Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:017444 (TNF)
 61,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present experiments was to test the possible involvement of nitric oxide (NO) in cytokine-induced enhancement of tumor cell (TC) adhesion to endothelial cells (ECs). Exposure of EA hyb 926 cells to TNF (500 U/ml) plus IFN (100 U/ml) for 24 h significantly enhanced their adhesivity for the 51Cr-labeled GLC1 (small cell lung carcinoma) TCs. Conversely, exposure of TCs to cytokines did not result in an increased adhesion of these cells to ECs. TC-stimulated adhesion to EA hyb 926 was abrogated by the glucocorticoid dexamethasone (Dex, 10(-7) M), the NO synthase inhibitors N omega-nitro-L-arginine methyl ester (L-NAME, 10(-5) M) and NG-monomethyl-L-arginine (L-NMMA, 10(-5) M) and the protein synthesis inhibitor cycloheximide (Cex, 10(-6) M). Furthermore, GLC1-stimulated adhesion to EA hyb 926 was reversed following removal of L-arginine from the medium or pretreatment with the guanylate cyclase inhibitor methylene blue. TC-stimulated adhesion was also prevented when TCs were pretreated with the monoclonal antibody CD15 directed against the endothelial-leukocyte adhesion molecule (ELAM-1) ligand or following exposure of ECs to anti-ELAM-1 monoclonal antibody. Although suppressing TC-stimulated adhesion, L-NMMA failed to modify significantly cytokine-induced ELAM-1 expression in EA hyb 926. These results (a) provide evidence for the NO-inducible pathway contributing to cytokine-induced enhancement of tumor cell adhesion to the vascular endothelium and (b) demonstrate the involvement of the ELAM-1/CD15 adhesion system in tumor cell-stimulated adhesion to ECs.
 ...
PMID:Involvement of nitric oxide in tumor cell adhesion to cytokine-activated endothelial cells. 128 56

Nitric oxide (NO) is synthesized in vascular endothelial cells, and appears to play an important role in the control of blood pressure and platelet aggregation. A detailed understanding of the regulation of NO synthesis by endothelial cells has been hampered by the lack of molecular clones for endothelial NO synthase; we now report the isolation and characterization of such clones. The constitutive NO synthases present in endothelial cells and in brain share common biochemical and pharmacologic features. We purified NO synthase from bovine brain, and determined the amino acid sequence of several tryptic peptides. These sequence data were utilized to design PCR-generated NO synthase cDNA probes, which were used to isolate clones encoding NO synthase from a bovine aortic endothelial cell (BAEC) cDNA library. A full-length NO synthase cDNA clone was isolated, representing a protein of 1,205 amino acids with a molecular mass of 133 kDa. The deduced amino acid sequence of the BAEC NO synthase cDNA differs at numerous residues from the sequence determined for the purified bovine brain protein, and shows 50-60% sequence identity with recently isolated molecular clones for murine macrophage and rat brain NO synthase isoforms. Bovine genomic Southern blots probed with bovine brain and BAEC NO synthase cDNA probes identify distinct bands, indicating that these cDNAs are the products of different genes. Prolonged treatment of BAEC with the cytokine TNF alpha, which results in a marked increase in NO synthase activity, is associated with a decrease in the abundance of the 4.8-kb BAEC NO synthase transcript.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Molecular cloning of constitutive endothelial nitric oxide synthase: evidence for a family of related genes. 128 83

Tumor necrosis factor alpha (TNF-alpha) exerts multiple actions on endothelial cells including among others the expression of pro-coagulant activity and adhesion molecules, and secretion of cytokines. We now show that TNF-alpha induces a time- and dose-dependent cytotoxic effect on cultured bovine aortic endothelial cells. This TNF-induced cytotoxicity, which is preceded by increased production of nitric oxide (NO), is significantly decreased by the NO synthase inhibitor N-iminoethyl-L-ornithine (L-NIO). Dexamethasone, which prevents the expression of cytokine-induced NO synthase in endothelial cells, also inhibits TNF-alpha-dependent cytotoxicity. The results indicate that NO is involved in the cytotoxic effect of TNF-alpha on endothelial cells.
 ...
PMID:Nitric oxide mediates tumor necrosis factor-alpha cytotoxicity in endothelial cells. 137 28

Tumor necrosis factor-alpha (TNF alpha) is elevated in the sera of rats administered non-lethal doses of carbon tetrachloride (CCl4) followed by endotoxin. Elevated TNF alpha levels are correlated with the increased release of hepatic enzymes indicating hepatic damage. Under these conditions, nitric oxide (NO) was also produced in the liver as evidenced by the formation of nitrosyl complexes which were measured by electron paramagnetic resonance (EPR) spectroscopy. Decreased nitrosyl complex formation occurred in livers following treatment with either an inhibitor or macrophage activation (gadolinium trichloride; GdCl3), an inhibitor of cytokine responses (dexamethasone) or a NO synthase inhibitor (NG-monomethyl-L-arginine; 1-NMA), GdCl3 or dexamethasone treatment decreased, while 1-NMA treatment increased, TNF alpha serum level. Taken together, these data suggest that TNF alpha and NO are induced following CCl4 and LPS exposure and may be important regulators in the hepatotoxicity of this liver injury model.
 ...
PMID:Tumor necrosis factor-alpha and nitric oxide production in endotoxin-primed rats administered carbon tetrachloride. 747 81

