Disease relevance of TNF

• Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock [1].
• Tumor necrosis factor (TNF alpha), both by direct action and by trafficking cells of the immune system, is implicated in cardiopulmonary derangements and PMN-mediated microvascular injury associated with gram-negative sepsis [2].
• The serum factor inducing hemorrhagic necrosis of transplantable tumors [tumor necrosis factor (TNF)], and the macrophage hormone associated with cachexia in cancer and certain infectious diseases [cachectin] are known to be the same protein [3].
• TNF induced chief cell dysfunction might be responsible for the high plasma pepsinogen concentrations seen in patients with NSAID gastropathy or H pylori induced gastritis [4].
• Clinical results of isolated limb perfusion with high-dose TNF and melphalan for the treatment of melanoma and sarcoma have been promising, and attempts have been made to extrapolate this success to the isolated liver perfusion setting [5].

Psychiatry related information on TNF

• Pigs injected I.C.V. with 50 ng/kg TNF-alpha showed anorexia, hypersomnia, and an abrupt increase in plasma cortisol concentration [6].

High impact information on TNF

• It was found that CPZ protects mice, normal or adrenalectomized, and guinea pigs against lethality of LPS, and inhibited TNF serum levels, like dexamethasone (DEX), a well-known inhibitor of TNF synthesis [1].
• The present study was designed to define the potential of chlorpromazine (CPZ) as a protective agent against lipopolysaccharide (LPS) toxicity in comparison with glucocorticoids, and to obtain initial correlations with its effects on the levels of tumor necrosis factor (TNF), a pivotal mediator of endotoxic shock [1].
• Tumor necrosis factor-alpha blockade prevents neutrophil CD18 receptor upregulation and attenuates acute lung injury in porcine sepsis without inhibition of neutrophil oxygen radical generation [2].
• We describe here that in porcine aortic endothelial cells, either IL-1 alpha, TNF alpha or LPS upregulates an inhibitor of NF kappa B which we refer to as ECI-6 [7].
• From a therapeutic perspective, genetic engineering of EC to express an NF-kappaB inhibitor such as A20 offers the mean of achieving an anti-inflammatory effect without sensitizing the cells to TNF-mediated apoptosis [8].

Chemical compound and disease context of TNF

• Since pulmonary alveolar macrophages (PAM) may participate in early sepsis by producing TNF, we hypothesized that the TNF activity of PAM is reduced by ibuprofen, cimetidine, and diphenhydramine [9].
• OBJECTIVE: Platelet-activating factor (PAF) and eicosanoids are putative mediators of septic shock that are associated with release of tumor necrosis factor (TNF) [10].
• CSF lactate concentration was increased progressively in both meningitis groups, and positively correlated with CSF leukocyte numbers (r=0.41, p<0.001) and TNF-alpha level (r=0.43, p<0.001) [11].
• Ibuprofen administration in sepsis significantly decreased peak TNF activity by 2 units/ml and attenuated many of the physiological alterations due to sepsis [12].
• Plasma concentrations of the eicosanoids leukotriene (LT)B4, LTC4D4E4, thromboxane (TX)A2 and prostaglandin (PG)I2, and tumor necrosis factor (TNF) were measured during acute bacteremic shock and injury/hemorrhage in two porcine models [13].

Biological context of TNF

• The TNF genes are arranged in a tandem repeat, as is the case for the human, mouse and rabbit TNF genes [14].
• Significant up-regulation of IL-1beta and TNF-alpha mRNA levels in alveolar macrophages was observed at 24 and 30 h, respectively, compared to those in cells not exposed to soluble neutrophil products [15].
• To investigate the mechanism whereby AA inhibits up-regulation of genes encoding proinflammatory mediators, we examined the ability of ETYA to inhibit tumor necrosis factor-alpha (TNF-alpha) mediated phosphorylation and degradation of IkappaBalpha [16].
• The augmented TNF-alpha-induced NF-kappaB activation in HG was associated with increased TNF-alpha-mediated transcriptional activation of the vascular cell adhesion molecule-1 promoter [17].
• This study investigates whether chief cells express TNF receptors and, if so, whether their activation results in cell death [4].

