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)

Agents that can arrest cellular proliferation are now providing insights into mechanisms of growth factor action and how this action may be controlled. It is shown here that the macrophage activating agents tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma), and lipopolysaccharide (LPS) can maximally inhibit colony stimulating factor-1 (CSF-1)-induced, murine bone marrow-derived macrophage (BMM) DNA synthesis even when added 8-12 h after the growth factor, a period coinciding with the G1/S-phase border of the BMM cell cycle. This inhibition was independent of autocrine PGE2 production or increased cAMP levels. In order to compare the mode of action of these agents, their effects on a number of other BMM responses in the absence or presence of CSF-1 were examined. All three agents stimulated BMM protein synthesis; TNF alpha and LPS, but not IFN gamma, stimulated BMM Na+/H+ exchange and Na+,K(+)-ATPase activities, as well as c-fos mRNA levels. IFN gamma did not inhibit the CSF-1-induced Na+,K(+)-ATPase activity. TNF alpha and LPS inhibited both CSF-1-stimulated urokinase-type plasminogen activator (u-PA) mRNA levels and u-PA activity in BMM, whereas IFN gamma lowered only the u-PA activity. In contrast, LPS and IFN gamma, but not TNF alpha, inhibited CSF-1-induced BMM c-myc mRNA levels, the lack of effect of TNF alpha dissociating the inhibition of DNA synthesis and decreased c-myc mRNA expression for this cytokine. These results indicate that certain biochemical responses are common to both growth factors and inhibitors of BMM DNA synthesis and that TNF alpha, IFN gamma, and LPS, even though they all have a common action in suppressing DNA synthesis, activate multiple signaling pathways in BMM, only some of which overlap or converge.
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PMID:Biochemical events accompanying macrophage activation and the inhibition of colony-stimulating factor-1-induced macrophage proliferation by tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide. 133 37

Polyribocytidylic-polyriboinosinic acid [poly r(I):r(C)]-inducible genes were isolated by a differential screening procedure from a human fibroblast cell (FS-4) cDNA bank. Among yet unidentified genes (gene 274), one codes for a protein with multiple finger motifs and has previously been detected in endothelial cells after tumor necrosis factor-alpha (TNF-alpha) treatment (A20; Opipari et al., 1990), the second one codes for a variant of the I kappa B family (Haskill et al., 1991), and a third one for the Ca2+ ATPase (isoform 1). Platelet-derived growth factor (PDGF) isoforms (AA, AB, and BB) stimulated the expression of these immediate-early genes. But the extent of the respective induction correlated neither with the number of the two receptors alpha or beta nor with the level of PDGF-stimulated receptor autophosphorylation on tyrosine. Although alpha-receptors were less abundant than beta-receptors (12,500 binding sites were estimated for PDGF-AA, KD 0.03 nM; 20,000 for PDGF-AB, KD 0.03 nM; 35,000 for PDGF-BB KD 0.16 nM) and tyrosine phosphorylation induced by PDGF-AA was significantly less than that evoked by PDGF-BB, some of the investigated genes were more strongly induced by PDGF-AA. We discuss how the differences in the biological potency of the PDGF isoforms may reside in different functions of the two receptors by activation of alternative signaling pathways.
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PMID:Platelet-derived growth factor isoforms AA, AB, and BB differentially activate poly r(I):r(C)-induced genes in human fibroblast FS4 cells. 141 21

The role of Na+/K+ exchange in regulating lipopolysaccharide (LPS)-mediated induction of cytokine gene expression has been examined in murine peritoneal macrophages. Depletion of K+ from the culture medium resulted in a three- to five-fold potentiation of tumor necrosis factor-alpha (TNF alpha), KC (gro), and IP-10 mRNA expression in LPS-treated macrophages. The potentiating effect was apparently the result of inhibition of Na+/K+ exchange through the Na+/K(+)-adenosine triphosphatase (ATPase) because ouabain-mediated inhibition of Na+/K(+)-ATPase was also able to potentiate cytokine mRNA expression as much or more than did K+ depletion. The effects of K+ depletion or ouabain treatment were not caused by depolarization of the macrophage membrane because depolarization mediated by elevating extracellular K+ levels was inhibitory to cytokine mRNA expression. Depletion of Na+ by substitution with choline in the culture medium also markedly potentiated LPS-induced gene expression. The Na+/H+ antiporter was not, however, involved in potentiating cytokine expression because treatment of macrophages with amiloride either had no effect on or was inhibitory to the LPS-induced changes in mRNA levels. The potentiation of gene expression was selective and was at least partially the result of increased transcriptional activity of each gene. Whereas Na+ depletion and ouabain both inhibited 86Rb+ uptake by macrophages, treatment with LPS had no effect either on Rb+ uptake or on efflux. Thus altered Na+/K+ exchange is not a component of the primary signalling pathway(s) mediating response to LPS. Nevertheless, modulation of macrophage Na+/K+ exchange by agents encountered during an inflammatory response may be an important determinant of the magnitude and quality of specific gene expression.
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PMID:Modulation of Na+/K+ exchange potentiates lipopolysaccharide-induced gene expression in murine peritoneal macrophages. 165 Mar 75

