Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In HL-60 and ML-3 human myeloid cell lines, gamma-interferon (IFN-gamma) and/or tumor necrosis factor (TNF) induce synergistic accumulation of transcripts of the genes encoding the heavy chain (gp91-phox) of cytochrome b558 and the cytosolic factors p47-phox and p67-phox, components of the superoxide-generating NADPH oxidase system. The accumulation of transcripts for gp91-phox and p47-phox, as quantitated at the single-cell level by in situ hybridization, is extremely heterogeneous; however, when the cells are stimulated by IFN-gamma and TNF together, most or all the cells in the induced cultures express higher accumulation of gp91-phox and p47-phox transcripts than cells from uninduced culture. In situ hybridization was performed on cellular subsets separated by fluorescence-activated cell sorting on the basis of surface expression of differentiation antigens or respiratory burst activity. The accumulation of gp91-phox and p47-phox transcripts correlated positively with the expression of the CD14 and CD11b antigens, two markers expressed on mature myelomonocytic cells. Similarly, accumulation of the two transcripts correlated with respiratory burst activity in cells separated by fluorescence-activated cell sorting after being loaded with dichlorofluorescein diacetate and stimulated with 12-O-tetradecanoylphorbol-13-acetate. These results suggest that all the cells in the culture are induced to differentiate by TNF and IFN-gamma but that at the time of analysis there is heterogeneity in the level of differentiation and a proportion of cells is present that shows more mature characteristics with a coordinate expression of the various differentiation markers and functions.
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PMID:Induction of expression of genes encoding components of the respiratory burst oxidase during differentiation of human myeloid cell lines induced by tumor necrosis factor and gamma-interferon. 156 22

Differentiation of myeloid cells is associated with the gradual acquisition of functional capacity to produce a respiratory burst. In our study HL-60 cells were differentiated to the monocyte phenotype with IFN-gamma or 1,25-dihydroxyvitamin D3, or to the neutrophil phenotype with retinoic acid or DMSO to compare the time-course of expression of membrane and cytosolic oxidase components, and to correlate this with the appearance of a functional oxidase. Over a 6-day period of induction the rank order of the ability of these agents to induce expression of PMA-stimulated superoxide production was: IFN-gamma greater than 1,25(OH)2D3 greater than retinoic acid greater than DMSO. Immunoblot analysis of HL-60 membranes and cytosol was used to assess the amount of specific phagocyte oxidase factors (91 and 22 kDa subunits of membrane cytochrome b558 (gp91 and p22), and 47 and 67 kDa cytosol oxidase factors (p47 and p67)). HL-60 cell membranes or cytosol were tested in a cell-free assay of superoxide production by mixing with normal neutrophil cytosol or membranes, respectively. p47 was first detected at 16 h of differentiation, increasing similarly thereafter with all induction regimens and reaching a maximum by 3 to 4 days. The earliest detection of p67 varied from 2 to 6 days depending on the inducing agent and appeared to be the limiting cytosol component. Small amounts of both subunits of cytochrome b558 were detected in uninduced HL-60 membranes, but were sufficient to support substantial superoxide production when combined with normal neutrophil cytosol. Both cytochrome b558 subunit proteins and membrane oxidase activity increased during differentiation in parallel. We conclude that membrane and cytosol components of the NADPH oxidase complex appear at different times and increase differently during HL-60 differentiation. The production of p67 is the major factor limiting the respiratory burst during HL-60 differentiation.
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PMID:Induction of the respiratory burst in HL-60 cells. Correlation of function and protein expression. 217 May 20

