Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:009512 (tumor necrosis factor)
 58,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocyte/macrophage-mediated tumor cytotoxicity was studied in patients infected with human immunodeficiency virus-1 (HIV-1) at various stages [Center for disease control (CDC) classification] of the disease. using the P-815 tumor cell line as target cells, the results demonstrated reduced monocyte/macrophage cytotoxicity early in HIV-1-related disease (CDCIII, P < 0.01). This cellular dysfunction sustained during the progression of the disease. Evidence could be presented that neither exogenous application of macrophage-stimulating cytokines (e.g. interferons) nor their endogenous induction in vitro restored monocyte/macrophage cytotoxicity. However, enhanced tumor necrosis factor (TNF)-alpha production, which parallels the observed reduced capacity to lyse P-815 tumor cells, might be the major source for monocyte/macrophage-mediated cell lysis. TNF-alpha-induced cytotoxicity can be inhibited by addition of anti-TNF-alpha. Other experimental models using TNF-sensitive tumor target cells may, therefore, mimic monocyte/macrophage-mediated lysis. Suppression of monocyte/macrophage cytotoxicity in later stages of HIV-1 infection (AIDS-related complex, AIDS) could partly be reverted by treatment with the cyclooxygenase blocker, indomethacin. The responsible arachidonic acid product mediating suppression was found to be prostaglandin E2, suggesting that in addition to the direct viral interference cellular dysfunction is at least in part a result of altered cytokine regulation.
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PMID:Cytokine-mediated regulation of monocyte/macrophage cytotoxicity in human immunodeficiency virus-1 infection. 128 2

A new approach to the treatment of malignant glioma is cytokine gene therapy to produce growth inhibitors in cells. Previously, we showed that human glioma cells selectively transfected with the gene of interferon (IFN)-beta and/or IFN-gamma by our novel liposomes tagged with monoclonal antibody against a glioma-associated antigen achieved a remarkable growth inhibition effect. In the present experiment, we demonstrated the effectiveness of gene therapy against glioma cells using liposomes bearing a plasmid containing the gene for tumor necrosis factor (TNF)-alpha. We also found that the effect of endogenous TNF-alpha was enhanced by treatment of IFN-gamma prior to the transfection with the TNF-alpha gene.
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PMID:Growth inhibition of glioma cells by liposome-mediated cell transfection with tumor necrosis factor-alpha gene--its enhancement by prior gamma-interferon treatment. 128 76

Human recombinant tumor necrosis factor-alpha (rTNF-alpha) was administered to normal Fischer 344 rats by stereotaxic intracerebral (IC) injection. Animals received a single injection of either 6 x 10(4) U rTNF-alpha or excipient in their right parietal lobe. Others received three consecutive daily injections of either 6 x 10(4) U rTNF-alpha or excipient to examine effects of higher accumulative doses. Histological examination of the brain revealed that both single and multiple IC injections of rTNF-alpha triggered an immigration of circulating leukocytes into the site of TNF-alpha injection. After one injection, this cell population was composed mainly of macrophages and neutrophils. Maximal leukocytic influx occurred by 48 h and was composed mostly of neutrophils which were limited to the injection site and perivascular space. Quantitation of the inflammatory reaction by measurement of tissue myeloperoxidase levels supported these histological observations. One day after multiple rTNF-alpha injections, leukocytic adhesion to endothelium, vascular cuffing and leukocytic infiltration into the neuropil was observed at levels comparable to those seen 3 days following a single rTNF-alpha injection. We conclude that while one or more IC injection(s) of 6 x 10(4) U rTNF-alpha was well tolerated in normal rats, at this dose the cytokine triggers a pronounced leukocytic infiltration at the site of injection. These results support a role for TNF-alpha as a mediator in inflammatory responses within the central nervous system.
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PMID:Histopathological effects of intracerebral injections of human recombinant tumor necrosis factor-alpha in the rat. 128

In vitro plasma perfusion experiments were performed using small columns containing either resin or charcoal adsorbents to assess the removal of cytokines and endotoxin. 125I-labelled tumor necrosis factor-alpha (TNF-alpha; 500 pg/ml) and interleukin-6 (IL-6; 10 ng/ml) were added individually to human plasma. Over 4 hr of perfusion, Amberlite XAD-7 resin removed 32.5% +/- 3.3% (n = 5) of the initial amount of TNF-alpha and 71.4% +/- 3.8% (n = 5) of the initial amount of IL-6. DHP-1 polyhema-coated activated charcoal removed 17.2% +/- 6.2% (n = 5) of TNF-alpha and 48.5% +/- 7.4% (n = 5) of IL-6. Preliminary experiments were performed with lipopolysaccharide (LPS; 100 ng/ml) and interleukin-1 alpha (IL-1 alpha; 500 pg/ml), which showed that, over 4 hr, Amberlite XAD-7 removed 10.3% of the initial LPS and 29.1% of IL-1 alpha, whereas DHP-1 charcoal removed 23.2% of the initial LPS and 65.3% of IL-1 alpha. In vitro plasma ultrafiltration with either polysulfone or polyacrylonitrile membranes, as used clinically in haemodialysis, was performed with recirculation of plasma containing LPS or TNF-alpha. Neither of the substances was filtered to a significant degree. In conclusion, direct removal of these inflammatory mediators from the circulation of patients with multiorgan failure due to fulminant hepatic failure or sepsis would be possible by perfusion of plasma through adsorbents but not by haemodialysis.
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PMID:In vitro plasma perfusion through adsorbents and plasma ultrafiltration to remove endotoxin and cytokines. 129 81

