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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three major subtypes of human interferon-alpha (IFN-alpha), isolated from virus-induced leukocytes, were compared for their antiviral and anticellular activities on one hand, and for their ability to induce (2'-5') oligoadenylate synthetase on the other hand. One subtype, IFN-alpha 1, was found to have low specific antiviral (6.10(6)-5.10(7) units/mg) and anticellular activities when measured on a variety of human cells. A second subtype, exhibiting an unusually high molecular weight (26,000) by SDS-polyacrylamide gel electrophoresis (IFN-alpha 26K), was found to have the highest known specific antiviral (8.10(8)-2.10(9) units/mg) and anticellular activities. Thus, these two subtypes of IFN-alpha differ by a factor of 330 and represent the two extremes in the antiviral scale on human cells. A third subtype, IFN-alpha 2, was tested as well and was found to have intermediate antiviral and anticellular activities. The ability of these three subtypes to induce (2'-5') oligoadenylate synthetase in human cells was then measured. It was found that on a weight basis, the three subtypes were equally effective in inducing the enzyme. Since the level of (2'-5') adenylate oligomers is affected also by the interferon-induced (2'-5') phosphodiesterase, the ability of these subtypes to induce this enzyme was compared as well and was found to be very similar. We therefore conclude that the differences in potency between these IFN-alpha subtypes are not related to their ability to induce (2'-5') oligoadenylate synthetase.
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PMID:High and low potency interferon-alpha subtypes induce (2'-5') oligoadenylate synthetase with similar efficiency. 631 31

The mechanism of interferon resistance was studied in two clones of Daudi cells, DIF2 and DIF3, which exhibit respectively moderate and pronounced resistance to both the antiviral and antiproliferative actions of human interferons-alpha and -beta. Clones DIF2 and DIF3 were found to possess specific high affinity interferon receptors similar to those of parental Daudi cells. However, DIF2 cells, which have a tetraploid karyotype, had approximately twice as many interferon-binding sites as either DIF3 or parental Daudi cells. One of the first detectable changes in Daudi cells following interferon treatment is a rapid increase in the intracellular concentration of cyclic GMP. No increase in cyclic GMP was observed in DIF2 or DIF3 cells treated with interferon-alpha. However, neither DIF2 nor DIF3 cells respond to sodium azide, a nonphysiological inducer of cyclic GMP. Interferon treatment was found to induce the production of 2'-5'-oligo-isoadenylate synthetase in DIF2 and DIF3 cells in a manner similar to parental Daudi cells, indicating that these cells possess functional interferon receptors. The levels of 2'-5'-oligo-isoadenylate synthetase and 2'-5' A phosphodiesterase activity were similar in all three cell lines, suggesting that the interferon resistance of clones DIF2 and DIF3 was not due to a deficiency of pp(A2' p)nA.
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PMID:Isolation of Daudi cells with reduced sensitivity to interferon. II. On the mechanisms of resistance. 631 52

The survival rate of mice with exposure of the whole body (700 cGy) was hardly changed by one dose as well as several doses of the phosphodiesterase inhibitor Amantadine and the interferon inductor measles vaccine. However, the survival rates were increased by one administration of L-dopa or by the long-term therapy using L-dopa at 700 and 900 cGy. The survival rates were also increased at 700 and 900 cGy if, after the exposure, thymus factor isolated from calf thymus was three times applied to the animals. The increased survival rates gained by using L-dopa and thymus factor are correlated with the determined leukocyte values.
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PMID:[The influence of L-dopa and of thymus fraction on the survival rate of whole-body-irradiated mice]. 675 89

Pentoxifylline (PTX), a methylxanthine derivative and phosphodiesterase inhibitor, is known to influence production and/or function of some cytokines. We examined the effect of PTX on the in vitro expression of cytokine genes using endotoxin- or phytohaemagglutinin (PHA)-stimulated human blood mononuclear cells. The expression of tumour necrosis factor (TNF)alpha, TNF beta interleukin (IL)-2 and interferon (IFN)gamma was inhibited by PTX in a dose-dependent manner, whereas expression of IL-1 alpha, IL-1 beta, and IL-6 was unaffected at concentrations up to 300 microM of PTX. The amount of TNF beta mRNA in PHA-stimulated blood mononuclear cells was reduced by PTX. Finally, PTX stimulated PHA-induced cell proliferation whereas antigen-induced cell proliferation was inhibited in the presence of PTX. The PTX analogues HWA-138 and A-802715 inhibited TNF alpha mRNA expression from endotoxin-stimulated mononuclear cells. These data suggest that PTX-analogues affect the in vitro immune response at different target points and that the response depends upon the respective triggering mechanism(s).
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PMID:In vitro immunomodulatory effects of pentoxifylline. 750

