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)

Interleukin-1 alpha (IL-1) stimulated the release of degraded proteoglycan from primary cultures of chondrocyte monolayers in a time- and dose-dependent fashion. Bafilomycin A1, a specific inhibitor of the vacuolar H(+)-ATPase, efficiently blocked acidification of the chondrocyte vacuolar system. Under these conditions IL-1-stimulated proteoglycan degradation was inhibited by bafilomycin A1 with an IC50 of < 10 nM in both chondrocyte monolayers and articular cartilage explants. This concentration was at least 100-fold less than that required to partially inhibit total protein synthesis. In chondrocyte monolayers, bafilomycin A1 could be added several hours after IL-1 and complete inhibition was still observed. Tumor necrosis factor-alpha and retinoic acid also stimulated proteoglycan degradation in chondrocyte monolayers, and in both cases the response was inhibited by bafilomycin A1. These results suggest that maintenance of vacuolar acidity is required for cytokine stimulated proteoglycan degradation and that this requirement is at a point distal to receptor binding and early signal transduction events. IL-1 also stimulated the synthesis and secretion of prostromelysin by chondrocyte monolayers, however, under conditions in which IL-1 stimulated proteoglycan release was totally blocked by bafilomycin A1, there was no effect on IL-1-stimulated stromelysin secretion or stromelysin enzyme activity. These results, in which stromelysin synthesis and proteoglycan degradation were dissociated, suggest that an additional enzyme is responsible for proteoglycan degradation in this chondrocyte monolayer system.
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PMID:Bafilomycin A1 inhibits IL-1-stimulated proteoglycan degradation by chondrocytes without affecting stromelysin synthesis. 786 40

Interleukin-1 (IL-1) causes a diuresis and natriuresis in experimental animals. The natriuresis is due, at least in part, to IL-1 stimulation of prostaglandin E2 (PGE2) synthesis by the inner medullary collecting duct (IMCD), with resultant inhibition of Na(+)-K(+)-adenosine triphosphatase activity. It is unknown whether IL-1 affects other signal transduction systems in the IMCDs that regulate nephron sodium and water reabsorption. Furthermore, indirect evidence suggests that IL-1 inhibits sodium and water transport in other nephron segments. Consequently we examined (1) the effect of IL-1 on cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) accumulation by rat IMCD cells and (2) IL-1 stimulation of signal transduction mechanisms throughout the nephron. IL-1 had no affect on cGMP or arginine vasopressin-dependent (AVP-dependent) or isoproterenol-dependent cAMP accumulation in cultured rat IMCD cells. IL-1 increased PGE2 levels in rabbit IMCD, cortical collecting tubule (CCT), and to a lesser extent, medullary thick ascending limb cells, but had no effect on proximal tubule cells. IL-1 also did not alter AVP-dependent cAMP accumulation in the CCT. The failure of IL-1 to reduce AVP responsiveness in the CCT was not due to culture conditions, because AVP-dependent cAMP accumulation in freshly isolated CCT cells was also not affected by the cytokine but was inhibited by exogenous PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-1 regulation of collecting duct prostaglandin E2 and cyclic nucleotide accumulation. 819 73

In vivo exposure to sulfuric acid aerosols produces profound effects on pulmonary macrophage (PM phi) phagocytic function and cytokine release and perturbs intracellular pH (pHi) homeostasis. Because pHi influences a multitude of cellular processes, we sought to investigate the mechanism by which acid aerosol exposure affects its regulation. Guinea pigs underwent a single or 5 repeated 3-hr exposures to sulfuric acid aerosol (969 and 974 micrograms/m3 for single and repeated exposures, respectively). PM phi harvested immediately after exposure were incubated in HCO3-free media and their pHi recovery from an intracellular acid load was examined. The overall pHi recovery was depressed after single and multiple exposures to sulfuric acid aerosol. delta pHi (the difference between initial pHi and the one measured at 150 sec) decreased by 15.6 and 23.3% (p < 0.05) for single and repeated exposures, respectively. Initial dpHi/dt (maximum pHi recovery rate) after cytoplasmic acidification diminished by 20.3 and 32.2%, which were not statistically significant (p = 0.08 for repeated exposure). To determine whether the activity of the H(+)-ATPase pump the Na(+)-H+ exchanger was specifically altered by the acid exposures, PM phi were first incubated in Na+ and HCO3-free media with NBD-Cl (7-chloro-4-nitrobenz-2-oxa-1,3-diazol, blocking H(+)-ATPase and leaving only the Na(+)-H+ exchanger in effect) and then challenged with 30 mM NaCl. The pHi recovery of PM phi after Na challenge was significantly reduced in acid aerosol exposed guinea pigs (p < 0.05) compared to controls (for delta pHi, 18.2% lower in single exposure and 22.7% in multiple exposure groups; for initial dpHi/dt, 26.9% lower in single exposure and 22.4% in multiple exposure groups). In contrast, the H(+)-ATPase pump was inconsistently affected as indicated by delta pHi and initial dpHi/dt measured in the presence of MIA (amiloride-5-N-methylisobutyl, inhibiting the Na(+)-H+ exchanger and leaving only the H(+)-ATPase pump in effect). These results suggest that in vivo exposure to sulfuric acid aerosols induces alterations in pHi regulation in guinea pig PM phi attributable to changes in Na(+)-H+ exchanger activity.
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PMID:Alteration of pulmonary macrophage intracellular pH regulation by sulfuric acid aerosol exposures. 839 19