Cell line IgSV195, derived from a pancreatic tumor that arose in an SV40 T-antigen transgenic mouse, retains certain morphological and physiological characteristics of pancreatic beta-cells throughout in vitro and in vivo passage. Insulin secretion is stimulated by exposure of these cells to fetal bovine serum and a combination of 3-isobutyl-1-methylxanthine and glutamine but not by concentrations of glucose in the physiological range. Insulin processing appears to be intact. Neither class I nor class II major histocompatibility complex (MHC) antigens are routinely expressed at the cell surface; however, MHC class I--but not class II--encoded gene products are detected after treatment with recombinant interferon-gamma (IFN-gamma) alone or in combination with tumor necrosis factor. Cytolysis of IgSV195 cells by SV40 T-antigen-specific H-2b-restricted lymphocytes is similarly dependent on IFN-gamma pretreatment. These results emphasize that SV40 T-antigen transgenic mice are likely sources of cell lines that retain their differentiated function in vitro. The IgSV195 cell line provides an accessible model in which to investigate the control of gene expression and function of pancreatic beta-cells.
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PMID:Functional pancreatic beta-cell line from SV40 T-antigen transgenic mouse. 250 59

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

Some nutrients influence the metabolic response of cytokines such as tumor necrosis factor. Inadequate levels of the essential trace element zinc may play a role in tumor necrosis factor-induced disruption of the vascular endothelial barrier function. To test this hypothesis, endothelial cells cultured on polycarbonate filters or culture plates were exposed to six different treatments for 3 d: medium 199 enriched with 5% fetal bovine serum (control), control+two levels of supplemental zinc (7.7 and 12.3 mumol/L medium), tumor necrosis factor (5 x 10(5) U/L) and tumor necrosis factor+the two levels of Zn as noted previously. Endothelial barrier function, expressed as albumin transfer across cultured endothelial monolayers, was not affected by Zn enrichment alone. Tumor necrosis factor treatment significantly increased albumin transfer compared with control cultures. The lower concentration of Zn partially and the higher concentration totally prevented the tumor necrosis factor-induced increase in albumin transfer. The increase in cytosolic release of [3H]adenine (marker of cell injury) induced by tumor necrosis factor was prevented by added Zn. Tumor necrosis factor treatment significantly decreased angiotensin-converting enzyme activity, and tumor necrosis factor also decreased activities of two other membrane-bound enzymes, total ATPase and Ca(2+)-ATPase. These activities all were restored by Zn enrichment. Tumor necrosis factor treatment caused a decrease in cellular Zn concentration, which was prevented when the culture media were enriched with Zn. These data suggest that an important relationship exists between Zn status and tumor necrosis factor-induced endothelial cell dysfunction.
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PMID:Zinc protects against tumor necrosis factor-induced disruption of porcine endothelial cell monolayer integrity. 838 99

Intrahepatic cholestasis in the setting of extrahepatic bacterial infection has been attributed to the effects of endotoxin and cytokines such as tumor necrosis factor-alpha (TNF-alpha) on bile acid transport. To define the mechanism of sepsis-associated cholestasis, taurocholate transport was examined in basolateral (bLPM) and canalicular (cLPM) rat liver plasma membrane vesicles derived from control and endotoxin [lipopolysaccharide (LPS)]-treated animals and in plasma membrane vesicles prepared after TNF-alpha treatment. Na(+)-dependent [3H]taurocholate uptake and both membrane-potential-dependent and ATP-dependent [3H]taurocholate transport were reduced in bLPM and cLPM vesicles, respectively, after LPS treatment. In membrane vesicles from TNF-alpha-treated animals, Na(+)-dependent [3H]taurocholate uptake was also reduced. Northern blot hybridization, using cDNA probes for the putative sinusoidal bile acid transporter (Ntcp) and canalicular ecto-adenosinetriphosphatase, demonstrated decreased mRNA levels after LPS and TNF-alpha treatment. Immunoblot analysis of membrane extracts from LPS-treated animals revealed decreased levels of these putative bile acid transporters. Impaired bile acid transport at the sinusoidal and canalicular membrane domains by these and other mediators of the inflammatory response may account for sepsis-associated cholestasis.
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PMID:Effect of endotoxin on bile acid transport in rat liver: a potential model for sepsis-associated cholestasis. 876 Jan 17

