View source for Tumor necrosis factor-alpha

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{{GNF_Protein_box
 | image = TNFa_Crystal_Structure.rsh.png
 | image_source = [[Protein_Data_Bank|PDB]] rendering based on 1TNF.
 | Name = Tumor necrosis factor (TNF superfamily, member 2)
 | HGNCid = 11892
 | Symbol = TNF
 | AltSymbols =; DIF; TNF-alpha; TNFA; TNFSF2
 | OMIM = 191160
 | ECnumber =  
 | Homologene = 496
 | MGIid = 104798
 | GeneAtlas_image1 = PBB_GE_TNF_207113_s_at.png
 <!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
 | DateOfBotUpdate = 00:29, 15 September 2007 (UTC)
 | Function = {{GNF_GO|id=GO:0005125 |text = cytokine activity}} {{GNF_GO|id=GO:0005164 |text = tumor necrosis factor receptor binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} 
 | Component = {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0005625 |text = soluble fraction}} {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}} 
 | Process = {{GNF_GO|id=GO:0000060 |text = protein import into nucleus, translocation}} {{GNF_GO|id=GO:0000122 |text = negative regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0001932 |text = regulation of protein amino acid phosphorylation}} {{GNF_GO|id=GO:0006006 |text = glucose metabolic process}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006915 |text = apoptosis}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006959 |text = humoral immune response}} {{GNF_GO|id=GO:0007159 |text = leukocyte adhesion}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0008625 |text = induction of apoptosis via death domain receptors}} {{GNF_GO|id=GO:0009615 |text = response to virus}} {{GNF_GO|id=GO:0009887 |text = organ morphogenesis}} {{GNF_GO|id=GO:0042127 |text = regulation of cell proliferation}} {{GNF_GO|id=GO:0042742 |text = defense response to bacterium}} {{GNF_GO|id=GO:0043123 |text = positive regulation of I-kappaB kinase/NF-kappaB cascade}} {{GNF_GO|id=GO:0045123 |text = cellular extravasation}} {{GNF_GO|id=GO:0045670 |text = regulation of osteoclast differentiation}} {{GNF_GO|id=GO:0045941 |text = positive regulation of transcription}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0045994 |text = positive regulation of translational initiation by iron}} {{GNF_GO|id=GO:0046325 |text = negative regulation of glucose import}} {{GNF_GO|id=GO:0046330 |text = positive regulation of JNK cascade}} {{GNF_GO|id=GO:0051023 |text = regulation of immunoglobulin secretion}} {{GNF_GO|id=GO:0051092 |text = activation of NF-kappaB transcription factor}} 
 | Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 7124
    | Hs_Ensembl = ENSG00000204490
    | Hs_RefseqProtein = NP_000585
    | Hs_RefseqmRNA = NM_000594
    | Hs_GenLoc_db =  
    | Hs_GenLoc_chr = 6
    | Hs_GenLoc_start = 31651314
    | Hs_GenLoc_end = 31654092
    | Hs_Uniprot = P01375
    | Mm_EntrezGene = 21926
    | Mm_Ensembl = ENSMUSG00000024401
    | Mm_RefseqmRNA = NM_013693
    | Mm_RefseqProtein = NP_038721
    | Mm_GenLoc_db =  
    | Mm_GenLoc_chr = 17
    | Mm_GenLoc_start = 34807442
    | Mm_GenLoc_end = 34810048
    | Mm_Uniprot = Q0X0E6
  }}
}}
{{CMG}}



==Overview==
'''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 all stimulate the [[acute phase reaction]]. 

TNF causes [[apoptosis|apoptotic]] cell death, cellular proliferation, differentiation, [[inflammation]], [[tumorigenesis]], and [[viral replication]].

TNF's primary role is in the regulation of [[immune cells]].

