Tumour necrosis factors

0 kDa polypeptide, is a potent chemoattractant and activating cytokine for neutrophils (Ba olini et al., 1989 Matsushima and Oppenheim, 1989). In addition, it causes up-regulation of neutrophil-derived da integrins which in turn, with ICAM-1, result in neutrophil adhesion. The source of IL-8 is monocytes and several cellular constituents of the alveolar capillary wall 

TNF has been shown to be present in the blood of patients with rheumatoid arthritis (Cope et al. 1992). 

ProTNF-a is initially produced as a membrane-bound form that is processes by TNF-a converting enzyme (TACE), a type I membrane-bound metalloproteinase (Black et al. 1997, Moss et al. 1997). TACE represents a potential target for the development of a therapeutic agent for inflammation and related diseases (Patel et al. 1998). TACE is inhibited by TIMP-3 but not by TIMP-1, -2 and -4 (Amour et al. 1998). 

TNF is a macrophage/monocyte-derived anticancer cytokine (Carswell et al. 1975, Matthews 1978, Niitsu et al. 1985) with strong cytotoxicity to tumour cells in vitro (Helson et al. 1975, Niitsu et al. 1988, Watanabe et al. 1985, 1988). In the transformed murine macrophage cell line RAW 264.7, TNF-a up-regulation 4h after lipopotysaccharide addition seems to involve protein kinase C, as stau-rosporine strongly inhibited (over 70 %) the expression of TNF-a mRNA while calphostin had no significant influence (Tremblay et al. 1995). 

Recombinant human TNF induced increased hydroxyl radical production in TNF-sensitive cells (Yamauchi et al. 1989). Liochev and Fridovich (1997) explained the 02 -dependent toxicity of TNF on the basis of a variant of the Fenton reaction  

Using the stable free radical, l,l-diphenyl-2-picrylhydrazyl (DPPH) and the electron spin resonance technique, Matsubara et al. (1991) showed TNF-a to have scavenging properties in vitro. 

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Hyperphosphorylation of ERAK-1 by itself and ERAK-4 causes ERAK-1 to dissociate from the membrane-bound complex. Tumour necrosis factor (TNF) receptor-associated factor-6 ( TRAF-6), a cytoplasmic protein, is activated by ERAK-1 and with TAB-2, another cytoplasmic protein, activates transforming growth factor-P (TFG-P)-activating kinase (TAK-1). During this process both TRAF-6 and TAK-1 become ubiquitinated. TAK-1 then promotes activation of the IkB kinases, or the IKK family, EKKa and EKK 3 (found in a complex with NFicB-essential modulator [NEMO]), which phosphorylate the IkB family, notably IkB-u. IkB-u is an inhibitor of NFkB as it sequesters NFkB in an... 

Interleukin-8j interleukJn-6j and soluble tumour necrosis factor... 

Moss ML, Jin SL, MiUa ME et al (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385 733-736 Nixon RA, Cataldo AM (2006) Lysosomal system pathways genes to neurodegeneration in Alzheimer s disease. J Alzheimers Dis 9 277-289 Noorbakhsh F, VergnoUe N, HoUenberg MD et al (2003) Proteinase-activated receptors in the nervous system. Nat Rev Neurosci 4 981-990... 

Tumour necrosis factor 157 amino acids E. coli Animal cells Treatment of cancer ... 

IkB inhibitory protein kappa B lCAM-1 intercellular adhesion molecule 1 lL-1 interleukin-1 LDL low density lipoprotein MAPKs mitogen activated protein kinases MCP-1 macrophage chemotactic protein 1 M-CSF macrophage colony stimulating factor mmLDL minimally modified LDL NAC A-acetylcysteine NF-kB nuclear factor-kappa B oxLDL oxidised LDL PKC protein kinase C PMA phobol myristate acetate ROS reactive oxygen species TNF-a tumour necrosis factor alpha AM-1 vascular cell adhesion molecule 1... 

Upon stimulation of cells by a wide range of agents, including H2O2, tumour necrosis factor-a (TNFa), interleukin-1 (IL-1), interleukin-6 (IL-6), phorbol... 

A number of diflFerent animal models of uveitis have been developed) including that induced by organ-specific ocular antigens such as retinal S-antigen, rhodopsin and lens protein (Wacker et al., 1977 Rao et al., 1979). Other models are based on the injection of proteins foreign to the host, such as intravitreal injections of albumin or 7-globulin (Zimmerman and Silverstein, 1959 Kaplan etal., 1979). More recently, a third group of models has been developed based on the injection of inflammatory mediators such as interleukins-1 and 2, and tumour necrosis factor (Bhattacherjee and Henderson, 1987 ... 

Zimmerman, RJ., Chan, A. and Leadon, S.A. (1989). Oxidative damage in murine tumour cells treated in vitro by recombinant human tumour necrosis factor. Cancer Res. 49, 1644-1648. 

Tumour necrosis factor provokes superoxide anion generation from neutrophils. Biochem. Biophys. Res. Commun. 137, 1094-1100. 