The bone marrow cytokine (Bio-Immuno Modulator, BIM or BM-Fr1) has been suggested to correct immunoincompetence by modulating brain Na(+)-K(+)-ATPase. The brain region affected and mechanism of action of BM-Fr1 are unknown, however. Here we report that immunization of immunocompetent rats indirectly inhibited Na(+)-K(+)-ATPase activity (59%) in the left cerebral lobe (LC) and irrespective of BM-Fr1 treatment, stimulation of the enzyme was observed in the LC at the peak of immune response. BM-Fr1 treatment, which corrected immunoincompetence in malnourished rats, also modulated a different LC Na(+)-K(+)-ATPase profile to that seen in immunocompetent animals. Immunogen and BM-Fr1 seem to exert their influence in brain via a cytosolic inhibitor protein of Na(+)-K(+)-ATPase. Thus we suggest that (1) BM-Fr1 plays an important role in immune homeostatasis by modulating Na(+)-K(+)-ATPase activity of LC and (2) Na(+)-K(+)-ATPase is not the receptor for either immunogen or BM-Fr1.
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PMID:Na(+)-K(+)-ATPase activity of different regions of rat brain in response to immunization and bone marrow cytokine treatment. 872 62

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

Cytokines, including TNF alpha and IL-l beta, are central to the chronic inflammatory process and tissue damage that characterises diseases such as rheumatoid arthritis. The mechanisms responsible for long-term generation of these molecules are poorly understood. We have previously demonstrated impaired activity of Na, K-ATPase, a key enzyme regulating intracellular cation levels, on rheumatoid mononuclear cells. Mimicking this 'defect' on normal mononuclear cells with ouabain has been shown to induce TNF alpha and, in particular, IL-l beta production, whereas IL-6 synthesis was suppressed. A similar pattern of cytokine generation was noted when mononuclear cells were treated with the sodium ionophore, monensin. Induction of cytokine production was related to up-regulation of the appropriate mRNA, although enhanced secretion of processed IL-l beta was also observed. The mechanism underlying these cellular responses appears to involve sodium/calcium exchange across the cell membrane. Impaired Na,K-ATPase activity might promote pro-inflammatory cytokine secretion in patients with rheumatoid arthritis.
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PMID:Modulation of cytokine production by human mononuclear cells following impairment of Na, K-ATPase activity. 903 Feb

The site of action of a series of pyridinyl imidazole compounds that are selective inhibitors of p38 mitogen-activated protein kinase in vitro and block proinflammatory cytokine production in vivo has been determined. Using Edman sequencing, 125I-SB206718 was shown to cross-link to the nonphosphorylated Escherichia coli-expressed p38 kinase at Thr175, which is proximal to the ATP binding site. Titration calorimetric studies with E. coli-expressed p38 kinase showed that SB203580 bound with a stoichiometry of 1:1 and that binding was blocked by preincubation of p38 kinase with the ATP analogue, FSBA (5'-[p-(fluorosulfonyl)benzoyl]adenosine), which covalently modifies the ATP binding site. The intrinsic ATPase activity of the nonphosphorylated enzyme was inhibited by SB203580 with a Km of 9.6 mM. Kinetic studies of active, phosphorylated yeast-expressed p38 kinase using a peptide substrate showed that SB203580 was competitive with ATP with a Ki of 21 nM and that kinase inhibition correlated with binding and biological activity. Mutagenesis indicated that binding of 125I-SB206718 was dependent on the catalytic residues K53 and D168 in the ATP pocket. These findings indicate that the pyridinyl imidazoles act in vivo by inhibiting p38 kinase activity through competition with ATP and that their selectivity is probably determined by differences in nonconserved regions within or near the ATP binding pocket.
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PMID:Pyridinyl imidazole inhibitors of p38 mitogen-activated protein kinase bind in the ATP site. 911 81