Dysregulation and, in particular, overproduction of TNF have been implicated in a variety of human [[disease|diseases]], as well as [[cancer]].<ref name="pmid11239407">{{cite journal | author = Locksley RM, Killeen N, Lenardo MJ | title = The TNF and TNF receptor superfamilies: integrating mammalian biology | journal = Cell | volume = 104 | issue = 4 | pages = 487–501 | year = 2001 | pmid = 11239407 | doi = 10.1016/S0092-8674(01)00237-9 | issn = }}</ref>

==History and nomenclature==
The theory of an [[anti-tumor]]al 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).<ref name="pmid5249808">{{cite journal | author = Kolb WP, Granger GA | title = Lymphocyte in vitro cytotoxicity: characterization of human lymphotoxin | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 61 | issue = 4 | pages = 1250–5 | year = 1968 | pmid = 5249808 | doi = 10.1073/pnas.61.4.1250 | issn = }}</ref> Subsequently in 1975 Dr. Lloyd Old from [[Memorial Sloan-Kettering Cancer Center]], New York, reported another cytotoxic factor produced by [[macrophages]], and named it tumor necrosis factor (TNF).<ref name="pmid1103152">{{cite journal | author = Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B | title = An endotoxin-induced serum factor that causes necrosis of tumors | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 72 | issue = 9 | pages = 3666–70 | year = 1975 | pmid = 1103152 | doi = 10.1073/pnas.72.9.3666 | issn = }}</ref> Both factors were described based on their ability to kill mouse [[fibrosarcoma]] L-929 cells.

When the [[cDNA]]s encoding LT and TNF were [[Clone (genetics)|cloned]] in 1984,<ref name="pmid6392892">{{cite journal | author = Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV | title = Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin | journal = Nature | volume = 312 | issue = 5996 | pages = 724–9 | year = 1984 | pmid = 6392892 | doi = 10.1038/312724a0 | issn = }}</ref> 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.<ref name="pmid2993897">{{cite journal | author = Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison J, Ulevitch R, Cerami A | title = Identity of tumour necrosis factor and the macrophage-secreted factor cachectin | journal = Nature | volume = 316 | issue = 6028 | pages = 552–4 | year = 1985 | pmid = 2993897 | doi = 10.1038/316552a0 | issn = }}</ref> These investigators then identified TNF as the key mediator of [[septic shock]] in response to infection. <ref> B Beutler, IW Milsark, and AC Cerami "Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin" http://www.sciencemag.org/cgi/content/abstract/229/4716/869].</ref> 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.<ref name="pmid2413547">{{cite journal | author = Old LJ | title = Tumor necrosis factor (TNF) | journal = Science | volume = 230 | issue = 4726 | pages = 630–2 | year = 1985 | pmid = 2413547 | doi = 10.1126/science.2413547 | issn = }}</ref> It maps to [[chromosome]] 6p21.3, spans about 3 kb and contains 4 [[exon]]s. The last exon codes for more than 80% of the secreted protein.<ref name="pmid2995927">{{cite journal | author = Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW | title = Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization | journal = Nucleic Acids Res. | volume = 13 | issue = 17 | pages = 6361–73 | year = 1985 | pmid = 2995927 | doi = 10.1093/nar/13.17.6361 | issn = | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=321958&blobtype=pdf}}</ref> The 3' UTR of TNF alpha contains an [[ARE (biochemistry)|ARE]].

== Structure ==
TNF is primarily produced as a 212 [[amino acid]]-long [[transmembrane protein|type II transmembrane protein]] arranged in stable homotrimers.<ref name="pmid3349526">{{cite journal | author = Kriegler M, Perez C, DeFay K, Albert I, Lu SD | title = A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF | journal = Cell | volume = 53 | issue = 1 | pages = 45–53 | year = 1988 | pmid = 3349526 | doi = 10.1016/0092-8674(88)90486-2 | issn = }}</ref><ref name="pmid8679576">{{cite journal | author = Tang P, Hung M-C, Klostergaard J | title = Human pro-tumor necrosis factor is a homotrimer | journal = Biochemistry | volume = 35 | issue = 25 | pages = 8216–25 | year = 1996 | pmid = 8679576 | doi = 10.1021/bi952182t | issn = }}</ref> 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]]).<ref name="pmid9034190">{{cite journal | author = 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 | title = A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells | journal = Nature | volume = 385 | issue = 6618 | pages = 729–33 | year = 1997 | pmid = 9034190 | doi = 10.1038/385729a0 | issn = }}</ref> 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 [[Beta sheet|antiparallel &beta;-pleated sheet]]s with [[Beta sheet|antiparallel &beta;-strand]]s, forming a 'jelly roll' &beta;-structure, typical for the TNF family, but also found in [[viral capsid|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 constitutively expressed in most tissues, and can be fully activated by both the membrane-bound and soluble trimeric forms of TNF, while TNF-R2 is only found 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.

