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Gene Review

TNF  -  tumor necrosis factor

Sus scrofa

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Disease relevance of TNF

  • Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock [1].
  • Tumor necrosis factor (TNF alpha), both by direct action and by trafficking cells of the immune system, is implicated in cardiopulmonary derangements and PMN-mediated microvascular injury associated with gram-negative sepsis [2].
  • The serum factor inducing hemorrhagic necrosis of transplantable tumors [tumor necrosis factor (TNF)], and the macrophage hormone associated with cachexia in cancer and certain infectious diseases [cachectin] are known to be the same protein [3].
  • TNF induced chief cell dysfunction might be responsible for the high plasma pepsinogen concentrations seen in patients with NSAID gastropathy or H pylori induced gastritis [4].
  • Clinical results of isolated limb perfusion with high-dose TNF and melphalan for the treatment of melanoma and sarcoma have been promising, and attempts have been made to extrapolate this success to the isolated liver perfusion setting [5].

Psychiatry related information on TNF

  • Pigs injected I.C.V. with 50 ng/kg TNF-alpha showed anorexia, hypersomnia, and an abrupt increase in plasma cortisol concentration [6].

High impact information on TNF


Chemical compound and disease context of TNF


Biological context of TNF


Anatomical context of TNF


Associations of TNF with chemical compounds

  • CPZ protected against LPS lethality when administered 30 minutes (min) before, simultaneously, or up to 10 min after LPS and was ineffective when given 30 min after LPS, paralleling the inhibitory effect on TNF production [1].
  • However, co-mounting of TNF alpha preincubated pig jejunal fibroblasts (P2JF) monolayers back to back with untreated T84 monolayers dose-dependently induced an indomethacin sensitive increase in Isc compared with values in untreated co-mounted monolayers (p < 0.001, n = 11) [21].
  • METHODS: Pigs underwent IHHP with TNF, melphalan, and MMC using balloon catheters or served as controls, receiving equivalent dosages of these agents intravenously [5].
  • Because tumour necrosis factor alpha (TNF alpha) is an early mediator of inflammation and stimulates prostaglandin secretion, we investigated its effect on intestinal ion transport [21].
  • Similarly, DEM and CDNB inhibited TNF-alpha-induced Akt and eNOS phosphorylation, suggesting that thiol modification is involved in eNOS inductive pathways [22].

Regulatory relationships of TNF

  • IL-6 expression in transformed swine testicular (TST) fibroblasts was enhanced by TNF and IL-1 beta and to a lesser extent by poly(I).(C) and LPS [23].
  • The expression of piap is strongly up-regulated upon treatment of endothelial cells (EC) with inflammatory cytokines TNF-alpha, IL-1 beta, and LPS [24].
  • Stimulation of DCs with IFN-alpha/TNF-alpha or polyinosinic-polycytidylic acid (pIC) induced phenotypic maturation with increased MHC and CD80/86 expression, both with mock-treated and infected DCs [25].
  • The role of TNF-alpha and IL-1 in the symptoms and pathology of porcine pleuropneumonia has recently been proven by use of an adenovirus vector expressing the anti-inflammatory IL-10 [26].
  • Nuclear run-on transcription analysis demonstrated that the TNF alpha-stimulated increase in stromelysin and collagenase message levels was, at least partially, due to increased transcription [27].

Other interactions of TNF

  • Treatment with anti-guinea pig TNF-alpha polyclonal antibody completely abolished the response of alveolar macrophages to neutrophil products [15].
  • The inhibitory effect of PCV2 DNA was more diversified than if it had simply targeted CpG-ODN-induced cytokines (IFN-alpha, TNF-alpha, interleukin-6, IL-12) [28].
  • The amount of secreted protein, as determined by TNF-alpha bioassay, was also suppressed by IL-4 [29].
  • We verified the expression of mRNAs encoding the cytokines IL-1alpha, -6, -7, -8, -18, TNF-alpha and GM-CSF, but not TGF-beta or MCP-1 [30].
  • We demonstrate that adenovirus mediated overexpression of I kappa B alpha, an inhibitor of NF-kappa B suppresses the expression of piap in response to TNF-alpha suggesting that piap is one of the NF-kappa B regulated genes that operates to prevent programmed cell death of EC in inflammation [24].

Analytical, diagnostic and therapeutic context of TNF

  • Circulating concentrations of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by use of specific bioassays [31].
  • Intra-arterial (i.a.) or intraperitoneal injections of double-stranded RNA induced pronounced fevers and strong elevations of circulating TNF-alpha and IL-6 [31].
  • Western blot analysis revealed that preincubation of EC with ETYA for 40 min prior to stimulation with TNF-alpha inhibits the phosphorylation and degradation of IkappaBalpha [16].
  • After termination of isolation, systemic TNF levels showed only a minor transient elevation, indicating that the washout procedure at the end of the perfusions was fully effective [5].
  • Similar TNF-alpha clearance was observed in the selective plasma filtration groups and the plasma exchange group [32].