Nitric oxide (NO) is a mediator of vasodilatation and bronchodilatation synthesised from L-arginine by the enzyme NO synthase, which is either constitutive or induced by lipopolysaccharides and/or cytokines. The presence and function of NO synthase in normal or diseased lung is not yet clear. Asthma is characterised by bronchial hyperresponsiveness, epithelial damage, inflammation, and increased cytokine production. To investigate the presence of NO synthase in asthma, we immunostained bronchial biopsies from non-steroid-treated people with asthma and non-asthmatic controls with specific polyvalent antisera to purified inducible NO synthase and to a selected peptide sequence of the same enzyme. Immunoreactivity was seen in the epithelium and some inflammatory cells in 22 of 23 biopsies from people with asthma, but in only 2 of 20 controls. To assess the relation of cytokines to NO synthase induction, bronchial epithelial cells in culture were stimulated with tumour necrosis factor (TNF alpha). Inducible enzyme immunoreactivity was found only in the treated cells. The existence of inducible NO synthase in human lungs suggests that increased production of NO, probably induced by cytokines, may be relevant to the pathology of asthma.
 ...
PMID:Induction of nitric oxide synthase in asthma. 750 73

1. Treatment of rat mesangial cells with interleukin 1 beta (IL-1 beta) or tumour necrosis factor alpha (TNF alpha) has been shown to induce a macrophage-type of nitric oxide (NO) synthase. Here we report that adenosine 3':5'-cyclic monophosphate (cyclic AMP) is another mediator that triggers induction of NO synthase in mesangial cells. 2. Incubation of mesangial cells with the beta-adrenoceptor agonist, salbutamol, forskolin or cholera toxin, which all activate adenylate cyclase and increase intracellular cyclic AMP concentration, increased nitrite formation in a dose-dependent manner. Likewise, the addition of the membrane-permeable cyclic AMP analogue, N6, 0-2'-dibutyryladenosine 3',5'-phosphate (Bt2 cyclic AMP) or the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine enhanced NO synthase activity in a dose-dependent manner. 3. There was a lag period of about 8 h before a significantly enhanced secretion of nitrite could be detected upon exposure of cells to forskolin and for maximal stimulation, forskolin had to be present during the whole incubation period. 4. Treatment of mesangial cells with actinomycin D, cycloheximide or dexamethasone completely suppressed forskolin-stimulated NO-synthase activity, thus demonstrating that transcription and protein synthesis are necessary for nitrite formation. 5. Bt2 cyclic AMP, the most potent inducer of nitrite production, increased NO synthase mRNA levels in mesangial cells in a time- and dose-dependent fashion. Dexamethasone completely inhibited the increase of NO synthase mRNA in response to Bt2 cyclic AMP. 6. Combination of Bt2 cyclic AMP and IL-1 beta or TNF alpha revealed a strong synergy in terms of nitrite formation. Time-course studies indicated that cyclic AMP needed to be increased during the whole period of IL-1 Beta stimulation for maximal nitrite production.7. These observations suggest that cyclic AMP controls NO synthase expression in mesangial cells.Furthermore, the signalling cascades triggered by IL-1 Beta and TNF alpha synergize with the cyclic AMP pathway to stimulate NO synthase activity.
 ...
PMID:Expression of nitric oxide synthase in rat glomerular mesangial cells mediated by cyclic AMP. 751

Vascular smooth muscle cells (SMC) respond by relaxation to nitric oxide (NO) released from the endothelium which expresses a constitutive, Ca(2+)-dependent NO synthase (cNOS). SMC can, however, produce NO themselves upon stimulation by proinflammatory cytokines which induce expression of an inducible, Ca(2+)-independent NO synthase (iNOS). Protein kinase C represents another important second messenger system involved in the regulation of SMC contraction. We have investigated iNOS expression and NO synthesis in rat vascular SMC treated with the cytokines, IFN gamma and TNF alpha, in the presence or absence of the activator of protein kinase C, beta-phorbol-12-myristate 13-acetate (PMA). Treatment with PMA did not induce any significant accumulation of nitrite, a major stable metabolite of NO, in SMC. When added simultaneously with the cytokines, PMA significantly reduced nitrite accumulation induced by cytokine stimulation in a dose-dependent fashion. This inhibitory effect was mediated by activation of PKC since calphostin C, a specific PKC inhibitor, abolished the PMA effect. Further analysis of iNOS mRNA with a rat iNOS cDNA probe demonstrated that addition of PMA reduced expression of SMC iNOS mRNA, indicating that the antagonism in induction of NO synthesis between PMA and the proinflammatory cytokines acts on the transcriptional level. The inhibitory effect of PMA may be mediated via induction of a suppressor of iNOS expression, since pretreatment with PMA reduced NO production after subsequent treatment with cytokines. These observations suggest that activation of the PKC pathway is involved in a negative regulation of iNOS gene expression and this is compatible with the observation that vascular SMC contraction can be induced by PKC activation.
 ...
PMID:Protein kinase C activation inhibits cytokine-induced nitric oxide synthesis in vascular smooth muscle cells. 752 Feb 82

