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Gene Review

TNF  -  tumor necrosis factor

Canis lupus familiaris

Synonyms: TNFA, cTNF
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Disease relevance of TNF

  • CONCLUSIONS: Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-alpha [1].
  • Exogenous tumor necrosis factor alpha (TNF-alpha) (1-10 ng/mL) did cause a minor increase in mucin secretion by the DGBE cells, but the effect of LPS from E. coli on mucin secretion could not be inhibited by preincubation with a TNF-alpha antibody (10 microg/mL) [2].
  • During 24 h of coincubation, cultures challenged with untreated or UV light-irradiated spirochetes produced similar levels of TNF-like and IL-1-like activities [3].
  • We conclude that subjection of a lung allograft to standard periods of cold-warm ischemia will result in a temporary early elevation of IL-2, TNF-alpha, and IFN-gamma detectable only in the bronchoalveolar compartment [4].
  • We conclude that intact B. burgdorferi or fractions of the bacterium can induce the local up-regulation of TNF-alpha, IL-1alpha, and IL-1beta in the synovium but that the interaction of viable spirochetes with synovial cells leads to the release of IL-8, which probably is a prime initiator of PMN migration during acute Lyme arthritis [3].

High impact information on TNF

  • Tyrosine kinase-dependent cell signaling is postulated to be a pivotal control point in inflammatory responses initiated by bacterial products and TNF [5].
  • Treatment with AG 556 had no effect on clearance of endotoxin or bacteria from the blood (both P = NS); however, AG 556 did significantly lower serum TNF levels (P = 0.03) [5].
  • We suggest that mast cell-derived TNF-alpha may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophil-induced injury [1].
  • Resident cardiac mast cells degranulate and release preformed TNF-alpha, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion [1].
  • Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-alpha in the ischemic myocardium [1].

Chemical compound and disease context of TNF

  • The clinical examination (body temperature, pulse and respiration rates, capillary filling times, peripheral pulse qualities, dehydration degrees), hematological and biochemical examinations (WBC, RBC, HGB, HCT, thrombocyte, serum urea, creatinine and TNF-alpha) were performed both before the treatment, and 2, 4, 12 and 24 h after the treatment [6].

Biological context of TNF

  • The latter was significantly correlated to up-regulation of IL-2, TNF-alpha, IFN-gamma and iNOS mRNA expression [7].
  • In addition, Smad7 inhibited TNF-alpha stimulation of NF-kappaB and increased TNF-alpha-mediated apoptosis in MDCK cells [8].
  • In this study, we examined the effect of the stable expression of Smad7 in two different cell lines on apoptosis induced by various stimuli including TGF-beta, serum withdrawal, loss of cell adhesion (anoikis) and TNF-alpha [8].
  • Cardiac output increased early after TNF alpha infusion (p < 0.05) and remained at greater than baseline values at study termination [9].
  • Mean arterial blood pressure decreased 1 h after infusion in TNF alpha animals (p < 0.05) with no significant change thereafter [9].

Anatomical context of TNF

  • The macrophages were positive for IL-1beta, TNF-alpha and i-NOS [10].
  • This study analyzed temporal expression levels of IL-1beta, IL-2, IL-6, IL-8, IFN-gamma, and TNF-alpha mRNA by peripheral blood leukocytes from dogs experimentally infected with a new virulent strain of E. canis by using real-time RT-PCR [11].
  • METHODS: Synovial fluid activities of proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) were determined by bioassay [12].
  • METHODS AND RESULTS: Constitutive expression of TNF-alpha and not IL-1beta was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells [1].
  • Inhibition of neutrophil-myocyte adhesion and adhesion-dependent myocyte injury by adenosine was evaluated using isolated TNF-alpha-activated canine cells [13].

Associations of TNF with chemical compounds

  • The plasma was analysed with respect to roxithromycin, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) [14].
  • These results indicate that exogenous or endogenous adenosine can inhibit neutrophil-myocyte adhesion and injury in cells activated with TNF-alpha by an A2-mediated mechanism [13].
  • We also investigated its effect on the serum concentrations of several inflammatory mediators, including endothelin (ET-1), endotoxin (LPS), tumor necrosis factor-alpha (TNF-alpha), and 6-keto prostaglandin F(1alpha) (6-kepto PGF(1alpha)) [15].
  • The effects of interleukin (IL)-1 alpha, IL-1 beta and TNF alpha on prostaglandin-E2 synthesis in Madin-Darby canine kidney (MDCK) cells were investigated [16].
  • The enhanced PGE2 synthesis was inhibited by indomethacin as well as actinomycin D, while cycloheximide surprisingly potentiated PGE2 synthesis in response to both IL-1 beta and TNF alpha [16].

