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Gene Review

Tnf  -  tumor necrosis factor

Mus musculus

Synonyms: Cachectin, DIF, TNF alpha, TNF-a, TNF-alpha, ...
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Disease relevance of Tnf


Psychiatry related information on Tnf


High impact information on Tnf


Chemical compound and disease context of Tnf


Biological context of Tnf


Genetic context of TNF




Anatomical context of Tnf


Associations of Tnf with chemical compounds

  • Tumor-necrosis factor (TNF), a pleiotropic cytokine, triggers physiological and pathological responses in several organs [29].
  • Tpl2 knockout mice produce low levels of TNF-alpha when exposed to lipopolysaccharide (LPS) and they are resistant to LPS/D-Galactosamine-induced pathology [26].
  • These effects of TNF-alpha and IL-1 on target cells may contribute to their reported protective activity against radiation as well as their ability to induce resistance to cell killing induced by the combination of TNF-alpha and cycloheximide [27].
  • In a dose-dependent manner, PGE2 inhibits LPS-induced release of TNF-alpha and IL-6, but not of lactate or nitric oxide [30].
  • Tartrate-resistant acid phosphatase-positive osteoclasts were also formed when M-BMM phi were further cultured for 3 d with mouse tumor necrosis factor alpha (TNF-alpha) in the presence of M-CSF [31].
  • By the use of HIF-1-deficient cells and by obliterating NF-kappaB activation, it was determined that the hypoxic TACE response is mediated by HIF-1 signaling, whereas the regulation by TNFalpha also requires NF-kappaB activation [32].
  • Activation of the protein kinase C pathway by treatment with phorbol ester, which has been shown previously to result in CUGBP1 phosphorylation, also causes TNF mRNA stabilization [33].
  • PDTC accelerated death and aggravated liver apoptosis in the GalN/LPS model, although it reduced nitric oxide production, attenuated glutathione depletion, and inhibited the expression of TNF-alpha in liver [34].
  • CcO isolated after TNFalpha treatment showed tyrosine phosphorylation on CcO catalytic subunit I and was approximately 50 and 70% inhibited at high cytochrome c concentrations in the presence of allosteric activator ADP and inhibitor ATP, respectively [35].
  • Accordingly, c-Flip(L/S) protein levels were elevated in livers of TNFalpha-tolerant mice, which correlated to a switch from JNK and ERK to p38 signaling after galactosamine/TNF re-challenge [36].
  • In BDL mice, cardiac mRNA and protein expression of NFkappaBp65, p38MAPK, iNOS, NOx, anandamide, and plasma TNFa were increased, whereas glutathione, Cu/Zn-SOD, and Mn-SOD were decreased [37].

Physical interactions of Tnf

  • Following its induction, TNFalpha gene transcription is rapidly attenuated, in part due to the accumulation of NF-kappaB p50 homodimers that bind to three kappaB sites in the TNFalpha promoter [38].
  • Furthermore, RA inhibited activator protein-1 binding to 12-O-tetradecanoylphorbol 13-acetate-response element (TRE) in the cells treated with TNF-alpha, suggesting that RA acts as a potent negative regulator for activator protein-1 binding activity to TRE in the osteoblastic cells [39].
  • We also found that LPL caused the nuclear migration of one member of the NFkB family that appears to bind to a site in the murine TNF alpha gene promoter [40].
  • Expression and purification of recombinant tristetraprolin that can bind to tumor necrosis factor-alpha mRNA and serve as a substrate for mitogen-activated protein kinases [41].
  • It efficiently antagonizes the effect of TNF-alpha binding to the TNF receptor (I) [42].
  • Using chromatin immunoprecipitation assays, we demonstrated that treatment of adipocytes with TNFalpha led to increased binding of NFkappaB p50, and decreased binding of p65 and Sp1, to this region of the apoE promoter in living cells [43].

