Tumour necrosis factor a

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... 

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. 

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). 

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

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. 

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. 

Cumberbatch, M., Dearman, R.J., and Kimber, I., Langerhans cells require signals from both tumour necrosis factor a and interleukin ip for migration. Immunology, 92,388,1997. 

Acute phase reactants tumour necrosis factor-a, interleukin-6 and -8,... 

The term cytokine was first introduced in the mid-1970s. It was applied to polypeptide growth factors controlling the differentiation and regulation of cells of the immune system. The interferons (IFNs) and interleukins (ILs) represented the major polypeptide families classified as cytokines at that time. Additional classification terms were also introduced, including lymphokines [cytokines such as interleukin-2 (IL-2) and interferon-y (IFN-y), produced by lymphocytes] and monokines [cytokines such as tumour necrosis factor-a (TNF-a) produced by monocytes]. However, classification on the basis of producing cell types also proved inappropriate, as most cytokines are produced by a range of cell types, e.g. both lymphocytes and monocytes produce IFN-a. 

Hauschildt, S., Scheipers, P., Bessler, W. G., and Mulsch, A. (1992). Induction of nitric oxide synthase in L929 cells by tumour-necrosis factor a is prevented by inhibitors of poly(ADP-ribose) polymerase. Biochem. J. 288, 255-260. 

Endotoxaemia. - Exposure to bacterial endotoxin (lipopolysaccharide) can induce the production of pro-inflammatory mediators (e.g. tumour necrosis factor a and interleukin 1), culminating in septic shock profound vasodilation... 

Recent evidence suggests that atherosclerosis is a chronic inflammatory process. The recruitment of mononuclear leukocytes and formation of intimal macrophage-rich lesions at specific sites of the arterial tree are key events in atherogenesis. Alterations of chemotactic and adhesive properties of the endothelium play an important role in this process [82]. Quercetin has been reported to inhibit the expression in glomerular cells of monocyte chemoattractant protein-1 (MCP-1) [83] a potent chemoattractant for circulating monocytes. Red wine reduced MCP-1 mRNA and protein expression in abdominal aorta of cholesterol fed rabbits after balloon injury and this effect was associated with a reduced neointimal hyperplasia [84]. The antioxidant-mediated inhibition of nuclear factor k B (NFkB) and the subsequent non selective reduction of cytokine transcription have been suggested to be responsible for these effects [83]. Additionally, quercetin downregulated both phorbol 12-myristate 13-acetate (PMA)- and tumour necrosis factor-a (TNFa)-induced intercellular adhesion molecule-1 (ICAM-1) expression in human endothelial cells [86]. 

Nicholas R. S. J., Compston A., and Brown D. R. (2001). Inhibition of tumour necrosis factor-a (TNFa)-induced NF-kB p52 converts the metabolic effects of microglial-derived TNFa on mouse cerebellar neurones to neurotoxicity. J. Neurochem. 76 1431-1438. 

Habtemariam, S. Natural inhibitors of tumour necrosis factor-a production, secretion and function, Planta Med., 66, 303-313, 2000. 

Hofmann, C., Lorenz, K, Braithwaite, S. S., Colca, J. R., Palazuk, B.J., Hotamisligil, G. S., and Spiegelman, B. M. (1994). Altered Gene Expression for Tumour Necrosis Factor-A and Its Receptors During Drug and Dietary Modulation of Insulin Resistance. Endocrinology 134, 264—270. 

Elliott, M. J., Maini, R. N., Feldmann, M., Kalden, J. R., Antoni, C., Smolen, J. S. et al. (1994). Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor a (cA2) versus placebo in rheumatoid arthritis. 

Ebert, E.C. 1998. Tumour necrosis factor-a enhances intraepithelial lymphocyte proliferation and migration. Gut 42 650-655. 

Tumour necrosis factor-a (TNFa) accumulates in the brain after trauma. This cytokine is known to be an important factor in delayed CNS damage. It was found that, in addition to its anti-NMDA effect, HU-211 causes up to 90% inhibition of the TNFa surge after closed head injury in rats [195], Bacterial and viral infections of the CNS are known to cause secretion of the TNFa as well as interleukin-1 and other cytokines which are involved in the inflammatory process and may cause secondary damage. Such infections may result in high mortality. It was found that rats infected with Streptococcus pneumoniae suffered less cerebral oedema on treatment with a combination of a suitable antibiotic with HU-211 than the antibiotic alone [196],... 

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