.[1]

The primary role of TNF is in the regulation of immune cells. TNF, being an endogenous pyrogen, is able to induce fever, apoptotic cell death, cachexia, inflammation and to inhibit tumorigenesis and viral replication and respond to sepsis via IL1 & IL6 producing cells. Dysregulation of TNF production has been implicated in a variety of human diseases including Alzheimer's disease,[2] cancer,[3] major depression[4] and inflammatory bowel disease (IBD).[5] While still controversial, studies of depression and IBD are currently being linked to TNF levels.[6] Recombinant TNF is used as an immunostimulant under the INN tasonermin. TNF 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.


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).[7] 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.[8] 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).[9] Both factors were described based on their ability to kill mouse fibrosarcoma L-929 cells. These concepts were extended to systemic disease in 1981, when Ian A. Clark, from the Australian National University, in collaboration with Elizabeth Carswell in Dr Old's group, working with pre-sequencing era data, reasoned that excessive production of TNF causes malaria disease and endotoxin poisoning.[10][11]

The cDNAs encoding LT and TNF were cloned in 1984[12] and 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 (this article) and LT as TNFβ. In 1985, Bruce A. Beutler and Anthony Cerami discovered that cachectin (a hormone which induces cachexia) was actually TNF.[13] They then identified TNF as a mediator of lethal endotoxin poisoning.[14] 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.[15][16] More recently, research in the Laboratory of Mark Mattson has shown that TNF can prevent the death/apoptosis of neurons by a mechanism involving activation of the transcription factor NF-kappaB which induces the expression of Mn-SOD and Bcl-2.


The human TNF gene (TNFA) was cloned in 1985.[17] 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.[18] The 3' UTR of TNFα contains an AU-rich element (ARE).


TNF is primarily produced as a 212-amino acid-long type II transmembrane protein arranged in stable homotrimers.[19][20] 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).[21] The soluble 51 kDa trimeric sTNF tends to dissociate at concentrations below the nanomolar range, thereby losing its bioactivity. The secreted form of human TNFα takes on a triangular pyramid shape, and weighs around 17-kD. Both the secreted and the membrane bound forms are biologically active, although the specific functions of each is controversial. But, both forms do have overlapping and distinct biology activities.[22]

The common house mouse TNFα and human TNF are structurally different.[23] 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[edit]

TNF can bind two receptors, TNFR1 (TNF receptor type 1; CD120a; p55/60) and TNFR2 (TNF receptor type 2; CD120b; p75/80). TNFR1 is 55-kDa and TNFR2 is 75-kDa.[24] TNFR1 is expressed in most tissues, and can be fully activated by both the membrane-bound and soluble trimeric forms of TNF, whereas TNFR2 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 TNFR1, the role of TNFR2 is likely underestimated.

Signaling pathway of TNFR1. Dashed grey lines represent multiple steps.




Enzyme regulation[edit]

This protein may use the morpheein model of allosteric regulation.[29]


TNF was thought to be produced primarily by macrophages,[30] 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 neurons.[1] 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).[31]







Main article: TNF inhibition

TNF 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).


TNFα has been shown to interact with TNFRSF1A.[35][36]




