TNF synthesis

Ferger B, Leng A, Mura A, Hengerer B, Feldon J (2004) Genetic ablation of tumor necrosis factor-alpha (TNF-alpha) and pharmacological inhibition of TNF-synthesis attenuates MPTP toxicity in mouse striatum. J Neurochem 89 822-833. 

Cytokine Production/Cellular Activation TNFa and IFNy mediate the induction of other cytokines (IL-1 and IL-6) and the activation of phagocytes. It has been suggested that particle-induced expression of MIP-2 and cytokine-induced neutrophil chemoattractant CKs in the rat lung are mediated at least in part by production of TNFa. TNF is involved in control of monocyte-mediated regulation of cytokine production by T cells. Preincubation of monocytes with rTNF enhanced their ability to induce IFNy production, and TNF synthesis inhibitors decreased this induction. However, Th2 cells are stimulated in the relative absence of monocyte co-stimulatory signal(s), probably IL-6. Concerning pain responsivity, TNFa produces dose-dependent hyperalgesia mediated via the induced release of IL-lp. ... 

Extensive investigations have been performed related to the synthesis of new adamantane derivatives with better therapeutic actions and less adverse effects. For example, it has been proved that adamantylamino-pyrimidines and -pyridines are strong stimulants of mmor necrosis factor-a (TNF-a) [132]. TNF is a substance that can improve the body s namral response to cancer by killing cancer cells. Another example is 1,6-diaminodiamantane [87], which possesses an antitumor and antibacterial activity. Also, many derivatives of aminoadamantanes have antiviral activity like 3-(2-adamantyl) pyrolidines with two pharmacophoric amine groups, which have antiviral activity against influenza-A virus [133]. 

IL-1 (17.5) Monocyte/macrophage, lymphocyte, neutrophil, endothelium, fibroblast keratinocyte Activation of T cells, B cells, natural killer cells, osteoblasts, and endothelium. Induces fever, sleep, anorexia, ACTH release, hepatic acute phase protein synthesis and HSPs. Leads to myocardial depression, hypercoagulability, hypotension/sbock, and death. Simulates production of TNF, IL-6, and IL-8 and stress hormone release. Suppression of cytochrome P-450, thyro-globulin, and lipoprotein synthesis. Procoagulant activity. Antiviral activity. 

Wang, X. C., C. Allen et al. (2007). Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages. J. Clin. Immunol. 27(2) 193-200. 

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. 

Like all other cytokines, administration of IL-2 can induce side effects that can be dose limiting. Serious side effects, including cardiovascular, hepatic or pulmonary complications, usually necessitate immediate termination of treatment. Such side effects may be induced not only directly by IL-2, but also by a range of additional cytokines whose synthesis is augmented by IL-2 administration. These cytokines, which can include IL-3, -4, -5 and -6, as well as TNF and IFN-y, also likely play a direct role in the overall therapeutic benefits accrued from IL-2 administration. 

Table 9.5 The major cellular sources of human TNF-p. As is evident, TNF-a synthesis is not restricted to cells of the immune system, but is undertaken by a wide variety of different cells in different anatomical locations, including the brain...

In addition, TNF-a influences immunity indirectly by promoting synthesis and release of a variety of additional cytokines, including interferons, IL-1, IL-6, IL-8 and some CSFs. 

It appears that TNF-R55 is capable of mediating most TNF activities, whereas the biological activities induced via the TNF-R75 receptor are more limited. For example, TNF s cytotoxic activity, as well as its ability to induce synthesis of various cytokines and prostaglandins, is all mediated mainly/exclusively by TNF-R55. TNF-R75 appears to play a more prominent role in the induction of synthesis of T-lymphocytes. All of the biological activities mediated by TNF-R75 can also be triggered via TNF-R55, and usually at much lower densities of receptors. TNF-R75 thus appears to play more of an accessory role, mainly to enhance effects mediated via TNF-R55. 

