Tumor necrosis factor Characterization at the molecular, cellular and in vivo level

Abstract

TNF was originally characterized as an antitumor agent and a factor cytotoxic for many malignant cells. It is now clear that it plays an important role in the defense against viral, bacterial and parasitic infections, -and in (auto-)immune responses. Natural induction of TWF is protective, but its overproduction may he detrimental and even lethal to the host. The steucture of TNF and its interaction with the two types of cellular receptor are becoming better understood. TNF elicits a variety of events in different cell types. It subverts the electron transport system or the mitochondria into production of oxygen radicals, which can kill the (malignant) cells when these do not contain or produce protective enzymes. Furthermore, TNF induces a set of genes and at least part of this transcriptional activation is mediated by NFKB. The prospects of TNF as an antitumor drug can be improved on the one hand by agents such as LI+, which synergizes, and on the other hand by inhibitors of the systemic toxicity which do not interfere with the antitumor efficacy. Also, in tumor-bearing animals which have been rendered tolerant by administration of small doses of TNF, an effective and complete elimination of the tumors can be obtained by the combined action of TNF plus interferon.

Genetic regulation of host responses to Salmonella infection in mice

“…TNFa (reviewed in Ref. 132 ) is a pleiotropic proinflammatory cytokine produced mainly by macrophages but also by activated NK cells and TH1 lymphocytes. It is encoded by the Tnf gene and exerts its effects through two types of receptors: TNFRp55 (encoded by Tnfrsf1a for TNF receptor superfamily 1a gene) and TNFRp75 (Tnfrsf1b).…”

Granulocyte macrophage-colony stimulating factor and interleukin-3 increase expression of type II tumour necrosis factor receptor, increasing susceptibility to tumour necrosis factor-induced apoptosis. Control of leukaemia cell life/death switching

“…1 Although TNF was first recognised for its ability to induce haemorrhagic necrosis of certain tumours, 2 it also mediates a variety of other physiological responses, including differentiation, inflammation and proliferation as well as apoptotic and necrotic cell death. 3 TNF also produces the systemic effects of fever and cachexia. 4 TNF mediates its actions by binding to distinct cell surface receptor types, Tumour necrosis factor receptor (TNFR)1 (p55TNFR or CD120a) and TNFR2 (p75TNFR or CD120b), 5 and the existence of two receptor subtypes may partially explain the disparity of TNF-induced effects.…”

Transgene expression of α tumor necrosis factor with mutations D142N and A144R under control of human telomerase reverse transcriptase promoter eradicates well-established tumors and induces long-term antitumor immunity

“…These include septic-like shock syndrome, hypotension, malaise, diarrhea, leukothrombopenia, anorexia, and so on. [8][9][10] The p55 TNF-a receptor (TNFR) is primarily responsible for signaling in variety of responses including cytotoxicity 11,12 and cytokine secretion, 13 whereas the p75 TNFR is responsible for lymphoproliferative signals and activation of T cells. 12,14,15 To induce high local concentration of TNF-a while limiting systemic use of a high dose of TNF-a, isolated limb perfusion with TNF-a has been applied with less systemic toxicity.…”