An expression plasmid encoding the extracellular portion of the human tumor necrosis factor (TNF) type 1 receptor (TNF-R1) was constructed and used to generate a stable cell line secreting soluble TNF-R1 (sTNF-R1). The sTNF-R1 was purified, and its biochemical properties and its interactions with human TNF-alpha were examined. SDS-PAGE resolved the purified sTNF-R1 into three bands of approximate Mr 24,200, 28,200, and 32,800. Sedimentation equilibrium analysis gave a molecular weight of 25,000 for sTNF-R1 whereas the molecular weight obtained by gel filtration chromatography was approximately 55,000-60,000. Scatchard analysis of [125I]TNF-alpha binding to sTNF-R1 revealed high-affinity binding (Kd = 93 pM), comparable to that observed for the intact receptor on whole cells. Competitive binding experiments showed that sTNF-R1 has a 50-60-fold higher affinity for TNF-alpha than for TNF-beta, in contrast to the equal affinities of TNF-alpha and TNF-beta for the full-length TNF-R1 transiently expressed in mammalian cells. The sTNF-R1 was found to block the cytotoxicity of TNF-alpha and TNF-beta on a murine L-M cell assay. The sizes of the sTNF-R1.TNF-alpha complex determined by gel filtration chromatography and sedimentation equilibrium were approximately 141 and 115 kDa, respectively. The stoichiometry of the complex was examined by Scatchard analysis, size-exclusion chromatography, HPLC separation, amino acid composition, sequence analysis, and sedimentation equilibrium. The data from these studies suggest that at least two molecules of sTNF-R1 can bind to a single TNF-alpha trimer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of a recombinant extracellular domain of the type 1 tumor necrosis factor receptor: evidence for tumor necrosis factor-alpha induced receptor aggregation. 131 Apr 20

Human cytomegalovirus (HCMV) is a potential cofactor in HIV-1 infection. To investigate the mechanism whereby HCMV promotes HIV-1 replication, a PBMC coculture assay which measures HIV-1 p24 antigen release was used as an index of viral replication. HCMV-stimulated PBMC were capable of inducing HIV-1 replication in cocultures with acutely infected PBMC; however, this occurred only when the PBMC were from HCMV-seropositive donors (598 +/- 207 versus 27 +/- 10 pg/ml p24 antigen with PBMC from HCMV-seronegative donors on day 6 of coculture). Upon stimulation with HCMV, PBMC obtained exclusively from HCMV-seropositive donors released tumor necrosis factor (TNF)-alpha (270 +/- 79 pg/ml at 18 h of culture). Monoclonal antibodies to TNF-alpha blocked the activity of HCMV-stimulated PBMC in cocultures both with acutely HIV-1-infected PBMC and with the chronically infected promonocytic line U1. Also, treatment of HCMV-stimulated PBMC with pentoxifylline, an inhibitor of TNF-alpha mRNA, markedly reduced HIV-1 replication in cocultures both with acutely and chronically infected cells. These results indicate that TNF-alpha is a key mediator of HIV-1 replication induced by HCMV-stimulated PBMC and support the concept that this cytokine plays an important role in the pathogenesis of HIV-1 infection.
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PMID:Human cytomegalovirus-stimulated peripheral blood mononuclear cells induce HIV-1 replication via a tumor necrosis factor-alpha-mediated mechanism. 131 Jun 98

The mechanism of tumor necrosis factor (TNF)-alpha signaling is unknown. TNF-alpha signaling may involve sphingomyelin hydrolysis to ceramide by a sphingomyelinase and stimulation of a ceramide-activated protein kinase. In a cell-free system, TNF-alpha induced a rapid reduction in membrane sphingomyelin content and a quantitative elevation in ceramide concentrations. Ceramide-activated protein kinase activity also increased. Kinase activation was mimicked by addition of sphingomyelinase but not by phospholipases A2, C, or D. Reconstitution of this cascade in a cell-free system demonstrates tight coupling to the receptor, suggesting this is a signal transduction pathway for TNF-alpha.
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PMID:Tumor necrosis factor-alpha activates the sphingomyelin signal transduction pathway in a cell-free system. 131 89

