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Tumor necrosis factor (TNF superfamily, member 2)

PDB rendering based on 1TNF.
Available structures
1a8m, 1tnf, 2az5, 2tun, 4tsv, 5tsw
Identifiers
Symbols TNF; DIF; TNF-alpha; TNFA; TNFSF2
External IDs OMIM191160 MGI104798 HomoloGene496 GeneCards: TNF Gene
RNA expression pattern
PBB GE TNF 207113 s at.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7124 21926
Ensembl ENSG00000204490 ENSMUSG00000024401
UniProt P01375 Q0X0E6
RefSeq (mRNA) NM_000594 NM_013693
RefSeq (protein) NP_000585 NP_038721
Location (UCSC) Chr 6:
31.65 - 31.65 Mb
Chr 17:
34.81 - 34.81 Mb
PubMed search [1] [2]

Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction.

The primary role of TNF is in the regulation of immune cells. TNF is also able to induce apoptotic cell death, to induce inflammation, and to inhibit tumorigenesis and viral replication. Dysregulation of TNF production has been implicated in a variety of human diseases, as well as cancer.[1] Recombinant TNF is used as an immunostimulant under the INN tasonermin.

Contents

Discovery

The theory of an anti-tumoral response of the immune system in vivo was recognized 100 years ago 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).[2] 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 and year.[3] 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).[4] Both factors were described based on their ability to kill mouse fibrosarcoma L-929 cells.

When the cDNAs encoding LT and TNF were cloned in 1984,[5] they 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 and LT as TNFβ. In 1985, Bruce A. Beutler and Anthony Cerami discovered that a hormone that induces cachexia and previously-named cachectin was actually TNF.[6] These investigators then identified TNF as the key mediator of septic shock in response to infection.[7] Subsequently, it was recognized that TNF is the prototypic member of a large cytokine family, the TNF family.

Gene

The human TNF gene (TNFA) was cloned in 1985.[8] It maps to chromosome 6p21.3, spans about 3 kb and contains 4 exons. The last exon codes for more than 80% of the secreted protein.[9] The 3' UTR of TNF alpha contains an AU-rich element (ARE).

Structure

TNF is primarily produced as a 212-amino acid-long type II transmembrane protein arranged in stable homotrimers.[10][11] 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).[12] The soluble 51 kDa trimeric sTNF tends to dissociate at concentrations below the nanomolar range, thereby losing its bioactivity.

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

Two receptors, TNF-R1 (TNF receptor type 1; CD120a; p55/60) and TNF-R2 (TNF receptor type 2; CD120b; p75/80), bind to TNF. TNF-R1 is expressed in most tissues, and can be fully activated by both the membrane-bound and soluble trimeric forms of TNF, whereas TNF-R2 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 TNF-R1, the role of TNF-R2 is likely underestimated.

Signaling pathway of TNF-R1. Dashed grey lines represent multiple steps.

Upon contact with their ligand, TNF receptors also form trimers, their tips fitting into the grooves formed between TNF monomers. This binding causes a conformational change to occur in the receptor, leading to the dissociation of the inhibitory protein SODD from the intracellular death domain. This dissociation enables the adaptor protein TRADD to bind to the death domain, serving as a platform for subsequent protein binding. Following TRADD binding, three pathways can be initiated.[13][14]

  • Activation of NF-kB: TRADD recruits TRAF2 and RIP. TRAF2 in turn recruits the multicomponent protein kinase IKK, enabling the serine-threonine kinase RIP to activate it. An inhibitory protein, IκBα, that normally binds to NF-κB and inhibits its translocation, is phosphorylated by IKK and subsequently degraded, releasing NF-κB. NF-κB is a heterodimeric transcription factor that translocates to the nucleus and mediates the transcription of a vast array of proteins involved in cell survival and proliferation, inflammatory response, and anti-apoptotic factors.
  • Induction of death signaling: Like all death-domain-containing members of the TNFR superfamily, TNF-R1 is involved in death signaling.[15] However, TNF-induced cell death plays only a minor role compared to its overwhelming functions in the inflammatory process. Its death-inducing capability is weak compared to other family members (such as Fas), and often masked by the anti-apoptotic effects of NF-κB. Nevertheless, TRADD binds FADD, which then recruits the cysteine protease caspase-8. A high concentration of caspase-8 induces its autoproteolytic activation and subsequent cleaving of effector caspases, leading to cell apoptosis.

The myriad and often-conflicting effects mediated by the above pathways indicate the existence of extensive cross-talk. For instance, NF-κB enhances the transcription of C-FLIP, Bcl-2, and cIAP1 / cIAP2, inhibitory proteins that interfere with death signaling. On the other hand, activated caspases cleave several components of the NF-κB pathway, including RIP, IKK, and the subunits of NF-κB itself. Other factors, such as cell type, concurrent stimulation of other cytokines, or the amount of reactive oxygen species (ROS) can shift the balance in favor of one pathway or another. Such complicated signaling ensures that, whenever TNF is released, various cells with vastly diverse functions and conditions can all respond appropriately to inflammation.