Tumor necrosis factor a (TNF-a) is a multifunctional cytokine produced by activated monocytes-macrophages. TNF-a is one of the most potent osteoclastogenic cytokines produced in inflammation, and, in addition, TNF-a induces IL-1 synthesis. Like the other known stimulators of bone resorption, it acts through osteoblastic cells however, it has been demonstrated that TNF-a is able to induce osteoclast formation from stromal-depleted macrophages, with potency similar to that of RANKL (Kobayashi et al. 2000). TNF-a is able to induce bone resorption in vitro (Thomson et al. 1987) as well as in vivo (Koning et al. 1988). Osteoclasts induced by TNF-a have the capacity to form resorption pits on dentine slices only in the presence of IL-la. TNF-a, together with IL-1, plays an important role in bone resorption in inflammatory diseases (Kobayashi et al. 2000). Inhibition of TNF by TNF binding protein (TNFbp) completely prevents bone loss and osteoclast formation (Kimble et al. 1997). 

Interleukin-6 (IL-6) is a member of the gpl30 cytokine family and is con-stitutively produced by several cells of bone microenvironment, particularly by osteoblasts and their precursors (Heymann et al. 2000). The main function in bone is on OCS and bone resorption, and its effects are connected to those of IL-1, TNF-a, and PTHrP. IL-6 induces osteoclastlike formation by inducing IL-1 synthesis, and the addition of anti-IL-1 inhibits osteoclast formation by IL-6 (Kurihara et al. 1990). Moreover, IL-6 mediates the effects of TNF-a and enhances PTHrP-induced hypercalcemia and bone resorption by increasing the osteoclast progenitor pool and differentiation into mature osteoclasts (Devlin et al. 1998). 

Independently, if these cytokines can exert their bone resorption functions without RANKL, they all stimulate the production of RANKL for stromal/OB cells, and conversely RANKL is able to increase IL-1 and TNF-a synthesis in vitro. To complicate this scenario, these systems of cytokines connect with the network of systemic hormones, such as PTH, PTH-related protein (PTHrP), vitamin D3, estrogens, androgens, glucocorticoids, and T4, since the hormones regulate the production of many of these cytokines by stromal/OB cells (Manolagas et al. 1995 Bellido et al. 1995 Lakatos et al. 1997). 

Fig. 7.3. Osteoclastogenesis after estrogen deficiency. Estrogen deprivation leads to an increase in the synthesis of RANKL for stromal/OB cells of the BM. This increase in the expression of RANKL leads to an increase in OCS. Estrogen deficiency also induces the synthesis and secretion of cytokines, such as IL-6 and M-CSF, that increase the number of preosteoclasts in the BM, and thus increases OCS. Nonetheless, certain cells of the immune system, such as monocytes and T-cells, intervene in the process when the supply of estrogens fails. These cells secrete IL-1 and TNF-a that are powerful inductors of OCS. When estrogens or agonists of estrogen receptors like raloxifene are administered, the synthesis and secretion of many of the mentioned cytokines diminish and the synthesis and liberation of OPG and TGF-/S are stimulated. These molecules inhibit OCS by inhibiting the RANKL/RANK signal pathway and by promoting osteoclast apoptosis...

Other Factors. ECT no doubt destroys the homeostasis of the cancerous cells by profoundly disturbing their microenvironment and by dismantling their structure. It might also lead to the inhibition of their DNA synthesis. It has been speculated that ECT might release the Tumor Necrosis Factor (TNF) or, somehow super-activate the immune system at the tumor site. 

TNF-a elicits a wide range of responses in cells and tissues. Apart from causing the lysis of certain tumours (by mechanisms probably related to the ability of the target to induce the synthesis of the mitochondrial manganese-dependent superoxide dismutase, Mn-SOD), it can also kill normal cells. These effects on normal cells are more apparent when biosynthesis is blocked - for example, by the addition of inhibitors of macromolecular bio-... 

IL-6 expression can be activated in neutrophils upon exposure to GM-CSF and TNF, whilst IL-3, G-CSF, y-interferon and lymphotoxin do not induce expression of this cytokine. Expression of IL-6 has been identified by analysis of mRNA levels and by protein analysis. Following GM-CSF exposure, expression is detectable by 2 h, maximal by 6 h and then returns to base-line levels. LPS, PMA (but not fMet-Leu-Phe) and cycloheximide also induce IL-6 transcripts. The finding that this protein-synthesis inhibitor increases mRNA levels suggests either that transcription is regulated by a short-lived repressor, or else that decay of its mRNA may be regulated by a short-lived RNase. 

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