The pathogenesis of retrovirus-induced erythroid aplasia in cats is unknown. In studies to define mechanisms of cytotoxicity associated with retroviral infections, bone marrow mononuclear cells (BMMC) from healthy specific pathogen-free cats were co-cultured with uninfected feline embryonic fibroblasts (FEA cells) and FEA cells infected with feline leukemia virus (FeLV) of subgroup A (FEA-A) or subgroup C (FEA-C). Moderate to marked cytotoxicity (CPE) developed in co-cultures of BMMC and FEA-C cells on Days 5 to 7 of incubation but not in co-cultures of BMMC and FEA-A or BMMC and uninfected cells (FEA-CT). Cytotoxicity was associated with adherent cells of light density (1.056) from bone marrow and peripheral blood, which were positive for alpha naphthyl butyrate esterase activity. Stimulation of adherent cells with phorbol ester or addition of recombinant human tumor necrosis factor-alpha (rhTNF-alpha) caused similar CPE in FEA-CT cells. The TNF-alpha concentrations in the culture supernatants of BMMC+FEA-C were higher than those of BMMC+FEA-A or BMMC+FEA-CT, and addition of anti-TNF antibodies to the cultures blocked the CPE. These data support the hypothesis that macrophages exposed to FeLV-C cause CPE in co-cultures of BMMC and FEA cells by a mechanism involving TNF-alpha. It is suggested that TNF-alpha may be involved in the suppression of hematopoiesis in cats which develop FeLV-C induced erythroid aplasia.
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PMID:Cytotoxicity in feline leukemia virus subgroup-C infected fibroblasts is mediated by adherent bone marrow mononuclear cells. 131 51

The mechanisms underlying the effects of alcohol (ethanol, ETOH) on host defense are poorly understood. ETOH modulation of the cytokine regulatory network is one possible way by which ETOH could alter nonspecific immune function. In this study we examined the ability of acute alcohol intoxication to alter lipopolysaccharide (LPS)-induced changes in tumor necrosis factor (TNF)-alpha binding to neutrophils and isolated liver plasma membranes. Rats were injected intravenously with a primed constant infusion of ETOH for 7 hr to maintain blood ETOH concentration at approximately 35 mM. Four hours after the start of ETOH infusion, the animals received intravenously either sterile saline or LPS (100 micrograms/100 g body weight) and were sacrificed at the end of ETOH infusion. Blood neutrophils and liver plasma membranes were isolated, and TNF-alpha binding characteristics determined using recombinant human [125I]TNF-alpha. ETOH treatment alone induced a significant decrease (51%) of neutrophil Bmax for TNF-alpha, without affecting the cytokine binding to plasma membranes. LPS, with or without ETOH, significantly decreased (61%) neutrophil Bmax for TNF-alpha and increased (115%) its binding to liver plasma membranes. The KD values of binding to either neutrophils or liver plasma membranes were not altered by ETOH or LPS treatment of animals. By decreasing the cytokine binding to neutrophils, ETOH may impair the control exerted by TNF-alpha on cell function, thus damaging host defense.
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PMID:Effect of acute alcohol administration on TNF-alpha binding to neutrophils and isolated liver plasma membranes. 132 Aug 7

Preincubation of human peripheral blood polymorphonuclear leukocytes (HPPMN) with recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) enhanced the formylmethionyl-leucylphenylalanine (FMLP)-induced superoxide (O2-.) generation in a concentration- and preincubation time-dependent manner. The enhancement was very high for the FMLP- or opsonized zymosan (OZ)-induced O2-. generation, but was low for arachidonic acid (AA)- and phorbol myristate acetate (PMA)-induced O.2- generation. The rHuTNF-alpha has no effect on the steady state of intracellular calcium ion concentration ([Ca2+]i) nor on the membrane potential of neutrophils. The rHuTNF-alpha-primed FMLP-induced O2-. generation was inhibited by nicotineamide (NA), pertussis toxin (PT), and by the tyrosine kinase (TK) inhibitor, genistein, but was enhanced by the protein kinase C (PKC) inhibitor, H-7 (1-(5-isoquinolinesulfonyl)-3-methyl-piperazine). The inhibitory actions of NA and PT were also observed in in vivo primed guinea pig peritoneal neutrophils (GPtPMN). However, FMLP-induced O2-. generation of GPtPMN was enhanced by genistein, but was inhibited by H-7. These data indicate that TNF-alpha does not induce changes in [Ca2+]i nor in membrane potential of HPPMN, and that TNF-alpha-primed FMLP-induced O.2- generation of HPPMN is coupled with ADP-ribosylation and activation of G-proteins, and that protein kinases, especially TK, seem to exert an important role in the priming action of TNF.
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PMID:Effect of tumor necrosis factor-alpha on the stimulus-coupled responses of neutrophils and their modulation by various inhibitors. 132 5


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