tumor necrosis factor tumor necrosis factor tumor necrosis factor (tnf, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or tnf-α) is an adipokine and a cytokine. tnf is a member of the tnf superfamily, which consists of various transmembrane proteins with a homologous tnf domain. tnfavailable structurespdbortholog search: pdbe rcsb list of pdb id codes1a8m, 1tnf, 2az5, 2e7a, 2tun, 2zjc, 2zpx, 3alq, 3it8, 3l9j, 3wd5, 4g3y, 4tsv, 4twt, 5tswidentifiersaliasestnf, dif, tnf-alpha, tnfa, tnfsf2, tumour necrosis factor, tnf-α, tumor necrosis factor, tnlg1f, tumor necrosis factor alphaexternal idsomim: 191160 mgi: 104798 homologene: 496 genecards: tnf gene location (human)chr.chromosome 6 (human)band6p21.33start31,575,565 bpend31,578,336 bpgene location (mouse)chr.chromosome 17 (mouse)band17 b1|17 18.59 cmstart35,418,357 bpend35,420,983 bprna expression patternbgeehumanmouse (ortholog)top expressed inbone marrowmonocytebone marrow cellsbloodlymph nodespleenappendixduodenumgallbladdersmooth muscle tissuetop expressed inendometriumspleenbloodsubcutaneous adipose tissuethymusjejunumconjunctival fornixduodenumileumcorneamore reference expression databiogpsmore reference expression datagene ontologymolecular function protein binding protease binding tumor necrosis factor receptor binding cytokine activity identical protein binding cellular component membrane cell surface integral component of membrane recycling endosome intracellular anatomical structure integral component of plasma membrane phagocytic cup external side of plasma membrane extracellular region plasma membrane membrane raft extracellular space biological process regulation of protein phosphorylation positive regulation of protein phosphorylation positive regulation of map kinase activity response to salt stress positive regulation of calcidiol 1-monooxygenase activity positive regulation of programmed cell death positive regulation of jnk cascade response to organic substance negative regulation of osteoblast differentiation positive regulation of cysteine-type endopeptidase activity involved in apoptotic process negative regulation of viral genome replication humoral immune response positive regulation of interleukin-8 production intrinsic apoptotic signaling pathway in response to dna damage positive regulation of protein localization to cell surface positive regulation of erk1 and erk2 cascade glucose metabolic process animal organ morphogenesis apoptotic signaling pathway negative regulation of alkaline phosphatase activity regulation of i-kappab kinase/nf-kappab signaling defense response to gram-positive bacterium regulation of branching involved in salivary gland morphogenesis positive regulation of phagocytosis negative regulation of fat cell differentiation negative regulation of myoblast differentiation positive regulation of protein kinase b signaling regulation of insulin secretion osteoclast differentiation regulation of tumor necrosis factor-mediated signaling pathway response to virus positive regulation of osteoclast differentiation negative regulation of cytokine production involved in immune response positive regulation of peptidyl-serine phosphorylation negative regulation of branching involved in lung morphogenesis jnk cascade death-inducing signaling complex assembly regulation of osteoclast differentiation defense response to bacterium positive regulation of interleukin-6 production i-kappab kinase/nf-kappab signaling positive regulation of translational initiation by iron sequestering of triglyceride positive regulation of chronic inflammatory response to antigenic stimulus positive regulation of chemokine (c-x-c motif) ligand 2 production positive regulation of jun kinase activity positive regulation of hair follicle development chronic inflammatory response to antigenic stimulus cellular response to organic cyclic compound positive regulation of fever generation extracellular matrix organization positive regulation of dna-binding transcription factor activity cellular response to nicotine positive regulation of podosome assembly regulation of reactive oxygen species metabolic process positive regulation of protein transport negative regulation of glucose import immune response leukocyte tethering or rolling positive regulation of chemokine production cellular extravasation negative regulation of lipid storage negative regulation of myosin-light-chain-phosphatase activity negative regulation of transcription, dna-templated cortical actin cytoskeleton organization embryonic digestive tract development leukocyte migration lipopolysaccharide-mediated signaling pathway positive regulation of smooth muscle cell proliferation positive regulation of protein kinase activity positive regulation of superoxide dismutase activity defense response positive regulation of ceramide biosynthetic process positive regulation of protein-containing complex assembly protein kinase b signaling positive regulation of cytokine production epithelial cell proliferation involved in salivary gland morphogenesis positive regulation of nitric oxide biosynthetic process negative regulation of interleukin-6 production positive regulation of membrane protein ectodomain proteolysis positive regulation of humoral immune response mediated by circulating immunoglobulin positive regulation of interferon-gamma production response to glucocorticoid positive regulation of vitamin d biosynthetic process positive regulation of mononuclear cell migration mapk cascade negative regulation of protein-containing complex disassembly multicellular organism development negative regulation of bicellular tight junction assembly positive regulation of protein-containing complex disassembly regulation of cell population proliferation cellular response to amino acid stimulus negative regulation of extrinsic apoptotic signaling pathway in absence of ligand cellular response to lipopolysaccharide negative regulation of lipid catabolic process regulation of establishment of endothelial barrier positive regulation of cell adhesion regulation of protein secretion positive regulation of apoptotic process inflammatory response activation of cysteine-type endopeptidase activity involved in apoptotic process tumor necrosis factor-mediated signaling pathway positive regulation of i-kappab kinase/nf-kappab signaling necroptotic signaling pathway positive regulation of gene expression extrinsic apoptotic signaling pathway extrinsic apoptotic signaling pathway via