Enzymatic interactions of Tnf

  • Jo2 and, to a lesser extent, TNF-alpha phosphorylate Akt [44].
  • Collectively, these findings suggest that pp130 and pp95 are constitutively associated with CD120a (p55) and become inducibly phosphorylated in macrophages in response to TNFalpha [45].
  • Both the insulin receptor and IRS-1 are tyrosine-phosphorylated to the same extent in response to acute insulin stimulation following cellular TNF-alpha exposure [46].
  • Western blot analyses showed significantly increased levels of TNF-alpha (1.8-fold) and phosphorylated-SAPK/JNK1/2 (1.5-fold) in transgenic hearts [47].
  • Here we demonstrate that Ser311 accounts for zetaPKC phosphorylation of RelA and that this site is phosphorylated in vivo in response to TNF-alpha [48].

Co-localisations of Tnf


Regulatory relationships of Tnf


Other interactions of Tnf


Analytical, diagnostic and therapeutic context of Tnf


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  2. Endotoxic shock in AUF1 knockout mice mediated by failure to degrade proinflammatory cytokine mRNAs. Lu, J.Y., Sadri, N., Schneider, R.J. Genes Dev. (2006) [Pubmed]
  3. A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Taylor, G.A., Carballo, E., Lee, D.M., Lai, W.S., Thompson, M.J., Patel, D.D., Schenkman, D.I., Gilkeson, G.S., Broxmeyer, H.E., Haynes, B.F., Blackshear, P.J. Immunity (1996) [Pubmed]
  4. Lymphotoxins and cytomegalovirus cooperatively induce interferon-beta, establishing host-virus détente. Benedict, C.A., Banks, T.A., Senderowicz, L., Ko, M., Britt, W.J., Angulo, A., Ghazal, P., Ware, C.F. Immunity (2001) [Pubmed]
  5. Endotoxin preconditioning protects against the cytotoxic effects of TNFalpha after stroke: a novel role for TNFalpha in LPS-ischemic tolerance. Rosenzweig, H.L., Minami, M., Lessov, N.S., Coste, S.C., Stevens, S.L., Henshall, D.C., Meller, R., Simon, R.P., Stenzel-Poore, M.P. J. Cereb. Blood Flow Metab. (2007) [Pubmed]
  6. Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. Popivanova, B.K., Kitamura, K., Wu, Y., Kondo, T., Kagaya, T., Kaneko, S., Oshima, M., Fujii, C., Mukaida, N. J. Clin. Invest. (2008) [Pubmed]
  7. Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption. Minagawa, M., Deng, Q., Liu, Z.X., Tsukamoto, H., Dennert, G. Gastroenterology (2004) [Pubmed]
  8. IL-4 inhibits the expression of mouse formyl peptide receptor 2, a receptor for amyloid beta1-42, in TNF-alpha-activated microglia. Iribarren, P., Chen, K., Hu, J., Zhang, X., Gong, W., Wang, J.M. J. Immunol. (2005) [Pubmed]
  9. Defense mechanisms in Peyer's patches and mesenteric lymph nodes against Yersinia enterocolitica involve integrins and cytokines. Autenrieth, I.B., Kempf, V., Sprinz, T., Preger, S., Schnell, A. Infect. Immun. (1996) [Pubmed]
  10. Serum insulin-like growth factor I regulates brain amyloid-beta levels. Carro, E., Trejo, J.L., Gomez-Isla, T., LeRoith, D., Torres-Aleman, I. Nat. Med. (2002) [Pubmed]
  11. Heightened expression of tumor necrosis factor alpha, interleukin 1 alpha, and glial fibrillary acidic protein in experimental Creutzfeldt-Jakob disease in mice. Kordek, R., Nerurkar, V.R., Liberski, P.P., Isaacson, S., Yanagihara, R., Gajdusek, D.C. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  12. Jawing about TNF: New Hope for Cherubism. Novack, D.V., Faccio, R. Cell (2007) [Pubmed]