The effect off amiodarone, a cationic amphiphilic drug, on cytokine release from, and on protein kinase C (PKC) activity of, mouse alveolar macrophages, bone marrow macrophages, and blood monocytes was examined. In addition, its effect on three enzymes in these cells was also determined. Amiodarone suppressed the growth of all cell types at high doses. As regards cytokine release, amiodarone caused an increase in interleukin-1 (IL-1) alpha, IL-1 beta, and tumor necrosis factor (TNF) alpha release from alveolar macrophages but not from marrow macrophages and monocytes. PKC activity was increased by amiodarone only in alveolar macrophages. And the treatment with amiodarone severely suppressed the H(+)-ATPase, sphingomyelinase, and phospholipase A2 activities in alveolar macrophages. But these enzyme activities in bone marrow macrophages and monocytes were not suppressed so much as in alveolar macrophages. This current study indicated that mouse alveolar macrophages treated with amiodarone undergo suppression of H(+)-ATPase, resulting in suppression of sphingomyelinase and phospholipase A2 activity, and in activation of PKC activity and release of cytokines. It also showed that changes in activities of all three enzymes in alveolar macrophages are different from those in bone marrow macrophages and monocytes with respect to reactivity toward amiodarone.
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PMID:Effect of amiodarone on cytokine release and on enzyme activities of mouse alveolar macrophages, bone marrow macrophages, and blood monocytes. 878 Sep 96

Tissue-type transglutaminases (TGases) were recently shown to exert dual enzymatic activities; they catalyze the posttranslational modification of proteins by transamidation, and they also act as guanosine triphosphatase (GTPase). Here we show that a tissue-type TGase is expressed in rat brain astrocytes in vitro, and is induced by the inflammation-associated cytokines interleukin-1beta and to a lesser extent by tumor necrosis factor-alpha. Induction is accompanied by overexpression and appearance of an additional shorter clone, which does not contain the long 3'-untranslated region and encodes for a novel TGase enzyme whose C terminus lacks a site that affects the enzyme's interaction with guanosine triphosphate (GTP). Expression of two clones revealed that the long form is inhibited noncompetitively by GTP, but the short form significantly less so. The different affinities for GTP may account for the difference in physiological function between these two enzymes.
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PMID:Expression of GTP-dependent and GTP-independent tissue-type transglutaminase in cytokine-treated rat brain astrocytes. 901 29

We recently reported that tumor necrosis factor-alpha (TNF-alpha) induction of the synthesis and secretion of transforming growth factor (TGF)-beta 1 by FRTL-5 cells is a thyroid-stimulating hormone (TSH)-dependent and age-dependent process. TNF-alpha is only cytotoxic to aged (> 40 passages) FRTL-5 cells grown in TSH-containing medium, whereas TGF-beta induces programmed cell death (apoptosis) in epithelial cells but not in FRTL-5 cells, which otherwise retain many properties of normal thyroid follicular cells. This cell line is, therefore, a convenient model for studies on the TSH-dependent and age-dependent inhibitory effects of these cytokines on epithelial cell growth, viability, and function. One prominent effect of TNF-alpha (and TGF-beta 1) on FRTL-5 cell function is suppression of iodide uptake, which is markedly stimulated by TSH. In aged FRTL-5 cells, iodide uptake is only about 10% that of young control cells. Na+/K(+)-ATPase activity, which drives iodide uptake by thyroid cells, is inhibited by TNF-alpha and TGF-beta. The following experiments quantitate the effects of TSH, aging, TNF-alpha, and TGF-beta 1 on the expression and activity of Na+/K(+)-ATPase activity in FRTL-5 cells. Young (< 20 passages) and aged (> 40 passages) FRTL-5 cells were treated with various doses (0-100 ng/ml) of recombinant human TNF-alpha or TGF-beta 1 for various times (0-3 days) with and without 2 U/liter TSH. These treatments reduced the rate-limiting Na+/K(+)-ATPase beta 1 mRNA level and Na+/K(+)-ATPase activity in parallel in a dose-dependent and time-dependent fashion. Aged FRTL-5 cells were more sensitive to the inhibitory effects of TNF-alpha, whereas young cells were more sensitive to the suppressive effects of TGF-beta 1 on the expression and activity of Na+/K(+)-ATPase. We conclude that inhibition of Na+/K(+)-ATPase activity by TNF-alpha and TGF-beta in FRTL-5 cells is differentially affected by aging and that this inhibitory effect can be dissociated from effects on cell viability.
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PMID:Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta 1 (TGF-beta 1) inhibit the expression and activity of Na+/K(+)-ATPase in FRTL-5 rat thyroid cells. 914 47


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