TNF-a release

TNF-a is considered the primary mediator of sepsis, and concentrations are elevated early in the inflammatory response during sepsis, and there is a correlation with severity of sepsis. TNF-a release leads to activation of other cytokines associated with cellular damage and it stimulates release of arachidonic acid metabolites that contribute to endothelial cell damage. IL-6 is a more consistent predictor of sepsis as it remains elevated for longer periods of time than does TNF-a. 

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... 

COMPOUNDS ON MOUSE TNF-a RELEASE AND THEIR CYTOTOXIC ACTIVITIES... 

Based on the above descriptions, we examined the inhibitory effect of the Artocarpus flavonoids on TNF-a release stimulated by okadaic acid using BALB/3T3 cells. This experiment was carried out in co-operation with Dr. Fujiki s group (Saitama Cancer Center Research Institute, Japan). All the compounds tested inhibit the TNF-a release stimulated by... 

In lipopolysaccharide (LPS (-treated BV2 microglial cells A3 receptor activation suppresses tumor necrosis factor-a (TNF-a) production by inhibiting PI3K/Akt and NF-kB activation (Lee et al. 2006). Furthermore, it has been reported that in mouse RAW 264.7 cells the A3 receptor inhibits LPS-stimulated TNF-a release by... 

In conclusion as for the role of A3 receptors in the inhibition of TNF-a production in macrophages discrepant results have been obtained and not only due to the different species considered. For example some studies attributed reduction of TNF-a to A3 receptors either in human and mouse species (Sajjadi et al. 1996 McWhinney et al. 1996), whilst other found this effect to be mediated essentially by A2A and in minor part by A2B without the involvement of the A3 receptors again in both human and mouse species (Zhang et al. 2005 Kreckler et al. 2006). Therefore it is difficult in this case to verify the relevance of the A3 receptor-induced cellular response when other adenosine subtypes like A2A and A2B are also activated. As for the effects exerted by the A3 subtype in human monocytes and macrophages it is possible to find support for an anti-inflammatory role for this receptor as attested by reduction of tissue factor, oxidative burst and perhaps TNF-a release. Also the recent discovery of an increase in MMP9 supports a role for A3 agonists in the therapy of myocardial infarction (Velot et al. 2008) (Fig. 12.4). 

Thl proinflammatory cytokines such as IFN-y, IL-1/3, IL-12, and TNF-a released by macrophage and T lymphocytes in the vicinity of pancreatic beta cells have been implicated in the pathogenesis of type I (insulin-dependent) diabetes mellitus. Moreover, IL-18 serum levels are increased selectively during the early, subclinical stage of type I diabetes mellitus (N5). 

TNFa Inhibition of mouse TNF-a release from BALB/3T3 cells... 

Deakin AM, Payne AN, Whittle BJ, Moncada S. The modulation of IL-6 and TNF-a release by nitric oxide following stimulation of J774 cells with LPS and IFN-y. Cytokine 1995 7 408-16. 

The ubiquity of adenosine receptors in mammalian tissues suggests a vast array of therapeutic options. For example, it has recently been found that stimulation of the A2b receptors on human blood cells leads to complete inhibition of TNF-a release, a cmcial feature in interfering with septic shock [4]. A drawback, however, to a possible therapeutic use of adenosine receptor agonists is the common hypotensive action of this class of compounds. 

PDE IV inhibitors, as well as some combined PDE IIl/IV inhibitors, are currently under development for the treatment of asthma (Christensen and Torphy, 1994 Nicholson and Shahid, 1994). The basis for this development includes bronchodilatory activity directly related to inhibition of PDE IV, and/or PDE III, in airway smooth muscle, as well as the antiinflammatory activity of these compounds. PDE IV is the major cAMP PDE isozyme present in inflammatory cell types and inhibition of PDE IV has been linked to elevation of cAMP and inhibition of histamine or leukotriene release from mast cells, inhibition of oxygen free radical release from eosinophils or neutrophils, inhibition of adhesion, migration, or activation of eosinophils, and inhibition of TNF-a release from human monocytes (see Nicholson and Shahid, 1994, or Christensen and Torphy, 1994, for some reviews). There are now known to be at least four sub-types of PDE IV that are encoded by different cDNAs (Bolger et al., 1993 Davis et al, 1989 Livi et al., 1990). Although sequence homology of 75-90% is evident among subtypes, key differences, as well as cellular distribution, are apparent. Currently there are no selective inhibitors of the PDE IV subtypes. 

These authors concluded that verbascoside is the most active compound on TX-synthase inhibition therefore, caffeoyl moiety is an important function for this activity. The replacement by a feruloyl radical, leads to a complete loss of this activity. The attachment of a caffeate moiety at C-6 of glucose (case of isoverbascoside) appears to be favorable for COX-1 activity and TNF-a release inhibition, although it is detrimental for TX-synthase inhibition activity. 

Granberg, M., Fowler, C. J., and Jacobsson, S. O. P. (2001). Effects of the caimabimimetic fatty acid derivatives 2-arachidonoylglycerol, anandamide, palmitoylethanolamide and methanandamide upon IgE-dependent antigen-induced p-hexosaminidase, serotonin and TNF a release from rat RBL-2H3 basophilic leukaemia cells. Naunyn Schmiedebergs Arch. Pharmacol. 364, (y6-l i. 

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