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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Through the blockade of the Na-K-ATPase, ouabain inhibits several biochemical and biological events leading to the proliferation of activated lymphocytes. Since we already found that interleukin 1 production was not prevented by ouabain, we investigated by which mechanism this drug inhibits mitogen-induced human T lymphocyte activation, with respect to the interleukin 2 (IL 2) pathway. Our data revealed that at concentrations lower than 0.2 microM, IL 2 accumulation was not reduced in ouabain-treated cultures, even when cell proliferation was completely inhibited (0.1-0.2 microM ouabain). Moreover, in this concentration range, ouabain stimulated in a dose-dependent manner the accumulation of IL 2 in the supernatant of Con A-stimulated lymphocytes (optimum for 0.05 microM corresponding to half inhibition of lymphocyte proliferation). Such an effect, which appears correlated to the inhibition of Na-K-ATPase, suggests a failure of the cell to utilize IL 2. At concentrations higher than 0.3 microM, ouabain inhibited both lymphocyte proliferation and IL 2 production. These observations show that the glycosteroid interacts differently with the different cell populations involved in the cascade of reactions leading to cell proliferation, and suggest that the mitogenic inhibition resulting from the blockade of Na-K-ATPase is not related to the blockade of IL 2 production. On the other hand, we observed that: ouabain inhibited the expression of the receptors for IL 2, an obligatory step in lymphocyte proliferation; ouabain blocked the proliferation of an IL 2 sensitive human T cell line; in both cases the inhibition paralleled that of lymphocyte proliferation. Our data suggest that the essential steps of lymphocyte proliferation in which Na-K-ATPase-dependent K+ fluxes play a critical role are the expression of IL 2 receptors and the IL 2-dependent proliferative step.
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PMID:Mechanism whereby ouabain inhibits human T lymphocyte activation: effect on the interleukin 2 pathway. 309 87

At concentrations as low as 10(-7) M, the cardiotonic glycosteroid ouabain, a specific inhibitor of the membrane Na+, K+-ATPase, is known to inhibit in vitro human lymphocyte proliferation produced in mixed lymphocyte cultures or induced by various stimulating agents (PHA, Con A, PWM, soluble antigens), while mouse lymphocyte proliferation is unaffected at this concentration. Ouabain inhibits most of proliferative response parameters at all stages of the transformation. This observation prompted us to suggest that ouabain could also act through inhibition of interleukin production which is known to occur during the first hours after T-cell stimulation in the presence of monocytes. In order to check the possible influence of ouabain on interleukin production, conditioned media from stimulated human mononuclear cells, prepared in the presence or in the absence of inhibitor, were tested for their ability to promote a mouse thymocyte response to PHA. Instead of the expected inhibition, we found that ouabain, even at high concentrations (2 X 10(-6) M) enhanced the stimulatory effect and/or the production of murine thymocyte activating factor(s). Moreover conditioned media from serum-free cultures of unstimulated human mononuclear cells exposed for 24 hr to low ouabain concentrations (10(-8) to 10(-7) M) showed a high activating effect on the response of murine thymocytes to PHA. This soluble factor produced upon ouabain treatment is produced by adherent cells and appears to be functionally similar to interleukin 1.
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PMID:Paradoxical production of mouse thymocyte activating factor by ouabain-treated human mononuclear cells. 660 30

This study addresses the role of intracellular calcium (Ca2+) in the expression of iNOS, an IL-1 inducible gene in human articular chondrocytes. The calcium ionophore A23187 and ionomycin did not induce NO release or iNOS expression but inhibited dose dependently IL-1-induced NO release with IC50 of 200 nM and 100 nM, respectively. Increased intracellular Ca2+ induced by thapsigargin or cyclopiazonic acid, inhibitors of the endoplasmic reticulum Ca2+ ATPase, had similar inhibitory effects with IC50 of 1 nM and 3 microM, respectively. LPS and TNF alpha induced NO production were also suppressed by these Ca2+ elevating drugs. Levels of IL-1-induced iNOS protein were reduced by A23187, thapsigargin, and cyclopiazonic acid. These drugs as well as Bay K 8644 and KCl inhibited IL-1-induced iNOS mRNA expression. To analyze the role of Ca2+ in the expression of other IL-1 responsive genes in chondrocytes, these Ca2+ modulating drugs were tested for effects on COXII. In contrast to the inhibitory effects on iNOS mRNA, these drugs induced COXII mRNA expression and in combination with IL-1, enhanced COXII mRNA levels. Ca2+ mediated increases in COXII mRNA expression were associated with an increase in COXII protein. The kinetics of Ca2+ effects on IL-1-induced iNOS mRNA levels suggested a posttranscriptional mechanism. Analysis of iNOS mRNA half life showed that it was 6-7 h in IL-1-stimulated cells and decreased by A23187 to 2-3 h. In conclusion, these results show that Ca2+ inhibits IL-1-induced NO release, iNOS protein, and mRNA expression in human articular chondrocytes by reducing iNOS mRNA stability. Under identical conditions increased Ca2+ enhances IL-1-induced COXII gene and protein expression.
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PMID:Increased intracellular Ca2+ selectively suppresses IL-1-induced NO production by reducing iNOS mRNA stability. 754 Jun 12

