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NameTumor necrosis factor
  • Cachectin
  • TNF-a
  • TNF-alpha
  • TNFA
  • TNFSF2
  • Tumor necrosis factor ligand superfamily member 2
Gene NameTNF
Amino acid sequence
>lcl|BSEQ0001404|Tumor necrosis factor
Number of residues233
Molecular Weight25644.15
Theoretical pI6.92
GO Classification
  • tumor necrosis factor receptor binding
  • protease binding
  • identical protein binding
  • transcription regulatory region DNA binding
  • cytokine activity
  • positive regulation of peptidyl-serine phosphorylation
  • positive regulation of osteoclast differentiation
  • positive regulation of protein kinase B signaling
  • positive regulation of podosome assembly
  • positive regulation of NF-kappaB import into nucleus
  • negative regulation of alkaline phosphatase activity
  • positive regulation of transcription from RNA polymerase II promoter
  • positive regulation of JUN kinase activity
  • negative regulation of growth of symbiont in host
  • positive regulation of chemokine (C-X-C motif) ligand 2 production
  • humoral immune response
  • positive regulation of translational initiation by iron
  • positive regulation of interleukin-8 production
  • regulation of establishment of endothelial barrier
  • negative regulation of cytokine secretion involved in immune response
  • regulation of insulin secretion
  • positive regulation of protein kinase activity
  • positive regulation of interleukin-8 biosynthetic process
  • extrinsic apoptotic signaling pathway via death domain receptors
  • inflammatory response
  • protein import into nucleus, translocation
  • activation of MAPK activity
  • regulation of I-kappaB kinase/NF-kappaB signaling
  • positive regulation of protein transport
  • cell surface receptor signaling pathway
  • defense response to Gram-positive bacterium
  • negative regulation of osteoblast differentiation
  • JNK cascade
  • sequestering of triglyceride
  • positive regulation of protein complex disassembly
  • positive regulation of interleukin-6 production
  • negative regulation of interleukin-6 production
  • response to salt stress
  • glucose metabolic process
  • tumor necrosis factor-mediated signaling pathway
  • positive regulation of chemokine production
  • positive regulation of hair follicle development
  • positive regulation of protein localization to cell surface
  • positive regulation of phagocytosis
  • negative regulation of viral genome replication
  • transformed cell apoptotic process
  • intrinsic apoptotic signaling pathway in response to DNA damage
  • positive regulation of cell adhesion
  • positive regulation of gene expression
  • positive regulation of chronic inflammatory response to antigenic stimulus
  • negative regulation of branching involved in lung morphogenesis
  • negative regulation of protein complex disassembly
  • extrinsic apoptotic signaling pathway
  • negative regulation of lipid storage
  • positive regulation of apoptotic process
  • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process
  • negative regulation of gene expression
  • positive regulation of humoral immune response mediated by circulating immunoglobulin
  • regulation of branching involved in salivary gland morphogenesis
  • response to glucocorticoid
  • positive regulation of calcidiol 1-monooxygenase activity
  • negative regulation of fat cell differentiation
  • positive regulation of protein phosphorylation
  • leukocyte tethering or rolling
  • positive regulation of interferon-gamma production
  • positive regulation of cytokine production
  • negative regulation of transcription from RNA polymerase II promoter
  • positive regulation of chemokine biosynthetic process
  • positive regulation of nitric oxide biosynthetic process
  • I-kappaB kinase/NF-kappaB signaling
  • cortical actin cytoskeleton organization
  • establishment of protein localization to plasma membrane
  • protein kinase B signaling
  • positive regulation of membrane protein ectodomain proteolysis
  • positive regulation of NIK/NF-kappaB signaling
  • cellular response to organic cyclic compound
  • positive regulation of heterotypic cell-cell adhesion
  • negative regulation of bicellular tight junction assembly
  • positive regulation of vitamin D biosynthetic process
  • negative regulation of glucose import
  • positive regulation of I-kappaB kinase/NF-kappaB signaling
  • activation of cysteine-type endopeptidase activity involved in apoptotic process
  • positive regulation of NFAT protein import into nucleus
  • negative regulation of myosin-light-chain-phosphatase activity
  • positive regulation of MAP kinase activity
  • receptor biosynthetic process
  • necroptotic signaling pathway
  • cellular response to amino acid stimulus
  • cellular response to nicotine
  • epithelial cell proliferation involved in salivary gland morphogenesis
  • response to virus
  • regulation of tumor necrosis factor-mediated signaling pathway
  • lipopolysaccharide-mediated signaling pathway
  • positive regulation of protein complex assembly
  • extracellular matrix organization
  • positive regulation of NF-kappaB transcription factor activity
  • negative regulation of lipid catabolic process
  • positive regulation of cytokine secretion
  • positive regulation of ERK1 and ERK2 cascade
  • positive regulation of sequence-specific DNA binding transcription factor activity
  • positive regulation of mononuclear cell migration
  • positive regulation of transcription, DNA-templated
  • negative regulation of extrinsic apoptotic signaling pathway in absence of ligand
  • positive regulation of fever generation
  • activation of MAPKKK activity
  • positive regulation of smooth muscle cell proliferation
  • positive regulation of programmed cell death
  • negative regulation of myoblast differentiation
  • death-inducing signaling complex assembly
  • MAPK cascade
  • osteoclast differentiation
  • negative regulation of transcription, DNA-templated
  • positive regulation of ceramide biosynthetic process
  • embryonic digestive tract development
  • chronic inflammatory response to antigenic stimulus
  • regulation of immunoglobulin secretion
  • cell surface
  • phagocytic cup
  • membrane raft
  • external side of plasma membrane
  • integral component of plasma membrane
  • recycling endosome
  • extracellular region
  • plasma membrane
  • extracellular space
General FunctionTumor necrosis factor receptor binding
Specific FunctionCytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918).The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.