During ischaemia, NOS is activated by calcium influx or by cytokines like tumour necrosis factor (TNF) or by lipopolysaccharide (LPS) and NO is produced in excess. It has been proposed that the excitotoxic effect of glutamate, which contributes to ischaemia-induced neuronal damage, is mediated by increased production of NO via a chain of events that includes increases in intracellular calcium (via glutamate activation of NMDA receptors), calcium activation of NOS, production of NO and peroxynitrite, and induction of lipid peroxidation. In fact, N-nitro-L-atginine, a selective inhibitor of NOS, has been shown to prevent glutamate-induced neurotoxicity in cortical cell cultures (Dawson rf /., 1991). 

Keffer J, Probert L, Cazlaris H, et al. Transgenic mice expressing human tumour necrosis factor a predictive genetic model of arthritis. EMBO J I99l 10(13) 4025 t031. 

D13. van Deuren, M., Kinetics of tumour necrosis factor-alpha, soluble tumour necrosis factor receptors, interleukin 1 -beta and its receptor antagonist during serious infections. Eur. J. Clin. Microbiol. Infect. Dis. 13,12-16 (1994). 

G10. Girardin, E., Roux-Lombard, P Grau, G. E., Suter, P., and Gallati, H., and Dayer J. M. The J5 Study Group. Imbalance between tumour necrosis factor-alpha and soluble TNF receptor concentrations in severe meningococcaemia. Immunology 76,20-23 (1992). 

K14. Kohan, D. E., Role of endothelin and tumour necrosis factor in the renal response to sepsis. Nephrol. Dial. Transplant. 9-4,73-77 (1994). 

K16. Kragsbjerg, P Holmberg, H and Vikerfors, T., Serum concentration of interleukin-6, tumour necrosis factor-a, and C-reactive protein in patients undergoing major operations. Eur. J. Surg. 161, 17-22 (1995). 

P10. Philip, R., and Epstein, L. B., Tumour necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, gamma-interferon and interleukin-1. Nature 323, 86-89(1986). 

W3. Waage, A., Halstensen, A., and Espevik, T., Association between tumour necrosis factor in serum and fatal outcome in pateints with meningococcal disease. Lancet 2,355-337 (1987). 

E, embryonic day BW, birthweight GR, growth-retardation OG, overgrowth N, normal TNF, tumour necrosis factor. 

Kaiser, G.C. and Polk, D.B. (1997) Tumour necrosis factor-a regulates proliferation in a mouse intestinal cell line. Gastroenterology 112, 1231-1240. 

Vassalli, P. (1992) The pathophysiology of tumour necrosis factor. Annual Review of Immunology 10, 411—452. 

Tumour Necrosis Factor Induces Pathology via iNOS... 

Garside, P., Bunce, C., Tomlinson, R.C., Nichols, B.L. and Mowat, A.M. (1993) Analysis of enteropathy induced by tumour necrosis factor alpha. Cytokine 5, 24-30. 

Mohler, KM., Sleath, P.R., Fitzner, J.N., Cerretti, D.P., Alderson, M., Kerwar, S.S., Torrance, D.S., Otten-Evans, C., Greenstreet, T., Weerawarna, K. et al. (1994) Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing. Nature 370, 218-220. 

Figure 10.4 Life and death decisions in cells. Cellular stimulation with tumour necrosis factor-a (TNFa) simultaneously activates survival and death signalling pathways. Reprinted with permission from Nature (from Pomerantz and Baltimore, 2000). Copyright (2000) Macmillan Magazines Limited. p50 and p65 are subunits of NFKB...

McCusker SM, Curran MD, Dynan KB, McCullagh CD, Urquhart DD, Middleton D et al. Association between polymorphism in regulatory region of gene encoding tumour necrosis factor a and risk of Alzheimer s disease and vascular dementia a case-control study. Lancet 2001 357 436 139. 

Chevalier S et al. Proteomic analysis of differential protein expression in primary hepatocytes induced by EGF, tumour necrosis factor alpha or the peroxisome pro-liferator nafenopin. Eur J Biochem 2000 267 4624-4634. 

VORDERMEIER S, SlNGH S, BiGGERSTAFF J, Harrison P, Grech H, Pearson TC, Dumonde DC, Brown KA. Red blood cells from patients with sickle cell disease exhibit an increased adherence to cultured endothelium pretreated with tumour necrosis factor (TNF). Br J Haematol 1992 81 591-597. 

Additional products Tumour necrosis factor (TNF), therapeutic enzymes 18 Various chapters... 

Tumour necrosis factor (human TNF-oc) 3 471 52 000 Mediator of inflammation and immunity... 

In other cases, the widespread application of a biopharmaceutical may be hindered by the occurrence of relatively toxic side effects (as is the case with tumour necrosis factor a (TNF-a, Chapter 9). Finally, some biomolecules have been discovered and purified because of a characteristic biological activity that, subsequently, was found not to be the molecule s primary biological activity. TNF-a again serves as an example. It was first noted because of its cytotoxic effects on some cancer cell types in vitro. Subsequently, trials assessing its therapeutic application in cancer proved disappointing due not only to its toxic side effects, but also to its moderate, at best, cytotoxic effect on many cancer cell types in vivo. TNF s major biological activity in vivo is now known to be as a regulator of the inflammatory response. 

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