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)

There has been increased recognition of the importance of inflammatory cells and their products in the pathogenesis of asthma. From this recognition has evolved a number of new approaches to treat the various components of the asthmatic inflammatory response. Nonselective anti-inflammatory agents such as cyclosporine and gold appear to decrease symptoms and allow a steroid-sparing effect in many cases, though side effects from cyclosporine often necessitate dose reduction. Novel oral compounds as the 5-lipoxygenase inhibitors have been effective in controlling asthma symptoms triggered by various stimuli, and the cysteinyl leukotriene receptor antagonists have shown promise in this regard as well. Neurokinin antagonists, inhaled loop diuretics, and lidocaine may play significant roles in asthma therapy through inhibition of neurogenic inflammation and possibly mast cell function. Inhibition of mast cell products by existing drugs such as heparin or the development of specific inhibitors of mast cell tryptase may also be effective agents, as are selective phosphodiesterase inhibitors, which appear to have anti-inflammatory properties. Finally, specific cytokine antagonists, agonists, inhibitors of T-cell function, selective inducible nitric oxide synthase inhibitors, and even gene-directed strategies may provide not only insights into the pathogenesis of asthma but also novel therapeutic approaches to treat the inflammation in this disease.
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PMID:Experimental treatments for asthma. 913 70

Interleukin-13 (IL-13) is a proinflammatory cytokine of T cell origin. Structural and functional studies suggest a key role for IL-13 in the genesis of chronic allergic inflammation; as such, its pharmacologic inhibition is of potential clinical utility. We studied the pharmacologic regulation of IL-13 expression by cyclic nucleotide phosphodiesterase (PDE) inhibitors in a panel of Amb a 1 (a major allergen of short ragweed, Ambrosia artemisiifolia)-specific T cell clones derived from a ragweed allergic, asthmatic subject. Proliferative responses of these cells were down-regulated by rolipram, a PDE4 inhibitor (% inhibitionMAX = 67%; IC50 = 20 microM). While the PDE3 inhibitor siguazodan provided no independent efficacy (IC50 > 10(-4) M), an increased efficacy of rolipram in the presence of 10(-5) M siguazodan was noted at 10(-6), 10(-5), and 10(-4) M rolipram (P < 0.03, 0.01, and 0.04, respectively). The EC50 values remained unchanged between assays using the PDE4 inhibitor with or without the PDE3 inhibitor. Both IL-13 gene expression and protein secretion into culture supernatants were down-regulated by the PDE4 inhibitor (P < or = 0.005). Once again, the use of a PDE3 inhibitor provided no independent efficacy (P > or = 0.2), and in this instance, increased efficacy of the PDE4 inhibitor with the PDE3 inhibitor was not apparent (P > or = 0.3). IL-13 production from clones with Th0, Th1, and Th2 phenotypes appeared equally sensitive to treatment with the PDE4 inhibitor. We conclude that the anti-inflammatory effects of PDE4 inhibitors may be mediated, in part, by down-regulation of IL-13.
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PMID:Regulation of interleukin-13 by type 4 cyclic nucleotide phosphodiesterase (PDE) inhibitors in allergen-specific human T lymphocyte clones. 917 20

In cultured rat hepatocytes, the gluconeogenic key enzyme, phosphoenolpyruvate carboxykinase (PCK), is induced by glucagon via elevation of cyclic 3',5' adenosine monophosphate (cAMP). The proinflammatory cytokine, interleukin-6 (IL-6), which in the liver together with IL-1beta and tumor necrosis factor alpha triggers the acute-phase response, had been shown to attenuate the glucagon-induced increase in PCK gene transcription, messenger (mRNA) levels, and enzyme activity. The molecular mechanism of this inhibition was investigated in the present study. Glucagon increased cyclic cAMP and PCK mRNA levels to a transient maximum twofold and fivefold, respectively. The increases were attenuated by IL-6. Forskolin, which stimulates adenylate cyclase activity, increased cAMP and PCK mRNA levels 1.6-fold and fivefold, respectively. However, IL-6 attenuated the forskolin-stimulated increase in PCK mRNA but not the increase in cAMP. This showed that IL-6 inhibited PCK mRNA increase in part by the attenuation of cAMP increase, but also beyond cAMP formation. This was confirmed in experiments in which PCK mRNA levels were increased by the nonhydrolyzable cAMP-analogue, chlorophenylthio (CPT)-cAMP. The increase in PCK mRNA was again attenuated by IL-6. In pertussis toxin- and in isobutylmethylxanthine-treated hepatocytes, IL-6 still inhibited the glucagon-stimulated increase in cAMP, indicating that IL-6 did not activate an inhibitory G-protein or phosphodiesterase, which could cause the impairment of cAMP increase. To demonstrate whether the inhibition of PCK gene expression by IL-6 beyond cAMP might be caused by the inhibition of the activation of the PCK gene promoter by cAMP, cultured rat hepatocytes were transfected with a luciferase reporter gene construct under the control of a PCK gene promoter fragment (base -979 to base +32). Luciferase activity was determined after stimulation of the cells with CPT-cAMP in the absence or presence of IL-6. CPT-cAMP increased luciferase activity by 1.7-fold, which was inhibited in the presence of IL-6. It is concluded that IL-6 had a dual inhibitory effect on the stimulation of PCK gene expression by glucagon. It inhibited the increase in cAMP at a site before cAMP formation by adenylate cyclase and at a site after cAMP formation, the activation of the PCK gene promoter by cAMP.
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PMID:Mechanism of the impairment of the glucagon-stimulated phosphoenolpyruvate carboxykinase gene expression by interleukin-6 in rat hepatocytes: inhibition of the increase in cyclic 3',5' adenosine monophosphate and the downstream cyclic 3',5' adenosine monophosphate action. 921 54

