TNF-a-production

Fig. 4.4 Simplified hypothesis of the mechanism of gpI20-induced dorsal root gangUon (DRG) neurotoxicity. CXCR4 binding on Schwann cells by SDF-Ia or gpI20 results in the release of RANTES, which induces tumor necrosis factor (TNF)-a production by DRG neurons, and subsequent TNFRl-mediated neurotoxicity in an autocrine/paracrine fashion. Reproduced with permission of John Wiley Sons, Inc. (Keswani et al. 2003b)...

Lee C, Tomkowicz B, Freedman BD, Collman RG. HIV-1 gpl20-induced TNF-a production by primary human macrophages is mediated by phosphatidylinositol-3 (PI-3) kinase and mitogen-activated protein (MAP) kinase pathways. J Leukoc Biol 2005 78(4) 1016-1023. 

In parallel, Tamura et al. [114] conducted a brief investigation into the cytotoxic effect of purified CNTs in cultured neutrophils isolated from human blood. Purified CNTs significantly increased superoxide anion and TNF-a production after 1 h, and caused cell death. Unfortunately, no details of the CNT structure, synthesis, or handling methods were provided. 

Compounds 674-676 are potent orally bioavailable inhibitors of tumor necrosis factor-a (TNF-a) production <2004BML4267, 2004JME2724>. 

It should also be mentioned that superoxide and not nitric oxide production by eNOS may have implications for atherosclerosis and septic shock due to imbalance between NO and superoxide formation, for example due to an increase in TNF-a production [164]. These pathophysiological functions of NO synthases will be considered in detail in Chapter 31. 

Early research showed that Pb exposure could increase sensitivity to bacterially-derived endotoxins [63] as well as increase production of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-a) by macrophages [64-67], Studies in several species indicate that Pb boosts production of TNF-a both immediately following adult exposure and in later life following gestational exposure. Flohe and coworkers [67] reported that Pb-induced elevation in TNF-a production is sensitive to both protein kinase C signaling as well as protein production. Not only can the production of TNF-a be elevated following exposure to Pb, but also the expression of the receptor for TNF-a (TNF-R) is elevated [68], Therefore, the combined effect of elevated cytokine production by macrophages as well as increased receptor expression would be expected to contribute to problematic inflammatory responses. 

Recently, the possibility to use C60 as anti-inflammatory compound has been reported (Huang et al., 2008). Fullerene-xanthine hybrids have been studied to determine if nitric oxide (NO) and tumor necrosis factor-alpha (TNF-a) production in lipopolysaccharide (LPS)-activated macrophages can be inhibited by hybrid administration, finding positive results. The presence of xanthine moiety seems to be essential for the inhibition of LPS-induced TNF-a production, while the fullerene portion ameliorates the efficiency in LPS-induced NO production blockage, leading to a new promising class of potent anti-inflammatoiy agents. It is necessary to mention also the opposite results obtained by an amino acid fullerene derivative tested on human epidermal keratinocytes at concentration from 0.4 to 400 pg/mL. 

Ground or unground MWNTs (0.2 or 5mg/rat) Female Sprague-Dawley rats Intratratracheal instillation 2 months, 3 Both ground MWNTs and unground MWNTs days, 15 induced inflammation and fibrotic days, 60 reactions and increased TNF-a production days Muller et al. (2005)... 

There is a great deal of evidence that AmB can exert a number of effects directly on cells of the immune system, and particularly on macrophages to increase nonspecific defense mechanisms against pathogens and cancer cells. These mechanisms include the production of nitric oxide (NO) (32) and tumor necrosis factor alpha (TNF-a) (33), which could contribute to the antifungal and antiparasitic activity of AmB. However, excess TNF-a production could also be responsible for some of the side effects associated with AmB treatment, such as fever and chills. 

Figure 5.12. Overview of the likely steps undertaken during the manufacture of the recombinant TNF-a product Beromun. Exact details do not appear to be freely available. It is unclear from the publicly available descriptions whether the product accumulates intracellularly in soluble form or in the form of inclusion bodies...

TNF -a production. Water-soluble cigarette smoke extract and/or respiratory syncytial virus (RSV), in cell culture, stimulated TNF-a release from monocytes by both RSV infection and smoke extract and an additive effect was observed. There was a decrease in NO release, significant only with smoke extract or a combination of smoke extract and RSV infection. Nicotine decreased both TNF-a and NO responses. The proportion of extreme responses with very high TNF-a and very low NO in the presence of both RSV and smoke extract... 

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