  1. Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock. Gadina, M., Bertini, R., Mengozzi, M., Zandalasini, M., Mantovani, A., Ghezzi, P. J. Exp. Med. (1991) [Pubmed]
  2. Tumor necrosis factor-alpha blockade prevents neutrophil CD18 receptor upregulation and attenuates acute lung injury in porcine sepsis without inhibition of neutrophil oxygen radical generation. Windsor, A.C., Walsh, C.J., Mullen, P.G., Cook, D.J., Fisher, B.J., Blocher, C.R., Leeper-Woodford, S.K., Sugerman, H.J., Fowler, A.A. J. Clin. Invest. (1993) [Pubmed]
  3. Effect of tumor necrosis factor on epithelial tight junctions and transepithelial permeability. Mullin, J.M., Snock, K.V. Cancer Res. (1990) [Pubmed]
  4. Isolated guinea pig gastric chief cells express tumour necrosis factor receptors coupled with the sphingomyelin pathway. Fiorucci, S., Santucci, L., Migliorati, G., Riccardi, C., Amorosi, A., Mancini, A., Roberti, R., Morelli, A. Gut (1996) [Pubmed]
  5. Isolated hypoxic hepatic perfusion with tumor necrosis factor-alpha, melphalan, and mitomycin C using balloon catheter techniques: a pharmacokinetic study in pigs. van Ijken, M.G., de Bruijn, E.A., de Boeck, G., ten Hagen, T.L., van der Sijp, J.R., Eggermont, A.M. Ann. Surg. (1998) [Pubmed]
  6. Coincidental changes in behavior and plasma cortisol in unrestrained pigs after intracerebroventricular injection of tumor necrosis factor-alpha. Warren, E.J., Finck, B.N., Arkins, S., Kelley, K.W., Scamurra, R.W., Murtaugh, M.P., Johnson, R.W. Endocrinology (1997) [Pubmed]
  7. Cytokine-inducible expression in endothelial cells of an I kappa B alpha-like gene is regulated by NF kappa B. de Martin, R., Vanhove, B., Cheng, Q., Hofer, E., Csizmadia, V., Winkler, H., Bach, F.H. EMBO J. (1993) [Pubmed]
  8. A20 inhibits NF-kappaB activation in endothelial cells without sensitizing to tumor necrosis factor-mediated apoptosis. Ferran, C., Stroka, D.M., Badrichani, A.Z., Cooper, J.T., Wrighton, C.J., Soares, M., Grey, S.T., Bach, F.H. Blood (1998) [Pubmed]
  9. Pharmacologic reduction in tumor necrosis factor activity of pulmonary alveolar macrophages. Leeper-Woodford, S.K., Fisher, B.J., Sugerman, H.J., Fowler, A.A. Am. J. Respir. Cell Mol. Biol. (1993) [Pubmed]
  10. Platelet-activating factor and arachidonic acid metabolites mediate tumor necrosis factor and eicosanoid kinetics and cardiopulmonary dysfunction during bacteremic shock. Quinn, J.V., Slotman, G.J. Crit. Care Med. (1999) [Pubmed]
  11. Effect of induced hyperglycemia on brain cell membrane function and energy metabolism during the early phase of experimental meningitis in newborn piglets. Park, W.S., Chang, Y.S., Lee, M. Brain Res. (1998) [Pubmed]
  12. Ibuprofen attenuates plasma tumor necrosis factor activity during sepsis-induced acute lung injury. Leeper-Woodford, S.K., Carey, P.D., Byrne, K., Fisher, B.J., Blocher, C., Sugerman, H.J., Fowler, A.A. J. Appl. Physiol. (1991) [Pubmed]
  13. Differences in eicosanoid and cytokine production between injury/hemorrhage and bacteremic shock in the pig. Foëx, B.A., Quinn, J.V., Little, R.A., Shelly, M.P., Slotman, G.J. Shock (1997) [Pubmed]
  14. The porcine tumor necrosis factor-encoding genes: sequence and comparative analysis. Kuhnert, P., Wüthrich, C., Peterhans, E., Pauli, U. Gene (1991) [Pubmed]
  15. Guinea Pig Neutrophils Infected with Mycobacterium tuberculosis Produce Cytokines Which Activate Alveolar Macrophages in Noncontact Cultures. Sawant, K.V., McMurray, D.N. Infect. Immun. (2007) [Pubmed]
  16. Arachidonic acid influences proinflammatory gene induction by stabilizing the inhibitor-kappaBalpha/nuclear factor-kappaB (NF-kappaB) complex, thus suppressing the nuclear translocation of NF-kappaB. Stuhlmeier, K.M., Kao, J.J., Bach, F.H. J. Biol. Chem. (1997) [Pubmed]