Pfam Domain Function
Transmembrane Regions36-56
GenBank Protein ID339741
UniProtKB IDP01375
UniProtKB Entry NameTNFA_HUMAN
Cellular LocationCell membrane
Gene sequence
>lcl|BSEQ0021837|Tumor necrosis factor (TNF)
GenBank Gene IDM16441
GeneCard IDNot Available
GenAtlas IDTNF
Chromosome Location6
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  2. Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV: Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20-1985 Jan 2;312(5996):724-9. 6392892
  3. Shirai T, Yamaguchi H, Ito H, Todd CW, Wallace RB: Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor. Nature. 1985 Feb 28-Mar 6;313(6005):803-6. 3883195
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  5. Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, Yamamoto R, Mark DF: Molecular cloning of the complementary DNA for human tumor necrosis factor. Science. 1985 Apr 12;228(4696):149-54. 3856324
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  7. Iris FJ, Bougueleret L, Prieur S, Caterina D, Primas G, Perrot V, Jurka J, Rodriguez-Tome P, Claverie JM, Dausset J, et al.: Dense Alu clustering and a potential new member of the NF kappa B family within a 90 kilobase HLA class III segment. Nat Genet. 1993 Feb;3(2):137-45. 8499947
  8. Neville MJ, Campbell RD: A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC. J Immunol. 1999 Apr 15;162(8):4745-54. 10202016
  9. Xie T, Rowen L, Aguado B, Ahearn ME, Madan A, Qin S, Campbell RD, Hood L: Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse. Genome Res. 2003 Dec;13(12):2621-36. 14656967
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  11. Takakura-Yamamoto R, Yamamoto S, Fukuda S, Kurimoto M: O-glycosylated species of natural human tumor-necrosis factor-alpha. Eur J Biochem. 1996 Jan 15;235(1-2):431-7. 8631363
  12. Pocsik E, Duda E, Wallach D: Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in transfected HeLa cells. J Inflamm. 1995;45(3):152-60. 8597870
  13. Watts AD, Hunt NH, Wanigasekara Y, Bloomfield G, Wallach D, Roufogalis BD, Chaudhri G: A casein kinase I motif present in the cytoplasmic domain of members of the tumour necrosis factor ligand family is implicated in 'reverse signalling'. EMBO J. 1999 Apr 15;18(8):2119-26. 10205166
  14. Van Ostade X, Tavernier J, Prange T, Fiers W: Localization of the active site of human tumour necrosis factor (hTNF) by mutational analysis. EMBO J. 1991 Apr;10(4):827-36. 2009860
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  17. Knight JC, Udalova I, Hill AV, Greenwood BM, Peshu N, Marsh K, Kwiatkowski D: A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet. 1999 Jun;22(2):145-50. 10369255
  18. Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF, Kuhn PH, Stauffer D, Rovelli G, Martoglio B: SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nat Cell Biol. 2006 Aug;8(8):843-8. Epub 2006 Jul 9. 16829952
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  20. Jinesh G G, Chunduru S, Kamat AM: Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-alpha but not through TRAIL and FasL. J Leukoc Biol. 2012 Jul;92(1):233-44. doi: 10.1189/jlb.1211623. Epub 2012 Apr 18. 22517918
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  27. Balding J, Kane D, Livingstone W, Mynett-Johnson L, Bresnihan B, Smith O, FitzGerald O: Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity. Arthritis Rheum. 2003 May;48(5):1408-13. 12746914
  28. Kim YJ, Lee HS, Yoon JH, Kim CY, Park MH, Kim LH, Park BL, Shin HD: Association of TNF-alpha promoter polymorphisms with the clearance of hepatitis B virus infection. Hum Mol Genet. 2003 Oct 1;12(19):2541-6. Epub 2003 Aug 5. 12915457