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)

HIV-1 Nef protein shares a significant homology with the immunosuppressive and highly conserved retroviral transmembrane protein p15E. In the present study, extracellular Nef protein is shown to induce interleukin (IL)-10 mRNA expression in human peripheral blood mononuclear cells as well as in cells of H9 T and U937 promonocytic human cell lines. Release of IL-10 protein into supernatants of peripheral blood mononuclear cells stimulated with Nef is dose-dependent. Expression of cytokines IL-2, IL-4, IL-5, IL-12 p40, IL-13, and interferon gamma is not affected by Nef stimulation. IL-10 protein production induced by Nef is inhibited by the calcium/calmodulin phosphodiesterase inhibitor W-7 but not by the protein kinase A inhibitor H-89 nor the protein kinase C inhibitors staurosporine and calphostin C. The calcium chelating agent EGTA also inhibits the IL-10 production induced by Nef, and this inhibition is reversed by the addition of calcium along with Nef. These findings indicate that extracellular Nef may contribute to the immunopathogenesis of HIV infection by inducing IL-10.
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PMID:Interleukin 10 is induced by recombinant HIV-1 Nef protein involving the calcium/calmodulin-dependent phosphodiesterase signal transduction pathway. 909 66

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

Human basophils have recently been shown to rapidly produce and release interleukin (IL-)4 and IL-13 as well as histamine and eicosanoids. Since both IL-4 and IL-13 can initiate and maintain late phase allergic reactions we addressed whether some widely used anti-allergic drugs can inhibit the anti-IgE induced release of these cytokines from enriched human basophils. Basophils were enriched (47-92% purity) by Ficoll density centrifugation followed by elutriation and negative selection of contaminating cells using immunomagnetic beads. Basophils were stimulated with sub-optimal dilutions of anti-IgE in the presence or absence of various drugs and the release of histamine and cytokines were measured after 30 min and 4 h, respectively. The beta-2 agonist salmeterol, the H1-receptor antagonist terfenadine and the phosphodiesterase inhibitor theophylline inhibited the release of IL-4 and IL-13 by more than 50% following 4 h of basophil stimulation with anti-IgE. These drugs also inhibited the release of histamine following 30 min stimulation, although with less efficacy than for IL-4 and IL-13. Short preincubation of basophils with salmeterol or terfenadine before stimulation gave rise to significantly greater inhibition of histamine release but had less effect on the inhibition of cytokine release. The effects of theophylline, however, were not significantly affected by preincubation of the cells with the drug. In contrast to the aforementioned drugs, salbutamol and cetirizine were ineffective at inhibiting both histamine and cytokine release from basophils. These results suggest that a number of anti-allergic drugs may mediate their effects, in part, in reducing late phase allergic responses due to their actions on IL-4 and IL-13 secretion from basophils.
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PMID:Inhibition of interleukin-4 and interleukin-13 release from immunologically activated human basophils due to the actions of anti-allergic drugs. 965 Aug 12

Proinflammatory cytokines, secreted by autoreactive CD4+ T lymphocytes may contribute to the pathogenesis of several human autoimmune diseases, including multiple sclerosis (MS). Since the antigen specificities of these T cells are not known at present, therapeutic strategies aiming at common effector pathways, in particular cytokine secretion, may be more feasible in the near future. We have studied the influence of the isoenzyme-specific phosphodiesterase inhibitor rolipram on the proliferation and cytokine secretion of human myelin basic protein-specific T cell clones. The inhibition of proliferation correlated with interference with the IL-2/IL-2 receptor system, while the effects of rolipram on several T helper 1-(TNF-alpha, TNF-beta, IFN-gamma) and T helper 2-like cytokines (IL-4, IL-13) as well as IL-10 revealed an interesting drug profile, with preferential inhibition of TNF-beta, TNF-alpha and IL-10. This profile suggest that rolipram differs from other currently used immunomodulatory drugs.
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PMID:Differential effects of phosphodiesterase type 4-specific inhibition on human autoreactive myelin-specific T cell clones. 1043 48

Asthma, a chronic inflammatory disease characterized by intermittent, reversible airflow obstruction and airway hyperresponsiveness (AHR), is classically characterized by an excess of Th2 cytokines (IL-13, IL-4) and depletion of Th1 cytokines (IFN-gamma, IL-12). Recent studies indicating an important role for Th1 immunity in the development of AHR with allergic inflammation suggest that Th1/Th2 balance may be important in determining the association of AHR with allergic inflammation. We hypothesized that administration of pentoxifylline (PTX), a phosphodiesterase inhibitor known to inhibit Th1 cytokine production, during allergen (OVA) sensitization and challenge would lead to attenuation of AHR in a murine model of allergic pulmonary inflammation. We found that PTX treatment led to attenuation of AHR when administered at the time of allergen sensitization without affecting other hallmarks of pulmonary allergic inflammation. Attenuation of AHR with PTX treatment was found in the presence of elevated bronchoalveolar lavage fluid levels of the Th2 cytokine IL-13 and decreased levels of the Th1 cytokine IFN-gamma. PTX treatment during allergen sensitization leads to a divergence of AHR and pulmonary inflammation following allergen challenge.
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PMID:Administration of pentoxifylline during allergen sensitization dissociates pulmonary allergic inflammation from airway hyperresponsiveness. 1146 94