  13. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Chang, L., Kamata, H., Solinas, G., Luo, J.L., Maeda, S., Venuprasad, K., Liu, Y.C., Karin, M. Cell (2006) [Pubmed]
  14. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Kamata, H., Honda, S., Maeda, S., Chang, L., Hirata, H., Karin, M. Cell (2005) [Pubmed]
  15. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Arnett, H.A., Mason, J., Marino, M., Suzuki, K., Matsushima, G.K., Ting, J.P. Nat. Neurosci. (2001) [Pubmed]
  16. Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes. Held, W., MacDonald, H.R., Weissman, I.L., Hess, M.W., Mueller, C. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  17. The beta-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Yadav, M., Schorey, J.S. Blood (2006) [Pubmed]
  18. Etoposide prevents apoptosis in mouse liver with D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure resulting in reduction of lethality. Nakama, T., Hirono, S., Moriuchi, A., Hasuike, S., Nagata, K., Hori, T., Ido, A., Hayashi, K., Tsubouchi, H. Hepatology (2001) [Pubmed]
  19. Noncleavable transmembrane mouse tumor necrosis factor-alpha (TNFalpha) mediates effects distinct from those of wild-type TNFalpha in vitro and in vivo. Mueller, C., Corazza, N., Trachsel-Løseth, S., Eugster, H.P., Bühler-Jungo, M., Brunner, T., Imboden, M.A. J. Biol. Chem. (1999) [Pubmed]
  20. Hyperplastic gastric tumors with spasmolytic polypeptide-expressing metaplasia caused by tumor necrosis factor-alpha-dependent inflammation in cyclooxygenase-2/microsomal prostaglandin E synthase-1 transgenic mice. Oshima, M., Oshima, H., Matsunaga, A., Taketo, M.M. Cancer Res. (2005) [Pubmed]
  21. Tumor necrosis factor receptors (Tnfr) in mouse fibroblasts deficient in Tnfr1 or Tnfr2 are signaling competent and activate the mitogen-activated protein kinase pathway with differential kinetics. Kalb, A., Bluethmann, H., Moore, M.W., Lesslauer, W. J. Biol. Chem. (1996) [Pubmed]
  22. A JNK-dependent pathway is required for TNFalpha-induced apoptosis. Deng, Y., Ren, X., Yang, L., Lin, Y., Wu, X. Cell (2003) [Pubmed]
  23. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Beg, A.A., Baltimore, D. Science (1996) [Pubmed]
  24. Genetics of susceptibility to leishmaniasis in mice: four novel loci and functional heterogeneity of gene effects. Havelková, H., Badalová, J., Svobodová, M., Vojtíková, J., Kurey, I., Vladimirov, V., Demant, P., Lipoldová, M. Genes. Immun. (2006) [Pubmed]
  25. Multiple immune abnormalities in tumor necrosis factor and lymphotoxin-alpha double-deficient mice. Eugster, H.P., Muller, M., Karrer, U., Car, B.D., Schnyder, B., Eng, V.M., Woerly, G., Le Hir, M., di Padova, F., Aguet, M., Zinkernagel, R., Bluethmann, H., Ryffel, B. Int. Immunol. (1996) [Pubmed]
  26. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Dumitru, C.D., Ceci, J.D., Tsatsanis, C., Kontoyiannis, D., Stamatakis, K., Lin, J.H., Patriotis, C., Jenkins, N.A., Copeland, N.G., Kollias, G., Tsichlis, P.N. Cell (2000) [Pubmed]
  27. Induction of manganous superoxide dismutase by tumor necrosis factor: possible protective mechanism. Wong, G.H., Goeddel, D.V. Science (1988) [Pubmed]
  28. Keratin 17 modulates hair follicle cycling in a TNFalpha-dependent fashion. Tong, X., Coulombe, P.A. Genes Dev. (2006) [Pubmed]