  17. Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells. Yerneni, K.K., Bai, W., Khan, B.V., Medford, R.M., Natarajan, R. Diabetes (1999) [Pubmed]
  18. Swine infection with Trichinella spiralis: Comparative analysis of the mucosal intestinal and systemic immune responses. Picherot, M., Oswald, I.P., Cote, M., Noeckler, K., Le Guerhier, F., Boireau, P., Vall??e, I. Vet. Parasitol. (2007) [Pubmed]
  19. Primary graft nonfunction and Kupffer cell activation after liver transplantation from non-heart-beating donors in pigs. Monbaliu, D., van Pelt, J., De Vos, R., Greenwood, J., Parkkinen, J., Crabbé, T., Zeegers, M., Vekemans, K., Pincemail, J., Defraigne, J.O., Fevery, J., Pirenne, J. Liver Transpl. (2007) [Pubmed]
  20. Ischemic training and immunosuppressive agents reduce the intensity of ischemic reperfusion injury after kidney transplantation. Treska, V., Molacek, J., Kobr, J., Racek, J., Trefil, L., Hes, O. Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. (2006) [Pubmed]
  21. Tumour necrosis factor alpha changes porcine intestinal ion transport through a paracrine mechanism involving prostaglandins. Kandil, H.M., Berschneider, H.M., Argenzio, R.A. Gut (1994) [Pubmed]
  22. Redox regulation of the signaling pathways leading to eNOS phosphorylation. Tanaka, T., Nakamura, H., Yodoi, J., Bloom, E.T. Free Radic. Biol. Med. (2005) [Pubmed]
  23. Regulation of interleukin-6 expression in porcine immune cells. Scamurra, R., Arriaga, C., Sprunger, L., Baarsch, M.J., Murtaugh, M.P. J. Interferon Cytokine Res. (1996) [Pubmed]
  24. Cytokine induced expression of porcine inhibitor of apoptosis protein (iap) family member is regulated by NF-kappa B. Stehlik, C., de Martin, R., Binder, B.R., Lipp, J. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  25. Interaction of classical swine fever virus with dendritic cells. Carrasco, C.P., Rigden, R.C., Vincent, I.E., Balmelli, C., Ceppi, M., Bauhofer, O., Tâche, V., Hjertner, B., McNeilly, F., van Gennip, H.G., McCullough, K.C., Summerfield, A. J. Gen. Virol. (2004) [Pubmed]
  26. In vivo studies on cytokine involvement during acute viral respiratory disease of swine: troublesome but rewarding. Van Reeth, K., Van Gucht, S., Pensaert, M. Vet. Immunol. Immunopathol. (2002) [Pubmed]
  27. Tumor necrosis factor alpha and epidermal growth factor regulation of collagenase and stromelysin in adult porcine articular chondrocytes. Mitchell, P.G., Cheung, H.S. J. Cell. Physiol. (1991) [Pubmed]
  28. Silencing of natural interferon producing cell activation by porcine circovirus type 2 DNA. Vincent, I.E., Balmelli, C., Meehan, B., Allan, G., Summerfield, A., McCullough, K.C. Immunology (2007) [Pubmed]
  29. Interleukin-4 suppresses inflammatory cytokine gene transcription in porcine macrophages. Zhou, Y., Lin, G., Baarsch, M.J., Scamurra, R.W., Murtaugh, M.P. J. Leukoc. Biol. (1994) [Pubmed]
  30. Characterization of a porcine intestinal epithelial cell line for in vitro studies of microbial pathogenesis in swine. Schierack, P., Nordhoff, M., Pollmann, M., Weyrauch, K.D., Amasheh, S., Lodemann, U., Jores, J., Tachu, B., Kleta, S., Blikslager, A., Tedin, K., Wieler, L.H. Histochem. Cell Biol. (2006) [Pubmed]
  31. Fever and circulating cytokines induced by double-stranded RNA in guinea pigs: dependence on the route of administration and effects of repeated injections. Voss, T., Rummel, C., Gerstberger, R., Hübschle, T., Roth, J. Acta physiologica (Oxford, England) (2006) [Pubmed]
  32. Selective plasma filtration for treatment of fulminant hepatic failure induced by D-galactosamine in a pig model. Ho, D.W., Fan, S.T., To, J., Woo, Y.H., Zhang, Z., Lau, C., Wong, J. Gut (2002) [Pubmed]
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