We established the system to detect superoxide produced by Epstein Barr virus lymphoblastoid cell line (EB-LCL). Superoxide production of EB-LCL was evaluated by measuring chemiluminescence (CL) enhanced with addition of horseradish peroxidase (HRP). Using this system, we measured CL of EB-LCL established from 13 patients with chronic granulomatous disease (CGD) and 8 normal individuals. Significant elevation of CL was observed in all control EB-LCLs, however, no remarkable CL was seen in any patients' EB-LCLs. We examined the effect of recombinant human interferon gamma (rh-IFN-gamma) and granulocyte colony stimulating factor (G-CSF) on CL of EB-LCL in vitro. With addition of rh-IFN-gamma, CL of normal control EB-LCL was significantly enhanced (p < 0.05), on the other hand, G-CSF was shown to have no effect. No significant CL was observed in any CGD patients' EB-LCLs even with addition of rh-IFN-gamma or G-CSF. It was suggested that superoxide produced by EB-LCL detected in this system was dependent on the same NADPH oxidase system which presents in phagocyte.
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PMID:[Establishment of superoxide production assay system using Epstein-Barr virus transformed cell line with chemiluminescence]. 755 50

Interferon (IFN)-gamma was subcutaneously administered to four patients with chronic granulomatous disease (CGD) in order to evaluate its effects in controlling infection. Patients 1 to 3 were all males, while patient 4 was female. In patients 2 and 4, the length of infection-associated hospitalization during the year of IFN therapy was significantly shorter than that during the whole observed period prior to IFN therapy. In patients 1 and 2, the length of hospitalization during a year of IFN therapy was shorter than that during 1 year prior to the therapy. Patient 3 exhibited no reduction in terms of the length of infectious disease during IFN therapy, because he suffered from a liver abscess before and during the therapy. As soon as the IFN therapy was stopped, patient 2 developed pneumonia and lymphadenitis, which were promptly relieved by readministering the agent. During 1 year of IFN therapy, patients 1, 2 and 4 showed no significant changes in either the nitroblue tetrazolium test, O2- production or the expression of NADPH oxidase components in neutrophils. On the other hand, the O2- generating ability of neutrophils from patient 3 slightly increased. Our limited observations suggest that IFN-gamma may be variably beneficial for infection control in CGD-patients, irrespective of the in vitro phagocyte functions. A longer follow-up time is needed to confirm the IFN response in CGD-patients.
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PMID:Interferon-gamma therapy for infection control in chronic granulomatous disease. 764 79

Secretion of the eicosanoids, nitric oxide (NO.) and superoxide anion (O2.-) was evaluated in human embryonic astrocytes and microglia. An inducible form of cyclo-oxygenase (COX 2) was demonstrated in astrocytes and microglia after IL-1 beta plus IFN-gamma stimulation; since 1) large amounts of PGF2 alpha were released; 2) PGF2 alpha secretion required protein synthesis and was blocked by indomethacin; and 3) the response was delayed and persistent. Using the same inducers, astrocytes, but not microglial cells, produced NO. and had an inducible form of nitric oxide synthase. Conversely, microglial cells were induced by IL-1 beta and IFN-gamma to generate superoxide anions (O2.-) through an NADPH oxidase-dependent pathway. We then investigated interactions between these different pathways of synthesis by inhibition experiments. The cytokine-induced production of PGF2 alpha in astrocytes was not affected by exposure to N-omega-monomethyl-L-arginine, which inhibits NO. production, whereas it was reduced by 40% in microglia. Since microglia did not secrete any detectable NO. in their supernatant, intracellular production of NO. could occur in these cells that positively regulated PGF2 alpha production. Exposure to indomethacin, which prevented PGF2 alpha production in both astrocytes and microglia, resulted in a 64% increase in cytokine-induced NO. production by astrocytes and a 70% inhibition of O2.- generation by stimulated microglia. Finally, superoxide dismutase depletion of O2.- in astrocytes and microglia had no effect on PGF2 alpha production in these cells. These results demonstrate that there are important interactions between the pathways of synthesis of inflammatory mediators in glial cells that could unveil additional regulatory mechanisms.
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PMID:Endogenous nitric oxide activates prostaglandin F2 alpha production in human microglial cells but not in astrocytes: a study of interactions between eicosanoids, nitric oxide, and superoxide anion (O2-) regulatory pathways. 875 37