Regulatory relationships of TNF


Other interactions of TNF

  • Administration of a soluble TNF-alpha inhibitor reduced NFkappaB activation, ICAM-1 upregulation, and myocardial injury following ischemia-reperfusion [18].
  • Furthermore, the expression of interleukin- (IL-2), IL-12(p40), tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-10 and transforming growth factor-beta (TGF-beta) as well as inducible nitric oxid synthase (iNOS) mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR) [7].
  • The regression of a canine Langerhans cell tumour is associated with increased expression of IL-2, TNF-alpha, IFN-gamma and iNOS mRNA [7].
  • Relative levels of IL-1beta and IL-8 transcripts normalized by the beta-actin transcript levels, were significantly upregulated, whereas those of TNF-alpha and IFN-gamma transcripts were only weakly upregulated in all three infected dogs, starting from 2 days up to 52 days post inoculation [11].
  • Twelve dogs tested positive for IL-8 mRNA in multiple tissues (synovia, pericardium, and peritoneum), and 10 dogs expressed TNF-alpha mRNA, but only in the tributary lymph nodes of the inflamed joints [19].

Analytical, diagnostic and therapeutic context of TNF

  • Intracellular levels of tumor necrosis factor alpha (TNF-alpha), measured by flow cytometry, and T cell proliferation after GFP peptide stimulation were measured [20].
  • BAL TNF-alpha levels were significantly increased 1 hr after transplantation (P < 0.05) (0 hr: 3.4 +/- 0.65 pg/ml; 1 hr: 13.3 +/- 8.0 pg/ml) returning to baseline after 24 hr (5.8 +/- 2.8 pg/ml) [4].
  • The titration of spirochetes revealed a dose-independent cytokine response, where 10(3) to 10(7) B. burgdorferi organisms induced similar TNF-like activities but only 10(7) spirochetes induced measurable IL-1-like activities [3].
  • The diastolic pressure-volume relationship did not change in the TNF-alpha group or the control group [21].
  • We performed bronchoalveolar lavage (BAL) at the end of the experiment and determined total protein concentration as well as tumor necrosis factor alpha (TNF-alpha) mRNA expression in cell-free supernatant and in BAL cells, respectively [22].