The influence of interferon (IFN)-gamma on vasodilation was examined in bovine isolated mesenteric arteries. Arterial rings were incubated with IFN-gamma (100 U ml-1) for 20 hr and subsequently the response to vasodilators was determined isometrically in an organ bath. Treatment with IFN-gamma markedly inhibited endothelium-dependent relaxation to bradykinin and impaired vasodilation to nitroprusside, which was endothelium-independent. The decrease in relaxation was correlated with a decrease in bradykinin- and nitroprusside-induced cGMP production. Relaxation to the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine or zaprinast was not altered after IFN-gamma, which suggests that the IFN-gamma effect is specific for guanylate cyclase-activating agonists. Nitrite concentration in the incubation medium was increased after IFN-gamma, which indicates the induction of nitric oxide release during the incubation period. Inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine during the 20-hr incubation with IFN-gamma completely prevented the decrease in relaxation and cGMP elevation to nitroprusside. We conclude that IFN-gamma induces a marked increase in release of arterial-derived nitric oxide resulting in a desensitization of guanylate cyclase, which contributes to a decrease in relaxation to bradykinin and nitroprusside. These results may implicate the existence of an important adaptive process in the regulation of vascular tone during pathological situations associated with the induction of nitric oxide synthesis.
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PMID:Induction of nitric oxide release by interferon-gamma inhibits vasodilation and cyclic GMP increase in bovine isolated mesenteric arteries. 750 93

2-5A Synthetase and 2-5A phosphodiesterase were determined by analytical capillary isotachophoresis in comparison to radioenzymatic methods. By means of isotachophoretic analysis, a frequently used radioenzymatic 2-5A synthetase assay was optimized and the results of both assays were compared. Using the isotachophoretic assay the influence of interferon-related cytokines (tumor necrosis factor-alpha and interleukin-2) on 2-5A synthetase induction in neuroblastoma cells was estimated. In contrast to mononuclear blood cells, the tumor necrosis factor induced 2-5A synthetase in these cells. 2-5A Phosphodiesterase was determined using an isotachophoretic assay and a radioenzymatic method. Degradation of A2'p5'A2'p5'A (trimeric form of 2-5A core) was measured by isotachophoresis whereas degradation of a mixture of phosphorus-32 labeled 2-5A cores was registered by radioenzymatic assay. Activity of 2-5A phosphodiesterase was only insignificantly enhanced by interferon in mononuclear blood and neuroblastoma cells. In contrast to the radioenzymatic assays, an accurate determination of 2-5A synthetase as well as of 2-5A phosphodiesterase is possible using the isotachophoretic method because the reactions are followed by measuring the substrates ATP and A2'p5'A2'p5'A, respectively.
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PMID:Determination of 2-5A synthetase and 2-5A phosphodiesterase in neuroblastoma cells by analytical capillary isotachophoresis: effects of cytokines and comparison with radioenzymatic methods. 814 79

We examined the effect of interleukin-10 (IL-10), gamma interferon (IFN-gamma), phorbol ester (PDB), opsonized zymosan (OZ) and aminophylline (a cAMP phosphodiesterase inhibitor) on the reducing power and oxidizing species generation by human neutrophils, using MTT dye reduction and luminol-dependent chemiluminescence assays, respectively. Gamma interferon (IFN-gamma), phorbol ester (PDB) and opsonized zymosan (OZ) were activators while interleukin-10 (IL-10) and aminophylline were inhibitors. A strong parallelism was observed between oxidizing species generation and cellular reducing power in both activation and inhibition experiments. Our results also demonstrate for the first time the effect of IL-10 on free radical generation by neutrophils. The consequence of these activating and inhibiting effects on the inflammatory process are discussed.
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PMID:Effect in vitro of gamma interferon and interleukin-10 on generation of oxidizing species by human granulocytes. 884 31