The aim of this study was to determine the role of reactive oxygen species (ROS) in checking the growth of intracellular mycobacteria within human phagocytes. Peripheral blood-derived neutrophils and monocyte-derived macrophages were isolated from Chronic Granulomatous Disease (CGD) patients and normal healthy human volunteers. CGD patients are known to have a defect in the NADPH oxidase pathway, resulting in their neutrophils and monocyte-derived macrophages being unable to generate oxygen radicals which are required to kill intracellular bacteria. The cells were then infected with Bacille Calmette Guerin (BCG) or Mycobacterium avium, and the bacterial growth in each cell type determined by Colony Forming Units (CFU) estimate. The results obtained indicate that there was no demonstrable inhibition in the intracellular mycobacterial growth within neutrophils or macrophages derived from either Chronic Granulomatous Disease (CGD:deficient in NADPH oxidase pathway) or normal healthy volunteers. Macrophage treatment with either IFN-gamma or TNF-alpha had no effect.
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PMID:The role of reactive oxygen species (ROS) in the effector mechanisms of human antimycobacterial immunity. 935 Mar 48

We investigated the effects of dexamethasone or indomethacin on the NADPH oxidase activity, cytochrome b558 content, and expression of genes encoding the components gp91-phox and p47-phox of the NADPH oxidase system in the human monocytic THP-1 cell line, differentiated with IFN-gamma and TNF-alpha, alone or in combination, for up to 7 days. IFN-gamma and TNF-alpha, alone or in combination, caused a significant up-regulation of the NADPH oxidase system as reflected by an enhancement of the PMA-stimulated superoxide release, cytochrome b558 content, and expression of gp91-phox and p47-phox genes on both days 2 and 7 of cell culture. Noteworthy was the tremendous synergism between IFN-gamma and TNF-alpha for all studied parameters. Dexamethasone down-regulated the NADPH oxidase system of cytokine-differentiated THP-1 cells as assessed by an inhibition on the PMA-stimulated superoxide release, cytochrome b558 content, and expression of the gp91-phox and p47-phox genes. The nuclear run-on assays indicated that dexamethasone down-regulated the NADPH oxidase system at least in part by inhibiting the transcription of gp91-phox and p47-phox genes. Indomethacin inhibited only the PMA-stimulated superoxide release of THP-1 cells differentiated with IFN-gamma and TNF-alpha during 7 days. None of the other parameters was affected by indomethacin. We conclude that dexamethasone down-regulates the NADPH oxidase system at least in part by inhibiting the expression of genes encoding the gp91-phox and p47-phox components of the NADPH oxidase system.
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PMID:Dexamethasone but not indomethacin inhibits human phagocyte nicotinamide adenine dinucleotide phosphate oxidase activity by down-regulating expression of genes encoding oxidase components. 979 32

We investigated the NADPH oxidase activity, cytochrome b558 content, and gene expression of gp91-phox and p47-phox in normal Epstein-Barr-virus (EBV)-transformed B lymphocytes, compared to EBV-transformed B lymphocytes from patients with X-linked chronic granulomatous disease (CGD), normal peripheral blood neutrophils or mononuclear cells, and the A301 or C8166 lymphoblastoid cell lines. CGD phenotypes included both "classic" disease with no detectable gp91-phox protein (termed X91(0)) and "variant" phenotype with reduced but detectable gp91-phox protein (X91(-)). Normal EBV-transformed B lymphocytes show a dose-dependent PMA-induced superoxide release. Culturing these cells with IFN-gamma (100 U/ml) and TNF-alpha (1000 U/ml), alone or in combination for 7 days, caused a modest increase in their NADPH oxidase activity (P > 0.05 in all situations). Normal EBV-transformed B lymphocytes have lower NADPH oxidase activity and cytochrome b558 content than peripheral blood neutrophils or mononuclear cells (P < 0.05 in all situations). In contrast, they have higher NADPH oxidase activity and cytochrome b558 content than X91(-) CGD EBV-transformed B lymphocytes (P < 0.05 in all situations). A301 or C8166 lymphoblastoid cell lines and X91(0) CGD EBV-transformed B lymphocytes have barely detectable NADPH oxidase activity or cytochrome b558 content (P < 0.05 in all situations). Gene expression studies also show a modest increase in expression and transcription rates of gp91-phox and p47-phox genes in normal EBV-transformed B cells cultured with IFN-gamma (100 U/ml) and TNF-alpha (1000 U/ml), alone or in combination for 7 days. We conclude that NADPH oxidase activity and cytochrome b558 content correlate with gp91-phox and p47-phox gene expression in EBV-transformed B lymphocytes.
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PMID:NADPH oxidase activity and cytochrome b558 content of human Epstein-Barr-virus-transformed B lymphocytes correlate with expression of genes encoding components of the oxidase system. 985 26

