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)

Recombinant human granulocyte/macrophage colony-stimulating factor (GM-CSF) induced significant superoxide production in human neutrophils within 30 minutes after addition of stimulus and the response was complete within 2 hr. Other agents known to prime neutrophils, including LPS and tumor necrosis factor-alpha, lacked activity under the experimental conditions employed. Using a panel of pharmacologic inhibitors, we sought to compare GM-CSF-induced neutrophil superoxide to that produced by cells exposed to N-formyl methionyl-leucyl-phenylalanine (fMet-Leu-Phe) and phorbol 12-myristate 13-acetate (PMA). Each stimulant displayed a different profile. Rolipram, a peak IV phosphodiesterase inhibitor, specifically inhibited neutrophil activation by GM-CSF and fMet-Leu-Phe, while superoxide production stimulated by PMA was unaffected. Staurosporine, a protein kinase C (PK-C) inhibitor, suppressed superoxide production induced by all three neutrophil stimulants. Cytochalasin B totally inhibited superoxide induced by GM-CSF under conditions that promote the fMet-Leu-Phe-induced response. Cytochalasin B did not markedly affect PMA-induced superoxide. The results are consistent with the hypothesis that intact PK-C activity is essential for neutrophil superoxide production, but that differences exist in the initial pathways induced by these neutrophil activators. Superoxide secretion from GM-CSF-treated neutrophils appears to be a direct, delayed response that requires assembly of microfilaments during exposure to the cytokine.
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PMID:Effect of recombinant human granulocyte/macrophage colony-stimulating factor on neutrophil superoxide production. 166 43

Using the closed cranial window technique, the present study was designed to test the hypothesis that the pial arteriolar response to acetylcholine is age dependent. In newborn pigs (1-5 days old) pretreated with the phosphodiesterase inhibitor isobutyl methyl xanthine (IBMX), acetylcholine (10(-5) M) produced pial arteriolar constriction with no change in CSF cyclic GMP (cGMP) that was blocked by indomethacin (5 mg/kg i.v.). In contrast, in indomethacin- and IBMX-treated juvenile pigs (3-4 weeks old), acetylcholine (10(-) M) increased the pial arteriolar diameter by 17 +/- 1% and increased CSF cGMP by 2.1 +/- 0.3-fold. Similar vascular and biochemical changes for acetylcholine were observed in juvenile pigs pretreated with only IBMX. In the absence of IBMX, acetylcholine produced modest pial constriction in juvenile pigs. In the IBMX-pretreated juvenile pigs, L-nitroarginine (LNA; 10(-6) M) decreased pial arteriolar diameter by 15 +/- 2% and blocked acetylcholine-induced dilation and associated changes in CSF cGMP. A23187, a calcium ionophore, and sodium nitroprusside (SNP) elicited similar dilation and changes in CSF cGMP in both age groups. LNA blocked A23187 dilation, but SNP dilation was unchanged. L-Arginine (10(-3) M) partially restored acetylcholine- and A23187-induced dilation to indomethacin- and LNA-pretreated juvenile pigs. These data show that acetylcholine produces dilation in the juvenile pig through the production of the putative endothelium-derived relaxing factor (EDRF) nitric oxide but does not do so in the new born period. We speculate that contributions of EDRF to the acetylcholine-induced changes in pial arteriolar diameter develop with age.
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PMID:Different pial arteriolar responses to acetylcholine in the newborn and juvenile pig. 752 28

Human neutrophils, plated on fibronectin-precoated wells, were found to release large quantities of superoxide anion (O2-) in response to GM-CSF. O2- production was reduced by prostaglandin E2 (PGE2) and the phosphodiesterase type IV (PDE IV) inhibitor RO 20-1724. Both agents are known to increase intracellular cyclic AMP (cAMP) levels by inducing its production (PGE2) or blocking its catabolism (RO 20-1724). When added in combination, PGE2 and RO 20-1724 had a marked synergistic inhibitory effect, which was reproduced by replacing PGE2 with a direct activator of adenylate cyclase, i.e. forskolin (FK). Moreover, the neutrophil response to GM-CSF was inhibited by a membrane-permeable analogue of cAMP in a dose-dependent manner. As GM-CSF and PGE2 are known to be generated at tissue sites of inflammation, the results suggest the existence of a PGE2-dependent regulatory pathway potentially capable of controlling the neutrophil response to GM-CSF, in turn limiting the risk of local oxidative tissue injury. Moreover, owing to its susceptibility to amplification by RO 20-1724, the PGE2-dependent pathway and in particular PDE-IV may represent a pharmacological target to reduce the generation of histotoxic oxidants by GM-CSF-responding neutrophils.
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PMID:Cyclic AMP-elevating agents down-regulate the oxidative burst induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) in adherent neutrophils. 766 97

