Disease relevance of TNF

• CD30 is a surface marker for neoplastic cells of Hodgkin's lymphoma and shows sequence homology to members of the tumor necrosis factor (TNF) receptor superfamily [1].
• Under the appropriate conditions, such human TNF mutants are expected to induce less systemic toxicity in man, while still exerting their direct antitumour effect [2].
• Unexpectedly, when both TNFRs were activated simultaneously by agonistic antibodies or coculture with cells expressing a noncleavable membrane form of TNF, HIV production was downregulated and induction of cell death was enhanced in ACH-2 cells [3].
• Tumor necrosis factor (TNF) and lymphotoxin (LT) are highly pleiotropic cytokines that play a central role in regulating HIV-1 replication [3].
• Passive immunization with anti-TNF-alpha/beta-neutralizing monoclonal antibody also conferred protection, indicating that it is TNF which is critical for initiating toxic shock symptoms [4].

Psychiatry related information on TNF

• Tumor necrosis factor (TNF) alpha initiates the cytokine cascade, and high levels are associated with dementia and atherosclerosis in persons aged 100 years [5].
• BACKGROUNDS AND AIMS: Polymorphisms of proinflammatory cytokines, such as interleukin (IL) 1beta and tumor necrosis factor (TNF) alpha, are associated with individual differences in gastric mucosal inflammation and acid inhibition in response to Helicobacter pylori infection [6].
• The role of TNF and its receptors in Alzheimer's disease [7].
• Within the 24 h TNF declined significantly in the therapy group (p = 0.006), while IL-6 showed a significant increase (p = 0.043) [8].
• Brain levels of IL-1 and TNF correlate with sleep propensity; for example, after sleep deprivation, their levels increase [9].

High impact information on TNF

• Disruption of the LT/TNF/LIGHT network alleviates inflammation in certain autoimmune disease models, but decreases resistance to selected pathogens [10].
• Randomized, placebo-controlled, multi-center clinical trials of human TNF alpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage [11].
• The last four years have seen a proliferation in knowledge of the proteins participating in the signaling by the TNF system and CD95 [12].
• However, the molecules that initiate these signaling events, including the death domain- and TNF receptor associated factor (TRAF) domain-containing adapter proteins and the signaling enzymes associated with them, are largely unique to the TNF/nerve growth factor receptor family [12].
• Active antigen-driven death is mediated by the expression of death cytokines such as FasL and TNF [13].

Chemical compound and disease context of TNF

• Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. VEST Investigators for TNF Genotype Analysis. Vesnarinone Survival Trial [14].
• RA treatment also decreased TNF receptors on acute monocytic leukemia cell line THP-1 [15].
• Hepatoma cells treated with TNF and cycloheximide undergo apoptosis, which is proceeded by a strong activation of JNK [16].
• PURPOSE: Isolated limb perfusion (ILP) with tumor necrosis factor (TNF), interferon gamma, and melphalan (M) has been reported to result in high response rates for extremity melanoma and sarcoma [17].
• The molecular basis of cross-resistance to tumor necrosis factor (TNF) and Adriamycin has been investigated using the breast adenocarcinoma cell line MCF7/p, its Adriamycin-resistant counterpart MCF7AdrR, and the MDR1 gene-transduced MCF-7 cells (MCF7/MDR1) [18].

Biological context of TNF

• Most importantly, JNK activation is not involved in induction of apoptosis, while activation of NF-kappaB protects against TNF-induced apoptosis [19].
• Tumor necrosis factor (TNF) is a proinflammatory cytokine that induces conflicting pro- and antiapoptotic signals whose relative strengths determine the extent of cell death [20].
• Through its type 1 receptor (TNFR1), the cytokine TNF elicits an unusually wide range of biological responses, including inflammation, tumor necrosis, cell proliferation, differentiation, and apoptosis [19].
• TRAF proteins are major mediators for the cell activation, cell survival, and antiapoptotic functions of the TNF receptor superfamily [21].
• A human tumor necrosis factor (TNF) binding protein from serum of cancer patients was purified to homogeneity and partially sequenced [22].

Anatomical context of TNF

• The response of human epithelial cells to TNF involves an inducible autocrine cascade [20].
• We show here that the transmembrane form of TNF is superior to soluble TNF in activating TNFR80 in various systems such as T cell activation, thymocyte proliferation, and granulocyte/macrophage colony-stimulating factor production [23].
• The TNF-R2-/- mice show normal T-cell development and activity, but we find that they have increased resistance to TNF-induced death [24].
• Our results indicate that there is a single class of specific high-affinity receptors for TNF on this cell line which has a Kd of about 0.2 nM and an average of 2,000 receptor sites per cell [25].
• Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock [26].