  29. Abnormal TNF activity in Timp3-/- mice leads to chronic hepatic inflammation and failure of liver regeneration. Mohammed, F.F., Smookler, D.S., Taylor, S.E., Fingleton, B., Kassiri, Z., Sanchez, O.H., English, J.L., Matrisian, L.M., Au, B., Yeh, W.C., Khokha, R. Nat. Genet. (2004) [Pubmed]
  30. Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. Strassmann, G., Patil-Koota, V., Finkelman, F., Fong, M., Kambayashi, T. J. Exp. Med. (1994) [Pubmed]
  31. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. Kobayashi, K., Takahashi, N., Jimi, E., Udagawa, N., Takami, M., Kotake, S., Nakagawa, N., Kinosaki, M., Yamaguchi, K., Shima, N., Yasuda, H., Morinaga, T., Higashio, K., Martin, T.J., Suda, T. J. Exp. Med. (2000) [Pubmed]
  32. Hypoxia-inducible factor mediates hypoxic and tumor necrosis factor alpha-induced increases in tumor necrosis factor-alpha converting enzyme/ADAM17 expression by synovial cells. Charbonneau, M., Harper, K., Grondin, F., Pelmus, M., McDonald, P.P., Dubois, C.M. J. Biol. Chem. (2007) [Pubmed]
  33. The RNA-binding protein CUGBP1 regulates stability of tumor necrosis factor mRNA in muscle cells: implications for myotonic dystrophy. Zhang, L., Lee, J.E., Wilusz, J., Wilusz, C.J. J. Biol. Chem. (2008) [Pubmed]
  34. Differential effects of pyrrolidine dithiocarbamate on TNF-alpha-mediated liver injury in two different models of fulminant hepatitis. Lu, J.W., Wang, H., Yan-Li, J., Zhang, C., Ning, H., Li, X.Y., Zhang, H., Duan, Z.H., Zhao, L., Wei, W., Xu, D.X. J. Hepatol. (2008) [Pubmed]
  35. Tumor necrosis factor alpha inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase. Samavati, L., Lee, I., Mathes, I., Lottspeich, F., Hüttemann, M. J. Biol. Chem. (2008) [Pubmed]
  36. Down-regulation of the de-ubiquitinating enzyme ubiquitin-specific protease 2 contributes to tumor necrosis factor-alpha-induced hepatocyte survival. Haimerl, F., Erhardt, A., Sass, G., Tiegs, G. J. Biol. Chem. (2009) [Pubmed]
  37. Mechanisms of TNFalpha-induced cardiac dysfunction in cholestatic bile duct-ligated mice: interaction between TNFalpha and endocannabinoids. Yang, Y.Y., Liu, H., Nam, S.W., Kunos, G., Lee, S.S. J. Hepatol. (2010) [Pubmed]
  38. BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages. Wessells, J., Baer, M., Young, H.A., Claudio, E., Brown, K., Siebenlist, U., Johnson, P.F. J. Biol. Chem. (2004) [Pubmed]
  39. Retinoic acid suppression of c-fos gene inhibits expression of tumor necrosis factor-alpha-induced monocyte chemoattractant JE/MCP-1 in clonal osteoblastic MC3T3-E1 cells. Hanazawa, S., Takeshita, A., Kitano, S. J. Biol. Chem. (1994) [Pubmed]
  40. Induction of tumor necrosis factor alpha gene expression by lipoprotein lipase. Renier, G., Skamene, E., DeSanctis, J.B., Radzioch, D. J. Lipid Res. (1994) [Pubmed]
  41. Expression and purification of recombinant tristetraprolin that can bind to tumor necrosis factor-alpha mRNA and serve as a substrate for mitogen-activated protein kinases. Cao, H., Dzineku, F., Blackshear, P.J. Arch. Biochem. Biophys. (2003) [Pubmed]
  42. A tumor necrosis factor-alpha antagonist inhibits inflammatory bone resorption induced by Porphyromonas gingivalis infection in mice. Suzuki, Y., Aoki, K., Saito, H., Umeda, M., Nitta, H., Baron, R., Ohya, K. J. Periodont. Res. (2006) [Pubmed]