Our study explores the relative efficacy of phosphodiesterase (PDE) inhibitors on antigen-specific Th1 and Th2 clonal responses. Proliferative responses for both phenotypes were down-regulated by the PDE4 inhibitor, rolipram, but not the PDE3 inhibitor, siguazodan. The Th2 clones were more sensitive than the Th1 clones to PDE4 inhibition (P < .05 at 10 and 100 microM rolipram). The addition of 1 microM of the adenylyl cyclase activator, isoproterenol, significantly decreased both the EC50 and IC50 of rolipram in both phenotypes (P < .05). Gene expression for interleukin-4, interleukin-5, or interferon-gamma, assessed by reverse transcription-polymerase chain reaction, was down-regulated by the PDE4 inhibitor, but not the PDE3 inhibitor, in each respective clone. Cytokine protein secretion paralleled the results of reverse transcription-polymerase chain reaction for IL-4 and interferon-gamma (P < .01 for each). No differential efficacy on cytokine generation parameters between T helper phenotypes was apparent. Rolipram treatment significantly elevated intracellular cyclic AMP (adenosine 3',5'-cyclic monophosphate) in clonal T cells (P < .01 for Th1 or Th2 clones); these elevations were consistently greater in the Th2 clones (P < .05). Finally, Th1 cells showed reduced gene expression for the PDE4C isoform and a lack of gene expression for the PDE4D isoform by reverse transcription-polymerase chain reaction, compared to the Th2 cells. These data demonstrate the potent immunomodulatory efficacy of PDE4 inhibition on antigen-specific T cell clones. The enhanced sensitivity of Th2 cells to PDE4 inhibition may be due, in part, to the differential expression of PDE4 isoforms between Th1 and Th2 cells.
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PMID:Differential regulation of human antigen-specific Th1 and Th2 lymphocyte responses by isozyme selective cyclic nucleotide phosphodiesterase inhibitors. 922 93

We have examined the effect of elevating cyclic AMP levels on cytokine-mediated enhancement of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) gene expression by astrocytes. Treatment of astrocytes with the cyclic AMP mimetic dibutyryl-cyclic AMP, or the agonists norepinephrine, forskolin, prostaglandin E2, and cholera toxin alone had no effect on ICAM-1 or VCAM-1 mRNA gene expression. However, elevating cyclic AMP levels within the cells by these agents suppressed interleukin-1beta- and tumor necrosis factor-alpha-induced adhesion molecule expression at both the mRNA and protein levels. The phosphodiesterase type IV inhibitor, rolipram, was able to potentiate the inhibitory effect of forskolin on ICAM-1 and VCAM-1 gene expression. Inhibition of tumor necrosis factor-alpha-induced VCAM-1 mRNA levels by forskolin was partially due to enhanced degradation of VCAM-1 message, whereas the decay rates of tumor necrosis factor-alpha-induced ICAM-1 message and interleukin-1beta-induced ICAM-1/VCAM-1 message were not affected by forskolin treatment. These results demonstrate that the pathways used by interleukin-1beta and tumor necrosis factor-alpha to induce adhesion molecule expression are antagonized by cyclic AMP-dependent protein kinase-mediated signaling pathways.
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PMID:Elevation of cyclic AMP levels in astrocytes antagonizes cytokine-induced adhesion molecule expression. 932 72