Physiology

TNF is produced mainly by macrophages, but they are produced also by a broad variety of other cell types including lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts, and neuronal tissue. Large amounts of TNF are released in response to lipopolysaccharide, other bacterial products, and Interleukin-1 (IL-1).

It has a number of actions on various organ systems, generally together with IL-1 and Interleukin-6 (IL-6):

A local increase in concentration of TNF will cause the cardinal signs of Inflammation to occur: heat, swelling, redness, and pain.

Whereas high concentrations of TNF induce shock-like symptoms, the prolonged exposure to low concentrations of TNF can result in cachexia, a wasting syndrome. This can be found, for example, in cancer patients.

Pharmacology

Tumor necrosis factor 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 using a TNF inhibitor. This inhibition can be achieved with a monoclonal antibody such as infliximab (Remicade) or adalimumab (Humira), or with a circulating receptor fusion protein such as etanercept (Enbrel).

See also

Interactions

Tumor necrosis factor-alpha has been shown to interact with TNFRSF1A.[16][17]

References

  1. ^ 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.  
  2. ^ Kolb WP, Granger GA (1968). "Lymphocyte in vitro cytotoxicity: characterization of human lymphotoxin". Proc. Natl. Acad. Sci. U.S.A. 61 (4): 1250–5. doi:10.1073/pnas.61.4.1250. PMID 5249808.  
  3. ^ Ruddle NH, Waksman BH (December 1968). "Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. 3. Analysis of mechanism". J. Exp. Med. 128 (6): 1267–79. doi:10.1084/jem.128.6.1267. PMID 5693925.  
  4. ^ Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975). "An endotoxin-induced serum factor that causes necrosis of tumors". Proc. Natl. Acad. Sci. U.S.A. 72 (9): 3666–70. doi:10.1073/pnas.72.9.3666. PMID 1103152.  
  5. ^ 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. doi:10.1038/312724a0. PMID 6392892.  
  6. ^ 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. doi:10.1038/316552a0. PMID 2993897.  
  7. ^ Beutler B, Milsark IW, Cerami AC (August 1985). "Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin". Science (journal) 229 (4716): 869–71. doi:10.1126/science.3895437. PMID 3895437.  
  8. ^ Old LJ (1985). "Tumor necrosis factor (TNF)". Science 230 (4726): 630–2. doi:10.1126/science.2413547. PMID 2413547.  
  9. ^ Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW (1985). "Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization". Nucleic Acids Res. 13 (17): 6361–73. doi:10.1093/nar/13.17.6361. PMID 2995927. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=321958&blobtype=pdf.  
  10. ^ 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.  
  11. ^ 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.  
  12. ^ 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 (1997). "A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells". Nature 385 (6618): 729–33. doi:10.1038/385729a0. PMID 9034190.  
  13. ^ Wajant H, Pfizenmaier K, Scheurich P (2003). "Tumor necrosis factor signaling". Cell Death Differ. 10 (1): 45–65. doi:10.1038/sj.cdd.4401189. PMID 12655295.  
  14. ^ Chen G, Goeddel DV (2002). "TNF-R1 signaling: a beautiful pathway". Science 296 (5573): 1634–5. doi:10.1126/science.1071924. PMID 12040173.  
  15. ^ Gaur U, Aggarwal BB (2003). "Regulation of proliferation, survival and apoptosis by members of the TNF superfamily". Biochem. Pharmacol. 66 (8): 1403–8. doi:10.1016/S0006-2952(03)00490-8. PMID 14555214.  
  16. ^ Bouwmeester, Tewis; Bauch Angela, Ruffner Heinz, Angrand Pierre-Olivier, Bergamini Giovanna, Croughton Karen, Cruciat Cristina, Eberhard Dirk, Gagneur Julien, Ghidelli Sonja, Hopf Carsten, Huhse Bettina, Mangano Raffaella, Michon Anne-Marie, Schirle Markus, Schlegl Judith, Schwab Markus, Stein Martin A, Bauer Andreas, Casari Georg, Drewes Gerard, Gavin Anne-Claude, Jackson David B, Joberty Gerard, Neubauer Gitte, Rick Jens, Kuster Bernhard, Superti-Furga Giulio (Feb. 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. (England) 6 (2): 97–105. doi:10.1038/ncb1086. ISSN 1465-7392. PMID 14755267.  
  17. ^ Micheau, Olivier; Tschopp Jürg (Jul. 2003). "Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes". Cell (United States) 114 (2): 181–90. ISSN 0092-8674. PMID 12887914.  

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