Associations of TNF with chemical compounds

• Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures [26].
• Geldanamycin (GA), an antitumor agent that disrupts the formation of this heterocomplex, prevents TNF-induced activation of IKK and NF-kappaB [27].
• Tumor necrosis factor (TNF) is a potentially useful adjunct to anticancer therapies [28].
• The present studies show that ionizing radiation, like TNF, induces rapid sphingomyelin hydrolysis to ceramide and apoptosis in bovine aortic endothelial cells [29].
• TNF immunoreactivity was maximum at 1.5 h, and total TNF (area under the curve) was 4.2- and 4.5-fold greater in subjects given endotoxin/ibuprofen compared to subjects given endotoxin alone (p = 0.026) or endotoxin/pentoxifylline (p = 0.004), respectively [30].

Physical interactions of TNF

• Human embryonic kidney cells transfected with a TNF-R expression vector specifically bind both 125I-labeled and biotinylated TNF-alpha [22].
• Identification of Grb2 as a novel binding partner of tumor necrosis factor (TNF) receptor I [31].
• Inhibition of tumor necrosis factor (TNF) activity by the addition of TNF-binding protein reduced IL-18-stimulated HIV-1 production by 48% [32].
• The TNF-alpha mediated transcriptional activation of a chloramphenicol acetyltransferase (CAT) plasmid containing three copies of the -72 kappa B binding site from the IL-6 promoter was abrogated by PDTC [33].
• GM2 and GM3 each inhibited Ig production, thymidine uptake, and TNF-alpha production by surface IgG1+ (slG1+), sIgG2+, sIgG3+, sIgG4+, and sIgM+ B cells without affecting IL-2 binding or TNF-alpha binding to B cells, but had no such inhibitory effects on sIgA1+ or sIgA2+ B cells [34].

Enzymatic interactions of TNF

• Here we show that TRAF1 (but not TRAF2-6) is cleaved by certain caspases in vitro and during TNF-alpha- and Fas-induced apoptosis in vivo [35].
• TNF-alpha-converting enzyme (TACE) is known to cleave TNF at the Ala-76-Val-77 site [36].
• In adherent neutrophils, when beta-integrin signaling is activated, TNF phosphorylates TNFR-1 and activates prosurvival and antiapoptotic signaling [37].
• Western blottings and electrophoretic mobility shift assays revealed that incubation with TNF-alpha induced degradation of inhibitor kappaB (I kappaB) and expression of phosphorylated ERK1/2 [38].
• In coimmunoprecipitation experiments, IKKalpha/beta was found to be associated with c-Src and to be phosphorylated on its tyrosine residues after TNF-alpha or TPA treatment [39].

Regulatory relationships of TNF

• Moreover, IFN-gamma applied to septic patients with low monocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-alpha secretion [40].
• Peripheral blood (PB) T cells activated by IL-15 induced significant TNF-alpha production by macrophages via a cell-contact-dependent mechanism [41].
• TNF induced a modest rise in IL-10 concentrations peaking after 45 min (47 +/- 32 pg/ml; p < 0.05) [42].
• In addition, IL-2 and IL-12 synergize with sCD23 to induce TNF-alpha production [43].
• The TNF-alpha-induced cell adhesion to HUVEC was found to be controlled almost exclusively by TNF-R55 [44].

Other interactions of TNF

• However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced [45].
• These observations raise the possibility that a surface LT alpha-LT beta complex may have a specific role in immune regulation distinct from the functions ascribed to TNF [46].
• They can be recruited to activated TNF receptors either by direct interactions with the receptors or indirectly via the adaptor protein TRADD [21].
• Here we describe human TNF mutants that sill interact with the human TNF-R55 receptor but which have largely lost their ability to bind to human TNF-R75 [2].
• These findings identify a physiologic role for c-IAP1 and define a mechanism by which TNF-RII-regulated ubiquitin protein ligase activity can potentiate TNF-induced apoptosis [47].

Analytical, diagnostic and therapeutic context of TNF

• But clinical trials in cancer patients have on the whole been disappointing, and it has been estimated that a TNF dose would be effective only at 5-25 times the maximum tolerated dose [2].
• Western blot analyses and cytotoxicity assays with L cells as targets indicated that these T cell lines and peripheral blood T cells secreted TNF [48].
• The induction of mRNA synthesis and accumulation of TNF/cachectin and lymphotoxin (LT) mRNAs in T leukemic cell lines and freshly isolated T cells were studied by Northern blot analyses [48].
• To assess the role of TNF in the induction of IL-10 in endotoxemia, four healthy men were studied after a bolus intravenous injection of recombinant human TNF (50 micrograms/m2) [42].
• Intravenous infusion of the p75TNF produced none of the hemodynamic changes seen after the infusion of TNF [28].

References