  1. ^ a b 9218250
  2. ^ Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010). "A meta-analysis of cytokines in Alzheimer's disease". Biol Psychiatry 68 (10): 930–941. doi:10.1016/j.biopsych.2010.06.012. PMID 20692646. 
  3. ^ Locksley RM, Killeen N, Lenardo MJ (2001). "The TNF and TNF receptor superfamilies: integrating mammalian biology". Cell 104 (4): 487–501. doi:10.1016/S0092-8674(01)00237-9. PMID 11239407. 
  4. ^ Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL (2010). "A meta-analysis of cytokines in major depression". Biol Psychiatry 67 (5): 446–457. doi:10.1016/j.biopsych.2009.09.033. PMID 20015486. 
  5. ^ Brynskov J, Foegh P, Pedersen G, Ellervik C, Kirkegaard T, Bingham A, Saermark T (2002). "Tumour necrosis factor alpha converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease". Gut 51 (1): 37–43. doi:10.1136/gut.51.1.37. PMC 1773288. PMID 12077089. 
  6. ^ Mikocka-Walus AA, Turnbull DA, Moulding NT, Wilson IG, Andrews JM, Holtmann GJ (2007). "Controversies surrounding the comorbidity of depression and anxiety in inflammatory bowel disease patients: a literature review". Inflammatory Bowel Diseases 13 (2): 225–234. doi:10.1002/ibd.20062. PMID 17206706. 
  7. ^ Kolb WP, Granger GA; Granger (1968). "Lymphocyte in vitro cytotoxicity: characterization of human lymphotoxin". Proc. Natl. Acad. Sci. U.S.A. 61 (4): 1250–5. Bibcode:1968PNAS...61.1250K. doi:10.1073/pnas.61.4.1250. PMC 225248. PMID 5249808. 
  9. ^ Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B; Old; Kassel; Green; Fiore; Williamson (1975). "An endotoxin-induced serum factor that causes necrosis of tumors". Proc. Natl. Acad. Sci. U.S.A. 72 (9): 3666–70. Bibcode:1975PNAS...72.3666C. doi:10.1073/pnas.72.9.3666. PMC 433057. PMID 1103152. 
  12. ^ Pennica, D.; Nedwin, G.E.; Hayflick, J.S.; Seeburg, P.H.; Derynck, R.; Palladino, M.A.; Kohr, W.J.; Aggarwal; Goeddel (1984). "Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin". Nature 312 (5996): 724–9. Bibcode:1984Natur.312..724P. doi:10.1038/312724a0. PMID 6392892. 
  13. ^ Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison J, Ulevitch R, Cerami A; Greenwald; Hulmes; Chang; Pan; Mathison; Ulevitch; Cerami (1985). "Identity of tumour necrosis factor and the macrophage-secreted factor cachectin". Nature 316 (6028): 552–4. Bibcode:1985Natur.316..552B. doi:10.1038/316552a0. PMID 2993897. 
  14. ^ Beutler B, Milsark IW, Cerami AC; Milsark; Cerami (August 1985). "Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin". Science 229 (4716): 869–71. Bibcode:1985Sci...229..869B. doi:10.1126/science.3895437. PMID 3895437. 
  15. ^ Tracey KJ, et al.; Beutler, B; Lowry, S.; Merryweather, J; Wolpe, S; Milsark, I.; Hariri, R.; Fahey, T. et al. (October 1986). "Shock and tissue injury induced by recombinant human cachectin". Science 234 (4775): 470–74. Bibcode:1986Sci...234..470T. doi:10.1126/science.3764421. PMID 3764421. 
  16. ^ Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A; Fong; Hesse; Manogue; Lee; Kuo; Lowry; Cerami (December 1987). "Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia". Nature 330 (6149): 662–64. Bibcode:1987Natur.330..662T. doi:10.1038/330662a0. PMID 3317066. 
  17. ^ Old LJ (1985). "Tumor necrosis factor (TNF)". Science 230 (4726): 630–2. Bibcode:1985Sci...230..630O. doi:10.1126/science.2413547. PMID 2413547. 
  19. ^ Kriegler M, Perez C, DeFay K, Albert I, Lu SD (1988). "A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF". Cell 53 (1): 45–53. doi:10.1016/0092-8674(88)90486-2. PMID 3349526. 
  20. ^ Tang P, Hung M-C, Klostergaard J (1996). "Human pro-tumor necrosis factor is a homotrimer". Biochemistry 35 (25): 8216–25. doi:10.1021/bi952182t. PMID 8679576. 
  21. ^ Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP; Rauch; Kozlosky; Peschon; Slack; Wolfson; Castner; Stocking; Reddy; Srinivasan; Nelson; Boiani; Schooley; Gerhart; Davis; Fitzner; Johnson; Paxton; March; Cerretti (1997). "A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells". Nature 385 (6618): 729–33. Bibcode:1997Natur.385..729B. doi:10.1038/385729a0. PMID 9034190. 
  22. ^ Palladino MA, Bahjat FR, Theodorakis EA, Moldawer LL (September 2003). "Anti-TNF-α therapies: the next generation". Nature Reviews Drug Discovery 2 (9): 736–46. Bibcode:203Natur.002..736B. doi:10.1038/nrd1175. PMID 12951580. 
  24. ^ Theiss. A. L. et al. 2005. Tumor necrosis factor (TNF) alpha increases collagen accuulation and proliferation in intestinal myofibrobasts via TNF Recptor 2. The Journal of Biological Chemistry. [Online] 2005. Available at: http://www.jbc.org/content/280/43/36099.long Accessed: 21/10/14
  26. ^ Chen G, Goeddel DV; Goeddel (2002). "TNF-R1 signaling: a beautiful pathway". Science 296 (5573): 1634–5. Bibcode:2002Sci...296.1634C. doi:10.1126/science.1071924. PMID 12040173. 
  27. ^ Kant S, Swat W, Zhang S, Zhang ZY, Neel BG, Flavell RA, Davis RJ (2011). "TNF-stimulated MAP kinase activation mediated by a Rho family GTPase signaling pathway". Genes Dev 25 (19): 2069–78. doi:10.1101/gad.17224711. PMC 3197205. PMID 21979919. 
  29. ^ T. Selwood and E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function". Arch. Biochem. Biophys. 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMC 3298769. PMID 22182754. 
  31. ^ Walsh LJ, Trinchieri G, Waldorf HA, Whitaker D, Murphy GF; Trinchieri; Waldorf; Whitaker; Murphy (May 1991). "Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1". Proc. Natl. Acad. Sci. U.S.A. 88 (10): 4220–4. Bibcode:1991PNAS...88.4220W. doi:10.1073/pnas.88.10.4220. PMC 51630. PMID 1709737. 
  36. ^ Micheau O, Tschopp J (July 2003). "Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes". Cell 114 (2): 181–90. doi:10.1016/S0092-8674(03)00521-X. PMID 12887920. 

External links[edit]