  43. Tumor necrosis factor-alpha-mediated suppression of adipocyte apolipoprotein E gene transcription: primary role for the nuclear factor (NF)-kappaB pathway and NFkappaB p50. Yue, L., Christman, J.W., Mazzone, T. Endocrinology (2008) [Pubmed]
  44. Akt protects mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis through NK-kappa B activation. Hatano, E., Brenner, D.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  45. Phosphorylation of 130- and 95-kDa substrates associated with tumor necrosis factor-alpha receptor CD120a (p55). Uh, S., Van Linden, A., Riches, D.W. J. Biol. Chem. (2000) [Pubmed]
  46. Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. Stephens, J.M., Lee, J., Pilch, P.F. J. Biol. Chem. (1997) [Pubmed]
  47. Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice mimics ischemic preconditioning through SAPK/JNK1/2 activation. Martire, A., Fernandez, B., Buehler, A., Strohm, C., Schaper, J., Zimmermann, R., Kolattukudy, P.E., Schaper, W. Cardiovasc. Res. (2003) [Pubmed]
  48. Essential role of RelA Ser311 phosphorylation by zetaPKC in NF-kappaB transcriptional activation. Duran, A., Diaz-Meco, M.T., Moscat, J. EMBO J. (2003) [Pubmed]
  49. The Peyer's patch high endothelial receptor for lymphocytes, the mucosal vascular addressin, is induced on a murine endothelial cell line by tumor necrosis factor-alpha and IL-1. Sikorski, E.E., Hallmann, R., Berg, E.L., Butcher, E.C. J. Immunol. (1993) [Pubmed]
  50. IL-4-Stat6 signaling induces tristetraprolin expression and inhibits TNF-alpha production in mast cells. Suzuki, K., Nakajima, H., Ikeda, K., Maezawa, Y., Suto, A., Takatori, H., Saito, Y., Iwamoto, I. J. Exp. Med. (2003) [Pubmed]
  51. A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss. Aoki, K., Saito, H., Itzstein, C., Ishiguro, M., Shibata, T., Blanque, R., Mian, A.H., Takahashi, M., Suzuki, Y., Yoshimatsu, M., Yamaguchi, A., Deprez, P., Mollat, P., Murali, R., Ohya, K., Horne, W.C., Baron, R. J. Clin. Invest. (2006) [Pubmed]
  52. Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. Federici, M., Hribal, M.L., Menghini, R., Kanno, H., Marchetti, V., Porzio, O., Sunnarborg, S.W., Rizza, S., Serino, M., Cunsolo, V., Lauro, D., Mauriello, A., Smookler, D.S., Sbraccia, P., Sesti, G., Lee, D.C., Khokha, R., Accili, D., Lauro, R. J. Clin. Invest. (2005) [Pubmed]
  53. NF-kappaB stimulates inducible nitric oxide synthase to protect mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis. Hatano, E., Bennett, B.L., Manning, A.M., Qian, T., Lemasters, J.J., Brenner, D.A. Gastroenterology (2001) [Pubmed]
  54. Short-term treatment of RAW264.7 macrophages with adiponectin increases tumor necrosis factor-alpha (TNF-alpha) expression via ERK1/2 activation and Egr-1 expression: role of TNF-alpha in adiponectin-stimulated interleukin-10 production. Park, P.H., McMullen, M.R., Huang, H., Thakur, V., Nagy, L.E. J. Biol. Chem. (2007) [Pubmed]
  55. Tumor necrosis factor receptor-1 can function through a G alpha q/11-beta-arrestin-1 signaling complex. Kawamata, Y., Imamura, T., Babendure, J.L., Lu, J.C., Yoshizaki, T., Olefsky, J.M. J. Biol. Chem. (2007) [Pubmed]
  56. Adenine nucleotide (ADP/ATP) translocase 3 participates in the tumor necrosis factor induced apoptosis of MCF-7 cells. Yang, Z., Cheng, W., Hong, L., Chen, W., Wang, Y., Lin, S., Han, J., Zhou, H., Gu, J. Mol. Biol. Cell (2007) [Pubmed]
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