In vascular smooth muscle cells (VSMC), inflammatory cytokines such as interleukin 1 (IL1) and tumour necrosis factor alpha (TNF alpha) stimulate nitric oxide (NO) production via the expression of an inducible type of NO synthase (iNOS). This study was performed to determine whether angiotensin II (AII) affected NO production in cultured VSMC. AII by itself did not stimulate the production of nitrite, a stable metabolite of NO, but dose-dependently inhibited IL1 beta-induced nitrite production. This inhibitory effect of AII was blocked by the AII type 1 (AT1) receptor antagonist, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (CV-11974), but not by the AII type 2 (AT2) receptor antagonist, (S)-1-[[4-(di-methylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl++ +- 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (PD-123319). In parallel with the decrease in nitrite production, AII suppressed IL1 beta-induced increases in iNOS mRNA and protein levels, as measured by Northern blotting using an iNOS cDNA probe and by immunoblotting using an anti-iNOS antibody, respectively. AII also inhibited the increases in nitrite production and iNOS mRNA and protein levels caused by TNF alpha. These results indicate that AII inhibits cytokine-induced NO production in VSMC by blocking iNOS expression through the AT1 receptor; this suggests that the AT1 receptor antagonist may modulate the development of atherosclerotic and postangioplastic lesions by blocking this inhibitory effect of AII.
 ...
PMID:Angiotensin II type 1 receptor-mediated inhibition of cytokine-stimulated inducible nitric oxide synthase expression in vascular smooth muscle cells. 753 78

Nitric oxide (NO) is a recently recognized messenger molecule that has been shown to possess pleiotropic properties, including vasodilation, neurotransmission, cytotoxicity and antimicrobial activity. Constitutive and inducible forms of NO synthase (NOS) have been identified. Activation of cNOS releases relatively low levels of NO for short periods of time whereas induction of iNOS releases high levels of NO for extended periods of time. In rodents, iNOS is predominantly found in cells of the monocyte/macrophage series, including microglia, where it is induced by a combination of bacterial products and cytokines. cNOS and iNOS have also been reported in rodent astrocytes. Activation of iNOS in the CNS could be toxic to many different cell types, including neurons and oligodendrocytes. iNOS, however, has been difficult to demonstrate in human peripheral blood cells, suggesting that the regulation of expression of this enzyme in humans is different from that found in rodents. In this overview, we show that in human glial cells cultured in vitro, astrocytes, but not microglia, can be induced by cytokines to express NO-like activity. Bacterial products are without effect, but a combination of IL-1 and TNF alpha or IFN gamma is a potent stimulus. NO production by astrocytes inhibits Cryptococcus neoformans growth in vitro. In vivo, we show in acute multiple sclerosis lesions, intense NADPH-diaphorase activity is present in hypertrophic astrocytes in the lesion center and at the lesion edge, whereas microglia are nonreactive. Increased NADPH-diaphorase activity colocalizes with immunoreactivity for IL-1 and TNF. These results suggests that the induction of reactive nitrogen intermediates in humans differs from that found in rodents, and supports the conclusion that hypertrophic astrocytes are the major source of NO-like activity in the inflamed CNS.
 ...
PMID:Reactive nitrogen intermediates in human neuropathology: an overview. 753 80

The growing knowledge on the pathological role of tumor necrosis factor alpha (TNF-alpha) and nitric oxide in septic shock stimulated efforts to control their generation pharmacologically in clinical situations. Pentoxifylline (PTXF) is well known as an inhibitor of TNF synthesis, whereas information about its role in suppression of NO generation is much less available. In our study, we have shown that PTXF suppresses the synthesis of both mediators, TNF and NO, released by macrophages activated with different stimuli. However, in contrast to N-monomethyl-L-arginine (an inhibitor of NO synthase), PTXF influenced NO generation only during the induction phase. In conclusion, we suggest that a possible new therapeutic approach in septic shock may result from the inhibition of these two major mediators by simultaneous application of PTXF and a specific inhibitor of NO generation. Further experimental investigations and clinical trials are necessary to evaluate the safety and effectiveness of application of these inhibitors.
 ...
PMID:Effect of pentoxifylline on nitric oxide released by murine macrophages. 753 29


1 2 3 4 5 6 7 8 9 10 Next >>