Anatomical context of TNF

• The expression levels of Type 1 (IFN-gamma, IL-12), Type 2 (IL-4, IL-6), pro-inflammatory (TNF-alpha) and regulatory (IL-10, TGF-beta) cytokines were assessed by RT-PCR in the intestinal mucosa and spleen [18].
• This study examined how PNF is affected by Kupffer cell activation (beta-galactosidase), the generation of cytokines tumor necrosis factor alpha and interleukin 6, antioxidant mechanisms (ascorbic acid, alpha-tocopherol, reduced glutathione), circulating redox-active iron, and sinusoidal endothelial cell function (hyaluronic acid clearance) [19].
• Kupffer cells were more activated in PNF recipients, as suggested by higher beta-galactosidase levels (15 minutes after reperfusion), and secondarily, by higher production of tumor necrosis factor alpha and interleukin 6 (180 minutes after reperfusion) [19].
• Blood from the transplanted kidney renal vein was sampled directly at 0, 10, 20, 40, and 60 minutes posttransplantation for malondialdehyde (a reactive oxygen species marker), tumor necrosis factor-alpha (TNF-alpha), interleukins 6 and 8 (inflammatory cytokines), and erythrocyte-reduced glutathione (an antioxidant) [20].
• This finding suggests that TNF-alpha produced by infected neutrophils may be involved in the activation of alveolar macrophages and hence may contribute to the containment of M. tuberculosis infection during the early period of infection [15].

Associations of TNF with chemical compounds

• CPZ protected against LPS lethality when administered 30 minutes (min) before, simultaneously, or up to 10 min after LPS and was ineffective when given 30 min after LPS, paralleling the inhibitory effect on TNF production [1].
• However, co-mounting of TNF alpha preincubated pig jejunal fibroblasts (P2JF) monolayers back to back with untreated T84 monolayers dose-dependently induced an indomethacin sensitive increase in Isc compared with values in untreated co-mounted monolayers (p < 0.001, n = 11) [21].
• METHODS: Pigs underwent IHHP with TNF, melphalan, and MMC using balloon catheters or served as controls, receiving equivalent dosages of these agents intravenously [5].
• Because tumour necrosis factor alpha (TNF alpha) is an early mediator of inflammation and stimulates prostaglandin secretion, we investigated its effect on intestinal ion transport [21].
• Similarly, DEM and CDNB inhibited TNF-alpha-induced Akt and eNOS phosphorylation, suggesting that thiol modification is involved in eNOS inductive pathways [22].

Regulatory relationships of TNF

• IL-6 expression in transformed swine testicular (TST) fibroblasts was enhanced by TNF and IL-1 beta and to a lesser extent by poly(I).(C) and LPS [23].
• The expression of piap is strongly up-regulated upon treatment of endothelial cells (EC) with inflammatory cytokines TNF-alpha, IL-1 beta, and LPS [24].
• Stimulation of DCs with IFN-alpha/TNF-alpha or polyinosinic-polycytidylic acid (pIC) induced phenotypic maturation with increased MHC and CD80/86 expression, both with mock-treated and infected DCs [25].
• The role of TNF-alpha and IL-1 in the symptoms and pathology of porcine pleuropneumonia has recently been proven by use of an adenovirus vector expressing the anti-inflammatory IL-10 [26].
• Nuclear run-on transcription analysis demonstrated that the TNF alpha-stimulated increase in stromelysin and collagenase message levels was, at least partially, due to increased transcription [27].

Other interactions of TNF

• Treatment with anti-guinea pig TNF-alpha polyclonal antibody completely abolished the response of alveolar macrophages to neutrophil products [15].
• The inhibitory effect of PCV2 DNA was more diversified than if it had simply targeted CpG-ODN-induced cytokines (IFN-alpha, TNF-alpha, interleukin-6, IL-12) [28].
• The amount of secreted protein, as determined by TNF-alpha bioassay, was also suppressed by IL-4 [29].
• We verified the expression of mRNAs encoding the cytokines IL-1alpha, -6, -7, -8, -18, TNF-alpha and GM-CSF, but not TGF-beta or MCP-1 [30].
• We demonstrate that adenovirus mediated overexpression of I kappa B alpha, an inhibitor of NF-kappa B suppresses the expression of piap in response to TNF-alpha suggesting that piap is one of the NF-kappa B regulated genes that operates to prevent programmed cell death of EC in inflammation [24].

Analytical, diagnostic and therapeutic context of TNF

• Circulating concentrations of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by use of specific bioassays [31].
• Intra-arterial (i.a.) or intraperitoneal injections of double-stranded RNA induced pronounced fevers and strong elevations of circulating TNF-alpha and IL-6 [31].
• Western blot analysis revealed that preincubation of EC with ETYA for 40 min prior to stimulation with TNF-alpha inhibits the phosphorylation and degradation of IkappaBalpha [16].
• After termination of isolation, systemic TNF levels showed only a minor transient elevation, indicating that the washout procedure at the end of the perfusions was fully effective [5].
• Similar TNF-alpha clearance was observed in the selective plasma filtration groups and the plasma exchange group [32].

References