Apoptosis or programmed cell death (PCD) was measured in two human cell models by flow cytometric analysis. Blood neutrophils underwent spontaneous apoptosis in short-term culture. Pentoxifylline (PTX) inhibited spontaneous neutrophil PCD. We confirmed that granulocyte/macrophage colony-stimulating factor (GM-CSF) inhibited apoptosis of polymorphonuclear neutrophils. Treatment with both GM-CSF and PTX did not increase the inhibition of PCD by either GM-CSF or PTX alone. Because apoptosis could be due to the accumulation of H2O2 in the culture medium, and because PTX has been described to reduce peroxide production, we studied the effect of adding catalase to the medium. Catalase reduced the neutrophil apoptosis and this effect was cumulative with the effect of PTX. Camptothecin, an inhibitor of topoisomerase I, induces a block in the S-phase of the cell cycle followed by apoptosis of the U937 cell line. This drug-induced apoptosis was partially inhibited by PTX, whereas the S-phase cell block was not affected. In conclusion, PTX was found to inhibit apoptosis in two different human cell types. In neutrophils, this effect appears to occur regardless of the inhibition of phosphodiesterase activity and inhibition of H2O2 release.
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PMID:Effect of pentoxifylline on apoptosis of cultured cells. 869 66

Many clinical trials have suggested that theophylline has anti-inflammatory properties in the treatment of bronchial asthma. Proposed mechanisms of theophylline inhibition include phosphodiesterase inhibition, an adenosine receptor antagonist, the increase of circulating adrenaline, mediator antagonist and inhibition of calcium ion influx. Further to these observations we report on the inhibition by theophylline of NF-kappaB, a key transcription factor found in human purified mast cells, which plays a role in the transcription of TNF alpha, GM-CSF, and IL-8 within this cell. The suppression of NF-kappaB activation, indicates that theophylline, in addition to its bronchodilator activities, has the potential for anti-inflammatory activity.
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PMID:Asthma, adenosine, mast cells and theophylline. 975 85

Malignant rat T9 glioma cells retrovirally transduced with the membrane form of macrophage colony stimulating factor (mM-CSF) were killed by bone marrow derived macrophages in 24 h cytotoxicity assays. Prostaglandin E2 (PGE) and interleukin-10 (IL10) were tested for their ability to block this tumoricidal reaction. Only at very high nonphysiological concentrations of PGE (10(-5) and 10(-6) M) was this cytotoxicity inhibited. Use of high doses of theophylline, a phosphodiesterase inhibitor, also prevented macrophages from killing the mM-CSF transduced target cells. IL10 did not alter the killing potential of the mM-CSF tumoricidal macrophages, even though IL10 reduced the production of nitric oxide by macrophages in response to tumor necrosis factor and lipopolysaccharide. IL10 enhanced the growth of bone marrow macrophages suggesting that IL10 has a complex role in the regulation of tumoricidal macrophages. Thus, the mM-CSF may be an ideal agent to treat tumors that utilize either of these two immunosuppressive defense mechanisms that may block other forms of treatment.
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PMID:Macrophages that kill glioma cells expressing the membrane form of macrophage colony stimulating factor are resistant to prostaglandin E2 and interleukin-10. 1054 Oct 53

Human airway smooth muscle (HASM) cells release granulocyte macrophage-colony stimulating factor (GM-CSF) and express cyclooxygenase (COX)-2 (resulting in the release of prostaglandin [PG] E2) after stimulation with cytokines. Because COX-2 activity can regulate a number of inflammatory processes, we have assessed its effects, as well as those of agents that modulate cyclic adenosine monophosphate (cAMP), on GM-CSF release by HASM cells. Cells stimulated with a combination of proinflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha each at 10 ng/ml) for 24 h released significant amounts of PGE2 (measured by radioimmunoassay) and GM-CSF (measured by enzyme-linked immunosorbent assay). Indomethacin and other COX-1/COX-2 inhibitors caused concentration-dependent inhibitions of PGE2 concomitantly with increases in GM-CSF formation. Addition of exogenous PGE2 or the beta2-agonist fenoterol, which increase cAMP, to cytokine-treated HASM cells had no effect on GM-CSF release unless COX activity was first blocked with indomethacin. The type 4 phosphodiesterase inhibitors rolipram and SB 207499 both caused concentration-dependent reductions in GM-CSF production. Thus, when HASM cells are activated with cytokines they release PGE2, which acts as a "braking mechanism" to limit the coproduction of GM-CSF. Moreover, agents that elevate cAMP also reduce GM-CSF formation by these cells.
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PMID:Effects of prostaglandin E2 and cAMP elevating drugs on GM-CSF release by cultured human airway smooth muscle cells. Relevance to asthma therapy. 1115 49

