Tumor necrosis factor alpha

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tumor necrosis factor
TNFa Crystal Structure.rsh.png
Available structures
PDB Ortholog search: PDBe RCSB
Aliases TNF, DIF, TNF-alpha, TNFA, TNFSF2, Tumour necrosis factor, Tumour necrosis factor alpha, TNF-α
External IDs MGI: 104798 HomoloGene: 496 GeneCards: 7124
RNA expression pattern
PBB GE TNF 207113 s at.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 6: 31.58 – 31.58 Mb Chr 17: 35.2 – 35.2 Mb
PubMed search [1] [2]
View/Edit Human View/Edit Mouse


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,[4] cancer,[5] major depression,[6] Psoriasis[7] and inflammatory bowel disease (IBD).[8] Though controversial, studies of depression and IBD are currently being linked to TNF levels.[9] 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).[10] 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.[11] 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).[12] 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.[13][14]

The cDNAs encoding LT and TNF were cloned in 1984[15] 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.[16] They then identified TNF as a mediator of lethal endotoxin poisoning.[17] 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.[18][19] 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.[20] 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.[21] The 3' UTR of TNFα contains an AU-rich element (ARE).


TNF is primarily produced as a 233-amino acid-long type II transmembrane protein arranged in stable homotrimers.[22][23] 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).[24] 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.[25]

The common house mouse TNFα and human TNF are structurally different.[26] 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]


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


  • Activation of the MAPK pathways: Of the three major MAPK cascades, TNF induces a strong activation of the stress-related JNK group, evokes moderate response of the p38-MAPK, and is responsible for minimal activation of the classical ERKs. TRAF2/Rac activates the JNK-inducing upstream kinases of MLK2/MLK3,[30] TAK1, MEKK1 and ASK1 (either directly or through GCKs and Trx, respectively). SRC- Vav- Rac axis activates MLK2/MLK3 and these kinases phosphorylate MKK7, which then activates JNK. JNK translocates to the nucleus and activates transcription factors such as c-Jun and ATF2. The JNK pathway is involved in cell differentiation, proliferation, and is generally pro-apoptotic.


Enzyme regulation[edit]

This protein may use the morpheein model of allosteric regulation.[32]


TNF was thought to be produced primarily by macrophages,[33] 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.[3] 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).[34]







Main article: TNF inhibition



TNFα has been shown to interact with TNFRSF1A.[39][40]




  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ a b 9218250
  4. ^ 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. 
  6. ^ 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. 
  7. ^ Victor FC, Gottlieb AB (2002). "TNF-alpha and apoptosis: implications for the pathogenesis and treatment of psoriasis". J Drugs Dermatol. 1 (3): 264–75. PMID 12851985. 
  8. ^ 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 1773288free to read. PMID 12077089. 
  9. ^ 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. 
  15. ^ Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV (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. 
  16. ^ Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison J, Ulevitch R, Cerami A (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. 
  17. ^ Beutler B, Milsark IW, Cerami AC (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. 
  18. ^ Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey TJ, Zentella A, Albert JD (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. 
  19. ^ Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A (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. 
  20. ^ Old LJ (1985). "Tumor necrosis factor (TNF)". Science. 230 (4726): 630–2. Bibcode:1985Sci...230..630O. doi:10.1126/science.2413547. PMID 2413547. 
  23. ^ Tang P, Klostergaard J (1996). "Human pro-tumor necrosis factor is a homotrimer". Biochemistry. 35 (25): 8216–25. doi:10.1021/bi952182t. PMID 8679576. 
  25. ^ 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:2003Natur.002..736B. doi:10.1038/nrd1175. PMID 12951580. 
  30. ^ 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 3197205free to read. PMID 21979919. 
  34. ^ Walsh LJ, Trinchieri G, Waldorf HA, Whitaker D, Murphy GF (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 51630free to read. PMID 1709737. 
  35. ^ Feng P, Jyotaki M, Kim A, Chai J, Simon N, Zhou M, Bachmanov AA, Huang L, Wang H (October 2015). "Regulation of bitter taste responses by tumor necrosis factor". Brain, Behavior, and Immunity. 49: 32–42. doi:10.1016/j.bbi.2015.04.001. PMID 25911043. 

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