  1. Resident cardiac mast cells degranulate and release preformed TNF-alpha, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion. Frangogiannis, N.G., Lindsey, M.L., Michael, L.H., Youker, K.A., Bressler, R.B., Mendoza, L.H., Spengler, R.N., Smith, C.W., Entman, M.L. Circulation (1998) [Pubmed]
  2. Lipopolysaccharide from Escherichia coli stimulates mucin secretion by cultured dog gallbladder epithelial cells. Choi, J., Klinkspoor, J.H., Yoshida, T., Lee, S.P. Hepatology (1999) [Pubmed]
  3. Borrelia burgdorferi induces the production and release of proinflammatory cytokines in canine synovial explant cultures. Straubinger, R.K., Straubinger, A.F., Summers, B.A., Erb, H.N., Härter, L., Appel, M.J. Infect. Immun. (1998) [Pubmed]
  4. The early release of interleukin-2, tumor necrosis factor-alpha and interferon-gamma after ischemia reperfusion injury in the lung allograft. Serrick, C., Adoumie, R., Giaid, A., Shennib, H. Transplantation (1994) [Pubmed]
  5. Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis. Sevransky, J.E., Shaked, G., Novogrodsky, A., Levitzki, A., Gazit, A., Hoffman, A., Elin, R.J., Quezado, Z.M., Freeman, B.D., Eichacker, P.Q., Danner, R.L., Banks, S.M., Bacher, J., Thomas, M.L., Natanson, C. J. Clin. Invest. (1997) [Pubmed]
  6. Evaluation of the anti-endotoxic effects of polymyxin-E (colistin) in dogs with naturally occurred endotoxic shock. Sentürk, S. J. Vet. Pharmacol. Ther. (2005) [Pubmed]
  7. The regression of a canine Langerhans cell tumour is associated with increased expression of IL-2, TNF-alpha, IFN-gamma and iNOS mRNA. Kaim, U., Moritz, A., Failing, K., Baumgärtner, W. Immunology (2006) [Pubmed]
  8. Smad7 inhibits the survival nuclear factor kappaB and potentiates apoptosis in epithelial cells. Lallemand, F., Mazars, A., Prunier, C., Bertrand, F., Kornprost, M., Gallea, S., Roman-Roman, S., Cherqui, G., Atfi, A. Oncogene (2001) [Pubmed]
  9. Tumor necrosis factor alpha decreases in vivo diaphragm contractility in dogs. Wilcox, P.G., Wakai, Y., Walley, K.R., Cooper, D.J., Road, J. Am. J. Respir. Crit. Care Med. (1994) [Pubmed]
  10. Localization and changes of intraneural inflammatory cytokines and inducible-nitric oxide induced by mechanical compression. Kobayashi, S., Baba, H., Uchida, K., Shimada, S., Negoro, K., Takeno, K., Yayama, T., Yamada, S., Yoshizawa, H. J. Orthop. Res. (2005) [Pubmed]
  11. Cytokine Gene Expression by Peripheral Blood Leukocytes in Dogs Experimentally Infected with a New Virulent Strain of Ehrlichia canis. Unver, A., Huang, H., Rikihisa, Y. Ann. N. Y. Acad. Sci. (2006) [Pubmed]
  12. Proinflammatory cytokine activities, matrix metalloproteinase-3 activity, and sulfated glycosaminoglycan content in synovial fluid of dogs with naturally acquired cranial cruciate ligament rupture. Fujita, Y., Hara, Y., Nezu, Y., Schulz, K.S., Tagawa, M. Veterinary surgery : VS : the official journal of the American College of Veterinary Surgeons. (2006) [Pubmed]
  13. Adenosine activates A2 receptors to inhibit neutrophil adhesion and injury to isolated cardiac myocytes. Bullough, D.A., Magill, M.J., Firestein, G.S., Mullane, K.M. J. Immunol. (1995) [Pubmed]
  14. Pharmacokinetic/Pharmacodynamic modelling of roxithromycin for the inhibitory effect of tumour necrosis factor-alpha and interleukin-6 production in dogs. Lim, J.H., Park, B.K., Yun, H.I. Journal of veterinary medicine. A, Physiology, pathology, clinical medicine. (2006) [Pubmed]
  15. The effect of intensive plasma water exchange by hemofiltration on hemodynamics and soluble mediators in canine endotoxemia. Bellomo, R., Kellum, J.A., Gandhi, C.R., Pinsky, M.R., Ondulik, B. Am. J. Respir. Crit. Care Med. (2000) [Pubmed]
  16. Interleukin 1- and tumor necrosis factor-stimulation of prostaglandin E2 synthesis in MDCK cells, and potentiation of this effect by cycloheximide. Leighton, J.D., Pfeilschifter, J. FEBS Lett. (1990) [Pubmed]
  17. Inhibition of JNK by HGF/SF prevents apoptosis induced by TNF-alpha. Reveneau, S., Paumelle, R., Deheuninck, J., Leroy, C., De Launoit, Y., Fafeur, V. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  18. Inhibition of TNF-alpha reduces myocardial injury and proinflammatory pathways following ischemia-reperfusion in the dog. Gu, Q., Yang, X.P., Bonde, P., DiPaula, A., Fox-Talbot, K., Becker, L.C. J. Cardiovasc. Pharmacol. (2006) [Pubmed]
  19. Borrelia burgdorferi migrates into joint capsules and causes an up-regulation of interleukin-8 in synovial membranes of dogs experimentally infected with ticks. Straubinger, R.K., Straubinger, A.F., Härter, L., Jacobson, R.H., Chang, Y.F., Summers, B.A., Erb, H.N., Appel, M.J. Infect. Immun. (1997) [Pubmed]
  20. Cyclosporine inhibits the development of green fluorescent protein (GFP)-specific immune responses after transplantation of GFP-expressing hematopoietic repopulating cells in dogs. Beagles, K.E., Peterson, L., Zhang, X., Morris, J., Kiem, H.P. Hum. Gene Ther. (2005) [Pubmed]
  21. Decrease in left ventricular contractility after tumor necrosis factor-alpha infusion in dogs. Walley, K.R., Hebert, P.C., Wakai, Y., Wilcox, P.G., Road, J.D., Cooper, D.J. J. Appl. Physiol. (1994) [Pubmed]
  22. Ischemic pre-conditioning of 5 minutes but not of 10 minutes improves lung function after warm ischemia in a canine model. Friedrich, I., Spillner, J., Lu, E.X., Bartling, B., Barnscheid, M., Sablotzki, A., Schade, U., Reidemeister, J.C., Silber, R.E., Gunther, A., Borgermann, J. J. Heart Lung Transplant. (2001) [Pubmed]
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