It has been reported that amiodarone induces disorders of alveolar macrophages and pulmonary fibrosis, but the mechanism is not well-understood. This study was performed to elucidate the toxic mechanism from the standpoint of cellular function. Using alveolar macrophages obtained from a male Slc:ICR mouse, several injuries caused by amiodarone were compared to those caused by amantadine and mianserin as cationic amphiphilic drugs (CADs). As parameters for the drug effects, H(+)-ATPase and acid sphingomylinase activities, cellular pH, cytokine and prostaglandin releases, phagocytosis and neutral red uptake were measured. Amiodarone decreased H(+)-ATPase activity initially and subsequently increased cellular pH and decreased acid sphingomyelinase activity. These changes, which were also observed with amantadine and mianserin, were considered to be CAD-related. Amiodarone increased cytokine and prostaglandin releases and suppressed neutral red uptake and phagocytosis. These changes, being not induced by amantadine and mianserin, were considered to be specific for amiodarone. The above data suggest that amiodarone has two types of toxic effects on alveolar macrophages.
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PMID:Amiodarone induces two different types of disorders in mouse alveolar macrophages. 919 93

The cell type specificity of the regulation of expression of the potent growth inhibitory cytokine transforming growth factor-beta (TGF-beta), prompted our analyses of the regulation of TGF-beta1 gene expression in glial cells by viral and cellular oncoproteins. We have shown that SV40 T-antigen diminished TGF-beta1 expression in glial cells and this repression was dependent on the ability of T-antigen to interact with the tumor suppressor protein, pRb, and two structurally related proteins, p107 and p130. The cellular transcription factor E2F-1, which is a downstream effector of T-antigen, was unable to influence expression from the TGF-beta1 promoter by itself. Interestingly, E2F-1 could overcome viral T-antigen-mediated repression of the TGF-beta1 promoter, suggesting potential feedback loop between TGF-beta and E2F in virally transformed glial cells. Using deletion analyses, we have mapped two E2F-1-responsive regions on the TGF-beta1 promoter: a T-antigen-dependent negative regulatory sequence (TdNRS) between -323 and -175, and a T-antigen-independent positive regulatory sequence (TiPRS) between -34 and +10 on the TGF-beta1 promoter. Further examination of TiPRS revealed the presence of a functional E2F binding site. Interestingly, the amino terminus of E2F-1 was required for its activation of TGF-beta1 expression, as mutations in that domain abolished the ability of E2F-1 to increase TGF-beta1 expression. These data suggest that yet-uncharacterized interaction between the amino terminus of E2F-1 and cellular proteins regulates TGF-beta1 expression. The mechanism for E2F-1-mediated T-antigen-dependent regulation of TGF-beta1 expression from TdNRS awaits further characterization.
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PMID:The transcription factor E2F-1 modulates TGF-beta1 RNA expression in glial cells. 920 3

Interferon-gamma (IFN-gamma) +/- tumor necrosis factor-alpha (TNF-alpha) induces antiproliferation and intracellular Ca2+ store depletion in a human submandibular ductal cell line (HSG), which can be reversed on cytokine removal [A. J. Wu, G. C. Chen, B. J. Baum, and I. S. Ambudkar. Am. J. Physiol. 270 (Cell Physiol. 39): C514-C521, 1996]. Here we have examined a possible mechanism for the IFN-gamma-induced intracellular Ca2+ store depletion. There was a time-dependent decrease in thapsigargin-dependent internal Ca2+ release after exposure of the cells to the cytokines. The intracellular Ca2+ pump [sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)] protein in lysates and membranes of cells treated with IFN-gamma +/- TNF-alpha, but not with TNF-alpha alone, showed a similar time-dependent decrease (examined using a SERCA2 antibody). Removal of the cytokines, which resulted in recovery of cell growth and refill of internal Ca2+ stores, also increased the level of SERCA protein. The decrease in SERCA is not a result of decreased cell proliferation, since thapsigargin, 2,5-di-(t-butyl)-1,4-hydroquinone, or serum-free growth conditions induced antiproliferative effects on HSG cells without any corresponding decrease in SERCA. We suggest that the IFN-gamma-induced decrease in the level of SERCA accounts for the depleted state of internal Ca2+ stores in cytokine-treated HSG cells. These data suggest a novel mechanism for the inhibition of HSG cell growth by IFN-gamma.
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PMID:Interferon-gamma induces a decrease in the intracellular calcium pump in a human salivary gland cell line. 943 10


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