death domain receptors negative regulation of transcription by rna polymerase ii positive regulation of nf-kappab transcription factor activity positive regulation of transcription, dna-templated positive regulation of transcription by rna polymerase ii positive regulation of leukocyte adhesion to arterial endothelial cell positive regulation of leukocyte adhesion to vascular endothelial cell positive regulation of blood microparticle formation negative regulation of endothelial cell proliferation positive regulation of heterotypic cell-cell adhesion negative regulation of mitotic cell cycle endothelial cell apoptotic process positive regulation of vascular associated smooth muscle cell proliferation negative regulation of gene expression protein localization to plasma membrane positive regulation of protein catabolic process regulation of signaling receptor activity regulation of inflammatory response cytokine-mediated signaling pathway positive regulation of calcineurin-nfat signaling cascade positive regulation of nik/nf-kappab signaling sources:amigo / quickgoorthologsspecieshumanmouseentrez712421926ensemblensg00000228978ensg00000230108ensg00000223952ensg00000204490ensg00000228321ensg00000232810ensg00000228849ensg00000206439ensmusg00000024401uniprotp01375p06804refseq (mrna)nm_000594nm_001278601nm_013693refseq (protein)np_000585np_001265530np_038721location (ucsc)chr 6: 31.58 – 31.58 mbchr 17: 35.42 – 35.42 mbpubmed searchwikidataview/edit humanview/edit mouse as an adipokine, tnf promotes insulin resistance, and is associated with obesity-induced type 2 diabetes. as a cytokine, tnf is used by the immune system for cell signaling. if macrophages (certain white blood cells) detect an infection, they release tnf to alert other immune system cells as part of an inflammatory response. tnf signaling occurs through two receptors: tnfr1 and tnfr2. tnfr1 is constituitively expressed on most cell types, whereas tnfr2 is restricted primarily to endothelial, epithelial, and subsets of immune cells. tnfr1 signaling tends to be pro-inflammatory and apoptotic, whereas tnfr2 signaling is anti-inflammatory and promotes cell proliferation. suppression of tnfr1 signaling has been important for treatment of autoimmune disease, whereas tnfr2 signaling promotes wound healing. tnf exists as a transmembrane form (mtnf) and as a soluble form (stnf). stnf results from enzymatic cleavage of mtnf, by a process called substrate presentation. mtnf is mainly found on monocytes/macrophages where it interacts with tissue receptors by cell-to-cell contact. stnf selectively binds to tnfr1, whereas mtnf binds to both tnfr1 and tnfr2. tnf binding to tnfr1 is irreversible, whereas binding to tnfr2 is reversible. the primary role of tnf is in the regulation of immune cells. tnf, as an endogenous pyrogen, is able to induce fever, apoptotic cell death, cachexia, and inflammation, inhibit tumorigenesis and viral replication, and respond to sepsis via il-1 and il-6-producing cells. dysregulation of tnf production has been implicated in a variety of human diseases including alzheimer's disease, cancer, major depression, psoriasis and inflammatory bowel disease (ibd). though controversial, some studies have linked depression and ibd to increased levels of tnf. under the name tasonermin, tnf is used as an immunostimulant drug in the treatment of certain cancers. drugs that counter the action of tnf are used in the treatment of various inflammatory diseases, for instance rheumatoid arthritis. certain cancers can cause overproduction of tnf. tnf parallels parathyroid hormone both in causing secondary hypercalcemia and in the cancers with which excessive production is associated. discovery the theory of an anti-tumoral response of the immune system in vivo was recognized by the physician thomas g. elliot. in 1964, gale a granger from the university of california, irvine, reported a cytotoxic factor produced by lymphocytes and named it lymphotoxin (lt). credit for this discovery is shared by nancy h. ruddle from yale university, who reported the same activity in a series of back-to-back articles published in the same month. subsequently, in 1974 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). both factors were described based on their ability to kill a 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 old's group, working with pre-sequencing era data, reasoned that excessive production of tnf causes malaria disease and endotoxin poisoning. the cdnas encoding lt and tnf were cloned in 1984 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 and lt as tnfβ. in 1985, bruce a. beutler and anthony cerami discovered that cachectin (a hormone which induces cachexia) was actually tnf. they then identified tnf as a mediator of lethal endotoxin poisoning. 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. 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-κb which induces the expression of antioxidant enzymes and bcl-2. gene the human tnf gene was cloned in 1985. it maps to chromosome 6p21.3, spans about 3 kilobases and contains 4 exons. the last exon shares similarity with lymphotoxin alpha (lta, once named as tnf-β). the three prime untranslated region (3'-utr) of tnf contains an au-rich element (are). structure tnf is primarily produced as a 233-amino acid-long type ii transmembrane protein arranged in stable homotrimers. 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). the soluble 51 kda trimeric stnf tends to dissociate at concentrations below the nanomolar range, thereby losing its bioactivity. the secreted form of human tnf takes on a triangular pyramid shape, and weighs around 17-kda. 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 biological activities. the common house mouse tnf and human tnf are structurally different. 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 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. 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 typically in cells of the immune system, and responds 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. at least partly because tnfr2 has no intracellular death domain, it shows neuroprotective properties. signaling pathway of tnfr1. 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. activation of nf-κb: 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. 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, tak1, mekk1 and ask1 (either directly or through gcks and trx, respectively). src- vav- rac