Microglial cell activation plays a central role in acute and chronic inflammatory processes associated with neurodegeneration. As macrophage activation is generally associated with the up-regulation of specific surface antigens, the expression of CD54, and CD29 were evaluated on CD11b positive neonatal rat microglial cell cultures by flow cytometry. These cells when exposed to lipopolysaccharide, LPS, and gamma interferon, IFN gamma, exhibited a 2-3 fold increase in CD54 expression, an increase in CD29 and no change in CD11b. Maximal increases in CD54 and CD29 staining on CD11b positive microglial cells were apparent 20-24 h after LPS and IFN gamma while nitrite production reflecting inducible nitric oxide synthase activity, continued to increase. The increases in CD29 and CD54 staining were inhibited in a dose dependent manner by agents which increased intracellular cAMP levels including 100 microM 8-bromoadenosine 3':5'-cyclic monophosphate but not 8-bromoadenosine monophosphate, the phosphodiesterase inhibitor isobutyl methylxanthine and by direct activation of adenylate cyclase with forskolin. Concomitant with the dose dependent decreases in CD29 and CD54 staining were increases in intracellular cAMP and reduced TNF secretion. These results suggest that regulation of CD29 and CD54 expression on activated microglial cells involves a cAMP dependent pathway.
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PMID:Expression of CD54 (intercellular adhesion molecule-1) and the beta 1 integrin CD29 is modulated by a cyclic AMP dependent pathway in activated primary rat microglial cell cultures. 948 53

Interleukin (IL)-12, interferon (IFN)-gamma, and other inflammatory cytokines play an important role in the pathogenesis of autoimmune insulitis and diabetes in NOD mice, and inhibition of these cytokines is likely to be beneficial. In this study, we found that Pentoxifylline (PTX) and Rolipram (phosphodiesterase [PDE] inhibitors that induce increased intracellular cAMP) can block inflammatory cytokine production. Inhibition of IL-12 and IFN-gamma secretion was demonstrated in macrophages activated with lipopolysaccharide or T-cells stimulated through the CD3/T-cell receptor complex, respectively. Moreover, strong inhibition of IL-12 was demonstrated in vivo in superantigen-immunized mice. Rolipram was inhibitory at concentrations as low as 10(-8) to 10(-7) mol/l, and on a molar basis, it was 100-fold more effective than PTX. Tumor necrosis factor-alpha was also inhibited, but IL-4 was less sensitive to suppression. In NOD mice, both PTX and Rolipram reduced the severity of insulitis and prevented diabetes, with or without cyclophosphamide administration (which precipitates onset of disease). This protection of NOD mice was still apparent over 10 weeks after withdrawal of the drug treatment. It appears that blocking the activity of type IV PDE is sufficient to mediate the effects reported in this study, since Rolipram inhibits only this isoform, unlike PTX (a general inhibitor). PTX and Rolipram may be effective in the treatment of autoimmune diabetes or other conditions characterized by excessive production of inflammatory cytokines.
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PMID:The phosphodiesterase inhibitors pentoxifylline and rolipram prevent diabetes in NOD mice. 956 89

The 2-5A system is an RNA degradation pathway that can be induced by the interferons (IFNs). Treatment of cells with IFN activates genes encoding several double-stranded RNA (dsRNA)-dependent synthetases. These enzymes generate 5'-triphosphorylated, 2',5'-phosphodiester-linked oligoadenylates (2-5A) from ATP. The effects of 2-5A in cells are transient since 2-5A is unstable in cells due to the activities of phosphodiesterase and phosphatase. 2-5A activates the endoribonuclease 2-5A-dependent RNase L, causing degradation of single-stranded RNA with moderate specificity. The human 2-5A-dependent RNase is an 83.5 kDa polypeptide that has little, if any, RNase activity, unless 2-5A is present. 2-5A binding to RNase L switches the enzyme from its off-state to its on-state. At least three 2',5'-linked oligoadenylates and a single 5'-phosphoryl group are required for maximal activation of the RNase. Even though the constitutive presence of 2-5A-dependent RNase is observed in nearly all mammalian cell types, cellular amounts of 2-5A-dependent mRNA and activity can increase after IFN treatment. One well-established role of the 2-5A system is as a host defense against some types of viruses. Since virus infection of cells results in the production and secretion of IFNs, and since dsRNA is both a frequent product of virus infection and an activator of 2-5A synthesis, the replication of encephalomyocarditis virus, which produces dsRNA during its life cycle, is greatly suppressed in IFN-treated cells as a direct result of RNA decay by the activated 2-5A-dependent RNase. This review covers the organic chemistry, enzymology, and molecular biology of 2-5A and its associated enzymes. Additional possible biological roles of the 2-5A system, such as in cell growth and differentiation, human immunodeficiency virus replication, heat shock, atherosclerotic plaque, pathogenesis of Type I diabetes, and apoptosis, are presented.
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PMID:The 2-5A system: modulation of viral and cellular processes through acceleration of RNA degradation. 962 81


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