[[Image:TNF signaling.jpg|thumbnail|right|400px|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.<ref name="pmid12655295">{{cite journal | author = Wajant H, Pfizenmaier K, Scheurich P | title = Tumor necrosis factor signaling | journal = Cell Death Differ. | volume = 10 | issue = 1 | pages = 45–65 | year = 2003 | pmid = 12655295 | doi = 10.1038/sj.cdd.4401189 | issn = }}</ref><ref name="pmid12040173">{{cite journal | author = Chen G, Goeddel DV | title = TNF-R1 signaling: a beautiful pathway | journal = Science | volume = 296 | issue = 5573 | pages = 1634–5 | year = 2002 | pmid = 12040173 | doi = 10.1126/science.1071924 | issn = }}</ref>

*'''Activation of [[NF-kB]]:'''  TRADD recruits [[TRAF2]] and RIP. [[TRAF]]2 in turn recruits the multicomponent protein [[kinase]] [[IκB 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 [[Cell nucleus|nucleus]] and mediates the transcription of a vast array of proteins involved in cell survival and proliferation, [[inflammatory response]], and anti-[[apoptotic]] factors.

*'''Activation of the [[MAPK]] pathways:'''  Of the three major [[MAPK]] cascades, TNF induces a strong activation of the [[Stress (medicine)|stress]]-related [[JNK]] group, evokes moderate response of the [[p38]]-[[MAPK]], and minimal activation of the classical [[ERK]]s. TRAF2 activates the [[JNK]]-inducing upstream [[kinases]] of [[MEKK1]] and [[ASK1]] (either directly or through GCKs and Trx, respectively), and these two [[kinases]] [[phosphorylate]] [[Mitogen-activated protein kinase kinase|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]].

*'''Induction of death signaling:'''  Like all death-domain containing members of the TNFR superfamily, TNF-R1 is involved in death signaling.<ref name="pmid14555214">{{cite journal | author = Gaur U, Aggarwal BB | title = Regulation of proliferation, survival and apoptosis by members of the TNF superfamily | journal = Biochem. Pharmacol. | volume = 66 | issue = 8 | pages = 1403–8 | year = 2003 | pmid = 14555214 | doi = 10.1016/S0006-2952(03)00490-8 | issn = }}</ref> 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 [[cFLIP]], [[Bcl-2]], and [[cIAP]], 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 mainly produced by [[macrophages]], but also by a broad variety of other cell types including [[lymphoid]] cells, [[mast cells]], [[endothelial cell]]s, [[cardiac myocyte]]s, [[adipose tissue]], [[fibroblasts]] and [[neuron]]al tissue. Large amounts of TNF are released in response to [[lipopolysaccharide]], other [[bacteria|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):
* On the [[hypothalamus]]:
** Stimulating of the [[hypothalamic-pituitary-adrenal axis]] by stimulating the release of [[corticotropin releasing hormone]] (CRH).
** Suppressing [[appetite]].
** [[Fever]].
* On the [[liver]]: stimulating the [[acute phase response]], leading to an increase in [[C-reactive protein]] and a number of other mediators. It also induces [[insulin resistance]] by promoting serine-phosphorylation of insulin receptor substrate-1 (IRS-1), which impairs insulin signaling.
* It is a potent chemoattractant for [[neutrophils]], and helps them to stick to the endothelial cells for migration.
* On macrophages: stimulates [[phagocytosis]], and production of IL-1 oxidants and the inflammatory lipid [[prostaglandin]] E2 PGE<sub>2</sub>. 
* On other tissues: increasing [[insulin resistance]].

A locally increasing concentration of TNF will cause the cardinal signs of Inflammation to occur: Heat, swelling, redness and pain.

Whereas high concentrations of TNF induce [[Shock (medical)|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 [[tumour]] patients.

== Pharmacology ==
{{main|TNF inhibition}}
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==
* [[Lymphotoxin]] (Tumor necrosis factor-beta)

==References==
{{Reflist|2}}

==External links==
* {{MeshName|Tumor+Necrosis+Factor-alpha}}

{{Cytokines}}
{{Tumor necrosis factors}}
{{Glycoproteins}}
[[Category:Cytokines]]

[[de:Tumornekrosefaktor]]
[[es:Factor de necrosis tumoral]]
[[fr:Facteur de nécrose tumorale]]
[[it:Fattore di necrosi tumorale]]
[[nl:Tumor necrosis factor α]]
[[pl:TNF-α]]
[[pt:Fator de necrose tumoral-alfa]]
[[sv:TNF-α]]
{{jb1}}
{{WH}}
{{WS}}