We investigated the effects of drugs, especially anti-pulmonary disease agents, on the production of cytokines from human peripheral blood mononuclear cells (PBMC). Roxithromycin (RXM), a macrolide antibiotic with the structure of 14-member macrocycline ring increased adherent cells (monocyte/macrophages), whereas it suppressed the proliferation of PBMC stimulated with phytohemagglutinin (PHA). RXM suppressed the production of IL-1 beta and TNF-alpha from lipopolysaccharide (LPS)-stimulated PBMC in a dose-dependent manner. Levofloxacin, a fluorinated quinolone, increased IL-2 production by PBMC stimulated with PHA. The production of GM-CSF and soluble IL-2 receptor was suppressed at high concentrations of LVFX. LVFX suppressed IL-1 beta production, but did not the production of TNF-alpha and IL-8 production. A beta-adrenoceptor agonists (beta-agonist), procaterol, clenbuterol, fenoterol and terbutaline suppressed the production of TNF- and IL-1 beta. TNF-alpha production was almost completely suppressed by dibutyryl cyclic AMP (dbcAMP), whereas IL-1 beta production appeared to be partially refractory even at the highest concentration examined. Both procaterol and theophylline elevated cAMP levels in LPS-stimulated PBMC, but the effect of procaterol was limited. The inhibition of the production of TNF-alpha and IL-1 beta by procaterol was additively potentiated with theophylline. Of examined phosphodiesterase (PDE) isozyme inhibitors type IV PDE inhibitors were more effective in inhibiting the production of TNF-alpha and IL-1 beta by LPS-stimulated PBMC than a nonselective, type III or type III/IV inhibitor. The addition of the beta-agonist increased the inhibitory effect of tested PDE inhibitors on the production of TNF-alpha and IL-1 beta Type IV, type III and nonselective PDE inhibitors were effective in inhibiting the production of IFN-gamma and IL-2 in a dose-dependent manner. In contrast, the production of IL-4 and IL-5 was inhibited by only the highest concentration of type IV inhibitor, and other agents had no effect on the production. Similarly, dbcAMP inhibited the production of IFN-gamma and IL-2 more potently than that of IL-4 and IL-5. The addition of the beta-agonist increased the inhibitory effect of tested PDE inhibitors on the production of IFN-gamma and IL-2 production. These findings indicate that these agents have an immunodulatory action on the production of cytokines by PBMC and also indicate that they could be potent pharmacological agents for the treatment of diseases in which several cytokines are important etiological factors.
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PMID:[Modulation of cytokine production from human mononuclear cells by several agents]. 1119 79

1. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory cytokine secreted by cells of the monocyte/macrophage lineage and has been implicated in the pathogenesis of bronchitis and asthma. 2. In the present study we have evaluated the effect of several cyclic AMP-elevating agents on lipopolysaccharide (LPS)-induced GM-CSF release from human monocytes and the extent to which the anti-inflammatory cytokine, interleukin (IL)-10, is involved. 3. LPS evoked a concentration-dependent generation of GM-CSF from human monocytes that was inhibited, at the mRNA and protein level, by 8-Br-cyclic AMP, cholera toxin, prostaglandin E2 (PGE2) and a number of structurally dissimilar phosphodiesterase (PDE) 4 inhibitors. 4. Pre-treatment of monocytes with a concentration of an anti-IL-10 monoclonal antibody that abolished the inhibitory action of a maximally effective concentration of exogenous human recombinant IL-10, significantly augmented LPS-induced GM-CSF generation. This effect was associated with a parallel upwards displacement of the concentration-response curves that described the inhibition of GM-CSF by PGE2, 8-Br-cyclic AMP and the PDE4 inhibitor, rolipram, without significantly changing the potency of any drug. Consequently, the maximum percentage inhibition of GM-CSF release was reduced. Further experiments established that the reduction in the maximum inhibition of GM-CSF release seen in anti-IL-10-treated cells was not due to functional antagonism as rolipram, PGE2 and 8-Br-cyclic AMP were equi-effective at all concentrations of LPS studied. 5. These data indicate that cyclic AMP-elevating drugs attenuate the elaboration of GM-CSF from LPS-stimulated human monocytes by a mechanism that is not mediated via IL-10. Suppression of GM-CSF from monocytes may explain, at least in part, the efficacy of PDE4 inhibitors in clinical trials of chronic obstructive pulmonary disease.
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PMID:Suppression of granulocyte/macrophage colony-stimulating factor release from human monocytes by cyclic AMP-elevating drugs: role of interleukin-10. 1152 97

The signalling pathways mediating neutrophil spontaneous apoptosis are still largely unknown. We report that the indolocarbazole compound KT5823, a specific inhibitor of cGMP-dependent protein kinases (cGK), dose-dependently inhibited spontaneous apoptosis of neutrophils. At the concentration eliciting the maximum effect (8 microM), it decreased apoptosis from 72.42+/-12.79% to 45.86+/-7.22% (p=0.0002, n=6). Similarly, the isoquinoline sulfonamide compound H89, another cGK inhibitor, prevented neutrophil apoptosis. At the concentration eliciting the maximum effect (20 microM), it decreased apoptosis from 72.42+/-12.79% to 31.84+/-10.70% (p=0.0004, n=6). The maximum effect of KT5823 and H89 was comparable to that of GM-CSF and LPS, respectively. Moreover, YC-1, a soluble guanylate cyclase activator, and 4-([3',4',-(methylenedioxy)benzyl]amino)-6-methoxyquinazoline, a specific phosphodiesterase 5 inhibitor, enhanced neutrophil apoptosis, and their effect was antagonised by KT5823. Taken together, these observations highlight a new role of cGK as important mediators of neutrophil spontaneous apoptosis.
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PMID:Inhibition of cGMP-dependent protein kinases potently decreases neutrophil spontaneous apoptosis. 1227 Jan 21


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