It was recently demonstrated that selective phosphodiesterase type 4 (PDE4) inhibition suppresses the clinical manifestations of acute experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), and inhibits the production of tumor necrosis factor-alpha (TNF-alpha), a pathogenetically central cytokine. Since the most common presentation of MS in humans is a relapsing-remitting course, we investigated the therapeutic potential of PDE4 inhibition in the relapsing-remitting EAE model of the SJL mouse. Administration of rolipram, the prototypic PDE4 inhibitor, reduced the clinical signs of EAE during both the initial episode of disease and subsequent relapses. In parallel, there was marked reduction of demyelination and also less inflammation throughout the central nervous system (CNS) of rolipram-treated animals. Gene expression of proinflammatory cytokines in the CNS was reduced in most of the rolipram-treated animals. Additional experiments demonstrated that PDE4 inhibition acted principally by inhibiting the secretion of Th1 cytokines, however, the encephalitogenic potential of myelin basic protein-specific T cells was not impaired. Our findings suggest that PDE4 inhibitors are a promising cytokine-directed therapy in chronic demyelinating disease.
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PMID:Therapeutic potential of phosphodiesterase type 4 inhibition in chronic autoimmune demyelinating disease. 935 47

One of the more complex developmental processes occurring postnatally in the CNS is the formation of the myelin sheath by oligodendrocytes. To examine the molecular events that take place during myelination, we isolated oligodendrocyte-derived cDNA clones, one of which (p421.HB) represents a putative alternatively spliced isoform of rat brain-specific phosphodiesterase I (PD-Ialpha) and a species homolog of the human cytokine autotaxin. Analysis of the structural composition of the p421.HB/PD-Ialpha protein suggests a transmembrane-bound ectoenzyme, which, in addition to the phosphodiesterase-active site contains presumed cell recognition and Ca2+-binding domains. Consequently, it may be involved in extracellular signaling events. Expression of p421.HB/PD-Ialpha is enriched in brain and spinal cord, where its mRNA can be detected in oligodendrocytes and in cells of the choroid plexus. Expression in the brain increases during development with an intermediate peak of expression around the time of active myelination and maximal expression in the adult. We have identified four presumably alternatively spliced isoforms, two of which appear to be CNS-specific. Decreased levels of p421.HB/PD-Ialpha mRNA in the dysmyelinating mouse mutant jimpy, but not shiverer, suggest a role for p421.HB/PD-Ialpha during active myelination and/or late stages of oligodendrocyte differentiation. Furthermore, p421.HB/PD-Ialpha mRNA levels were reduced in the CNS at onset of clinical symptoms in experimental autoimmune encephalomyelitis. These data together implicate the importance of p421.HB/PD-Ialpha in oligodendrocyte function, possibly through cell-cell and/or cell-extracellular matrix recognition.
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PMID:Phosphodiesterase I, a novel adhesion molecule and/or cytokine involved in oligodendrocyte function. 936 56