1. The bulk of studies of the actions of atrial natriuretic peptides (ANP) have focussed on the carboxyterminal derivative (ANP 99-126) of the prohormone (ANP 1-126), but recent evidence indicates that an additional peptide derived from ANP 1-126, namely, ANP 31-67 also circulates, and has natriuretic actions. 2. The effects of ANP 31-67 on inner medullary collecting duct (IMCD) Na+ transport have been examined in freshly prepared suspensions of rabbit IMCD cells. Like ANP 99-126, ANP 31-67 reduces Na+ transport in these cells. 3. However, unlike ANP 99-126, this effect is not mediated by cGMP, and does not result from inhibition of apical Na+ channels. Rather, ANP 31-67 inhibits basolateral Na/K-ATPase, probably via the stimulation of PGE2 synthesis. 4. These results are discussed in the context of other natriuretic substances (interleukin 1 and endothelin), which also inhibit Na+ reabsorption by PGE2-mediated inhibition of Na/K-ATPase.
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PMID:Regulation of collecting duct Na+ reabsorption by ANP 31-67. 762 4

We have evaluated the effect of lipopolysaccharides (LPS), endotoxins from gram negative bacteria, on sodium-coupled amino acid and phosphate transport by alveolar epithelial type II cells and on their alteration induced by oxidants. Alveolar type II cells were obtained by enzymatic digestion of rat lung and grown for 24 h prior to incubation with LPS and then exposed or not exposed to H2O2 (2.5 mM; 20 min). LPS (10 micrograms/ml, 24 h) induced a significant increase in the Na-dependent component of alanine and phosphate uptake while they decreased Na,K-ATPase activity measured by ouabain-sensitive 86Rb influx. We showed that this stimulatory effect i) was independent from macrophage products since it was not mimicked either by supernatant of LPS-treated alveolar macrophages or by pretreatment with tumor necrosis factor and/or interleukin 1 and ii) was dependent on protein synthesis since it was abolished by protein synthesis inhibitors cycloheximide and actinomycin D. Moreover, LPS blunted H2O2-induced decrease of Na-dependent alanine and phosphate uptake. This protective effect of LPS against H2O2 injury i) was independent of macrophage products, ii) was abolished by cycloheximide, and iii) was not associated with either changes in extracellular H2O2 clearance or catalase and glutathione peroxidase activities. We conclude that, in alveolar type II cells, LPS stimulate sodium-coupled transport by a process involving protein synthesis and partially prevent H2O2-induced decrease of Na-coupled transport without discernible change in antioxidant activities.
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PMID:Lipopolysaccharides stimulate Na-dependent transport in alveolar cells and protect against oxidant injury. 770 77

Ion-motive ATPase play an essential role in many aspects of cell biology, including mononuclear cell (MNC) functions relevant to chronic inflammation. For example, ouabain, a specific inhibitor of Na+, K+ ATPase, suppresses both T and B cell proliferation but induces synthesis of IL-1. Using a cytochemical assay quantified by microdensitometry, total and ouabain-sensitive ATPase activities have been compared in MNC from rheumatoid and control subjects. The sensitivity of these enzymes to inactivation by thiol-blocking reagents has been studied by preincubation with an impermeant SH blocker p-hydroxymercuriphenylsulphonate (pHMPSA). The results show that rheumatoid MNC have significantly impaired ATPase activity compared to healthy cells and that both total and ouabain-sensitive ATPase activities are readily inhibited by pHMPSA. The depressed ATPase activity in rheumatoid MNC could thus be due to blockade/oxidation of a reactive surface thiol, and could contribute to perpetuation of the chronic inflammatory process in these patients.
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PMID:Impaired activity of thiol-dependent ATPases in rheumatoid mononuclear cell membranes. 827 44

While effector molecules produced by activated macrophages (including nitric oxide, tumor necrosis factor alpha, interleukin 1, etc.) help to eliminate pathogens, high levels of these molecules can be deleterious to the host itself. Despite their importance, the mechanisms modulating macrophage effector functions are poorly understood. This work introduces two key negative regulators that control the levels and duration of macrophage cytokine production. Vacuolar-type H+-ATPase (V-ATPase) and calcineurin (Cn) constitutively act in normal macrophages to suppress expression of inflammatory cytokines in the absence of specific activation and to inhibit macrophage cytokine responses induced by bacterial lipopolysaccharide (V-ATPase), interferon gamma (V-ATPase and Cn), and calcium (Ca2+) flux (Cn). Cn and V-ATPase modulate effector gene expression at the mRNA level by inhibiting transcription factor NF-kappaB. This negative regulation by Cn is opposite to its crucial positive role in T cells, where it activates NFAT transcription factor(s) leading to expression of interleukin 2, tumor necrosis factor alpha, and other cytokine genes. The negative effects of V-ATPase and Cn on NF-kappaB-dependent gene expression are not limited to the macrophage lineage, as similar effects have been seen with a murine fibroblast cell line and with primary astrocytes.
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PMID:Calcineurin and vacuolar-type H+-ATPase modulate macrophage effector functions. 1033 86

Interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) markedly stimulate glucose utilization in primary cultures of mouse cortical astrocytes. The mechanism that gives rise to this effect, which takes place several hours after application of cytokine, has remained unclear. Experiments were conducted to identify the major signaling cascades involved in the metabolic action of cytokine. First, the selective IL-1 receptor antagonist (IL-1ra) prevents the effect of IL-1alpha on glucose utilization in a concentration-dependent manner, whereas it has no effect on the action of TNF-alpha. Then, using inhibitors of three classical signaling cascades known to be activated by cytokines, it appears that the PI3 kinase is essential for the effect of both IL-1alpha and TNF-alpha, whereas the action of IL-1alpha also requires activation of the MAP kinase pathway. Participation of a phospholipase C-dependent pathway does not appear critical for both IL-1alpha and TNF-alpha. Inhibition of NO synthase by L-NAME did not prevent the metabolic response to both IL-1alpha and TNF-alpha, indicating that nitric oxide is probably not involved. In contrast, the Na(+)/K(+) ATPase inhibitor ouabain prevents the IL-1alpha- and TNF-alpha-stimulated 2-deoxyglucose (2DG) uptake. When treatment of astrocytes with a cytokine was followed 24 h later by an acute application of glutamate, a synergistic enhancement in glucose utilization was observed. This effect was greatly reduced by ouabain. These data suggest that Na(+) pump activity is a common target for both the long-term metabolic action of cytokines promoted by the activation of distinct signaling pathways and the enhanced metabolic response to glutamate.
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PMID:Long-term modulation of glucose utilization by IL-1 alpha and TNF-alpha in astrocytes: Na+ pump activity as a potential target via distinct signaling mechanisms. 1211 71

There is considerable evidence that osteoclasts are involved in the pathogenesis of juxta-articular bone destruction in rheumatoid arthritis. Vacuolar ATPases (V-ATPases), which are highly expressed in the ruffled border membrane of osteoclasts, play a central role in the process of bone resorption, and V-ATPase inhibitors are effective in preventing bone destruction in several animal models of lytic bone diseases. Here, we evaluated for the first time the effects of V-ATPase inhibition in rats with adjuvant-induced arthritis (AIA) using FR177995, a novel V-ATPase inhibitor. FR177995 completely inhibited H(+) transport driven by V-ATPase, but exerted no effect on the H(+) transport activities of F- and P-ATPase, indicating that FR177995 is a specific inhibitor of V-ATPase. FR177995 acted directly on osteoclastic bone resorption and equally inhibited in vitro bone resorption stimulated by IL-1, IL-6 or PTH. In addition, FR177995 dose-dependently reduced retinoic acid-induced hypercalcemia in thyroparathyroidectomized-ovariectomized rats. When FR177995 was administered to AIA rats once a day, the loss of femoral bone mineral density was significantly improved. Moreover, indicators of cartilage damage (arthritis score and glycosaminoglycan content in the femoral condyles) and inflammation parameters (paw swelling volume, erythrocyte sedimentation rate and plasma sialic acid level) were found to be unexpectedly ameliorated. These results strongly suggest that V-ATPase may be an interesting drug target in the treatment of rheumatoid arthritis.
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PMID:FR177995, a novel vacuolar ATPase inhibitor, exerts not only an inhibitory effect on bone destruction but also anti-immunoinflammatory effects in adjuvant-induced arthritic rats. 1715 74

Interleukin-1beta (IL-1beta) is a mediator cytokine that is released by macrophages and epithelial cells in pregnancy and tumorigenesis before antigen recognition. a2V-ATPase is a protein expressed during pregnancy and tumorigenesis and has a novel role in immune regulation. It is expressed as a 70 kDa molecule in intracellular vesicles. Upon cell stimulation it migrates to the surface followed by the cleavage of a 20 kDa portion (a2 N-terminus domain, a2NTD). This study aimed to determine whether a2NTD could induce IL-1beta production in immune cells. Peripheral blood mononuclear cells (PMBC) were stimulated with a2NTD and analyzed for cytokine gene expression by gene arrays. Supernatants were analyzed for IL-1beta by enzyme-linked immunosorbent assay, and cells were analyzed for intracellular expression of IL-1alpha, IL-1beta, and TNF-alpha by flow cytometry. When PBMC were cultured with a2NTD, there was a 2.5-fold increase in IL1A and IL1B gene expression and no induction of TNF gene expression. There was a 72-fold increase in IL-1beta in supernatants of PBMC cultured with a2NTD. Finally, there was a 204-fold increase in intracellular expression of IL-1beta in monocytes incubated with a2NTD. These results indicate a regulatory role for a2NTD in IL-1 cytokine production and suggest a unique role for this molecule in inflammation.
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PMID:Novel role for the N-terminus domain of the a2 isoform of vacuolar ATPase in interleukin-1beta production. 1750 46


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