Chronic granulomatous disease (CGD) is an inherited immune deficiency caused by mutations in any of the following four phox genes encoding subunits of the superoxide generating phagocyte NADPH oxidase. It consists of membranous cytochrome b558 composed of gp91-phox and p22-phox, and four cytosolic components, p47-phox, p67-phox, rac p21 and p40-phox, which translocate to the membrane upon activation. In our group study, more than 220 CGD patients has been enrolled. The incidence of CGD patients was estimated as 1 out of 250,000 births. The expected life span of the CGD patients is 25 to 30 years old by the Kaplan Meier analysis. Comparing with the ratio of CGD subtype in US and Europe, that with p47-phox deficiency is lower (less than 10% vs. 23%) and that of gp91-phox deficiency is higher (more than 75% vs. 60%). Prophylactic administration of ST antibiotics and IFN-gamma and bone marrow transplantation have been successfully employed in our therapeutic strategy. However, it is necessary to develop the gene therapy technology for CGD patients as more promising treatment. In the current study we constructed two retrovirus vectors; MFGS-gp91/293 SPA which contains only the therapeutic gp91-phox gene, a bicistronic retrovims pHa-MDR-IRES-gp91/PA317 which carries a multi drug resistant gene (MDR1) and the gp91-phox gene connected with an internal ribosome entry site (IRES). We demonstrate high efficiency transduction of gp91-phox to CGD EB virus established cell line with high levels of functional correction of the oxidase by MFGS-gp91 and by pHa-MDR-IRES-gp91, respectively. We also demonstrate sufficient transduction of gp91-phox to CD34+ haematopoietic stem cell from the patients with gp91-phox deficiency by MFGS-gp91/293 SPA. Our current studies suggest that the combination of the 293-SPA packaging system and the bicistronic retrovirus system inserted MDR1 gene make our CGD gene therapy more feasible for clinical application.
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PMID:[Statistical evaluation of chronic granulomatous disease in Japan and basic studies for gene therapy for CGD patients]. 1044 45

Trehalose dimycolate (TDM), a glycolipid present in the cell wall of Mycobacterium spp., is a powerful immunostimulant. We have developed an original model of macrophage activation where TDM is injected in vivo to prime peritoneal macrophages. These primed macrophages do not express inducible NO synthase (NOS II), however, they can be fully activated, i.e. induced to express NOS II and to develop a NOS II-dependent antiproliferative activity, following in vitro exposure to low concentrations of LPS. In a previous paper, we have shown that TDM-priming of mouse peritoneal macrophages is mediated by the sequential production of IL-12 and IFN-gamma. In the present paper, we investigated the role of TNF in the priming of macrophages by TDM. By semi-quantitative RT-PCR, we have shown that TDM injection induced transcription of TNF-alpha in peritoneal cells. TNF-mRNA levels peaked 5 hours after TDM injection and remained elevated for at least 32 hours. TNF expression was absolutely necessary for macrophage priming, as injection of an anti-TNF monoclonal antibody, 4 h before and 20 hours after TDM injection, prevented LPS-dependent activation of macrophages in vitro. This result was confirmed by the inability of TDM to prime macrophages from LT-alpha/TNF-alpha knockout (LT/TNFKO) mice. In addition, analysis of LT/TNFKO mice treated with TDM revealed that induction of the IL-12 transcript in their peritoneal cells and expression of a functional NADPH oxidase in macrophages are TNF-independent events.
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PMID:Tumor necrosis factor is required for the priming of peritoneal macrophages by trehalose dimycolate. 1058 20


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