As illustrated in Figure 1, a disturbance of the intracellular Ca2+ homeostasis is thought to be a common pathogenic factor for the generation of secondary nerve cell damage that develops after brain trauma or stroke or during the course of neurodegenerative diseases. A neuronal Ca2+ overload which may result from an excessive glutamate-evoked membrane depolarization and consecutive Ca2+ influx as well as from an activation of metabotropic receptors and consecutive intracellular Ca2+ mobilization is known to have direct toxic effects on the cytoskeleton and the cell metabolism of neurons. In addition, a Ca(2+)-dependent activation of glial cells along with the loss of physiologically required mature astrocyte functions and with the acquisition of potentially neurotoxic microglial properties, has more recently been recognized as an additive pathogenic factor. This may provide an effective target for pharmacological interference. Specifically, the reinforcement of an endogenous homeostatic regulator, which obtained its sophisticated know-how during evolution, may provide a neuroprotective therapy which can handle the complexity of the pathological process with a minor risk of pharmacological side effects. Adenosine is such an ancient molecular signal that acts on both neurons and glial cells. In neurons, adenosine activates K+ and Cl- conductances, which limits synaptically evoked depolarization, thus counteracting the Ca2+ influx through voltage-dependent and NMDA receptor-operated ion channels. This A1 receptor-mediated effect seems to be the major action by which adenosine adds directly to the protection of neurons against Ca(2+)-dependent damage. In glial cells, the prevalent effect of adenosine is its regulatory influence on the Ca2+ and cAMP-dependent molecular signaling that determines the cellular proliferation rate, the differentiation state and related functions. When mimicking the activation of metabotropic glutamate receptors in cultures of immature rat astrocytes, which largely resemble pathologically activated astrocytes, a transient Ca2+ mobilization was initiated by adenosine. This A1 receptor-mediated Ca2+ signal caused a prolonged potentiation of the A2 receptor-mediated intracellular cAMP rise. An experimentally sustained enhancement of the cAMP signaling initiated the differentiation of cultured astrocytes and the new expression of K+ and Cl- channels which are required for the physiological astrocyte function to maintain the extracellular ion homeostasis. Evidence is accumulating that a strengthening of the cAMP signaling, which can be achieved by adenosine agonists and also by the pharmacon propentofylline (an adenosine uptake blocker and phosphodiesterase inhibitor), stimulates the mRNA production of neurotrophic factors in astrocytes. In cultured microglial cells, several days' treatment with adenosine agonists or propentofylline markedly inhibited their proliferation rate, the in vitro spontaneously occurring transformation into macrophages and their particularly high formation of free oxygen radicals. Adenosine agonists also depressed the release of the potentially toxic cytokine TNF alpha and induced programmed cell death in immunologically activated microglial cells. We conclude that a pharmacological reinforcement of the endogenous cell modulator adenosine may provide neuroprotection by counteracting neuronal Ca2+ overload, by depressing potentially neurotoxic microglial functions and by regaining physiologically required properties of differentiated astrocytes. Further information about the influence of adenosine on the molecular signaling and on ischemic brain damage is given in Refs. 37 and 38, and about the implicated possible relevance for the treatment of stroke in Ref. 39.
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PMID:Protective mechanisms of adenosine in neurons and glial cells. 936 70

Human peripheral blood basophils are known to secrete interleukin (IL)-4 and IL-13 after cross-linking of cell surface IgE. However, little is known about the pharmacological regulation of allergic cytokine release from basophils. In the present study, we investigated the effects of cyclic 3',5'-adenosine monophosphate (cAMP)-elevating agents on antigen-induced IL-4 and IL-13 release from basophil-enriched leukocyte preparations. We obtained venous blood from 27 atopic asthmatic patients (mean age was 45.8+/-3.6 years, all patients were sensitive to mite antigen) and prepared basophil-enriched leukocyte preparations by double-Percoll gradients (basophil purity was 13.4+/-1.6%). The cell preparations were treated with phosphodiesterase (PDE) inhibitors, dexamethasone, forskolin or dibutyryl cAMP for 10 min and were challenged with mite antigen for 6 h. The released IL-4 and IL-13 in the supernatants were measured by enzyme-linked immunosorbent assay systems. No IL-4 or IL-13 was detected in the supernatant of the basophil-depleted preparation after the challenge with mite antigen, suggesting that basophils specifically produce these cytokines. A nonselective PDE inhibitor, theophylline, and a PDE IV-selective inhibitor, rolipram, significantly suppressed the release of IL-4 and IL-13 from the basophil-enriched preparation. Although several concentrations of cilostazol, a PDE III-selective inhibitor, had no effect on the release of both cytokines, cilostazol suppressed the release of IL-4 additively when applied with rolipram. Forskolin and dibutyril cAMP also significantly suppressed the release of both cytokines, suggesting that the suppressive effects by PDE inhibitors were accompanied by the elevations in cAMP levels. We conclude that basophil-enriched leukocyte preparations produce IL-4 and IL-13 in response to antigen and that the release of these cytokines could be regulated by cAMP-modulating agents.
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PMID:Cyclic AMP-elevating agents inhibit mite-antigen-induced IL-4 and IL-13 release from basophil-enriched leukocyte preparation. 941 38

Vesnarinone is a new and novel inotropic drug that has unique and complex mechanisms of action. It inhibits phosphodiesterase, thereby leading to increased intracellular calcium, and also affects numerous myocardial ion channels, resulting in the prolongation of the opening time of sodium channels and the decrease in the delayed outward and inward rectifying potassium current. In vitro, it has also demonstrated significant effects on cytokine production, which may account for some of its observed clinical benefits. Hemodynamic studies in humans with congestive heart failure reveal that vesnarinone can improve ventricular function. Placebo-controlled studies in large numbers of patients with heart failure have suggested a morbidity and mortality benefit with a 60 mg daily dose. There is increased mortality with vesnarinone at the 120 mg daily dose, however, suggesting a narrow therapeutic window for the drug. Its predominant toxic side effect is a 2% incidence of reversible neutropenia.
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PMID:Vesnarinone: a new inotropic agent for treating congestive heart failure. 942 Jun 57


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