Increased cyclic AMP (cAMP)-phosphodiesterase (PDE) activity in peripheral blood leucocytes is associated with the immunological inflammation that characterizes allergic diseases, such as atopic dermatitis and allergic rhinitis. Recently, it has been found that IL-13 has similar biological functions to IL-4. The aim of this study was to investigate the possible involvement of cAMP-PDE activity on IL-13 release from peripheral blood mononuclears cells (PBMC) from atopic asthma patients. Phytohaemagglutinin (PHA)-induced IL-13 release from PBMC was concentration-dependently inhibited by rolipram, a type 4 PDE inhibitor, as well as by dibutyryl cAMP, a membrane-permeant cAMP analogue. However, theophylline, a non-specific PDE inhibitor, and cilostazol, a type 3 PDE inhibitor, failed to inhibit IL-13 release. The inhibitory effect of rolipram was enhanced by the addition of forskolin (10(-4) m), an adenylyl cyclase stimulator. PHA itself did not alter the intracellular cAMP level. Rolipram concentration-dependently increased cAMP level in PHA-stimulated PBMC, and this increase was synergistically facilitated by the addition of forskolin (10(-4) m). These results suggest that type 4 PDE inhibitors, alone or synergistically in combination with forskolin, inhibit PHA-induced IL-13 release from PBMC of atopic asthma patients by elevating intracellular cAMP concentrations. These inhibitors have the potential to exert an anti-inflammatory effect by inhibiting IL-13 production in allergic diseases such as atopic asthma.
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PMID:Differential effect of phosphodiesterase inhibitors on IL-13 release from peripheral blood mononuclear cells. 1173 51

L-826,141 [4-(2-(3,4-bis-difluromethoxyphenyl)-2-(4-(1,1,1, 3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl)-3-methylpyridine-1-oxide] is a selective and potent inhibitor of phosphodiesterase 4 (PDE4) with an IC(50) value of 0.26 to 2.4 nM for inhibition of the catalytic activity of PDE4A, B, C, and D. The cAMP elevation that can be maintained by PDE4 inhibitors attenuates the signaling cascades that lead to the production of certain cytokines. In cellular-based assays, L-826,141 transcriptionally down-regulates production of tumor necrosis factor (TNF)-alpha in peripheral blood mononuclear cell and whole blood assays with IC(50) values of 31 and 310 nM, respectively. Profiling the effect of this compound on various cytokines in the signaling cascade attenuated by cAMP elevation demonstrates that L-826,141 is also a potent inhibitor of interleukin (IL)-12, granulocyte macrophage-colony stimulating factor, and interferon (IFN)gamma (IC(50) values of 0.3-0.9 microM) as well as TNF-alpha formation. We have also shown that the PDE4 inhibitors rolipram and L-826,141 are potent inhibitors of CD3-plus CD28-stimulated IL-2 production in naive human T cells. To address the effect of PDE4 inhibitors on cytokine release from T helper (Th)1 and Th2 effector cells, we used a well characterized model in which T cells are derived from ovalbumin (323-339)-specific T cell receptor transgenic mice. L-826,141 inhibits Th0-mediated IL-2 production with an IC(35) value of 25 nM and Th1-mediated IFNgamma production with an IC(30) value of 46 nM. In contrast, L-826,141 had no significant inhibitory effect (IC(30) value > 2.5 microM) on Th2 cell-mediated IL-4 nor IL-13 production. Together, these data demonstrate that specific inhibition of PDE4 preferentially blocks the production of Th1 versus Th2 effector cytokines in vitro.
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PMID:Preferential inhibition of T helper 1, but not T helper 2, cytokines in vitro by L-826,141 [4-[2-(3,4-Bisdifluromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]3-methylpyridine-1-oxide], a potent and selective phosphodiesterase 4 inhibitor. 1508 48

The aim of the present study was to determine whether inhibition of cyclic nucleotide phosphodiesterase (PDE) modulates the stimulated generation of the cytokines, interleukin-4 (IL-4) and IL-13, from human basophils. This was addressed by evaluating the effects of both nonselective and selective inhibitors of PDEs on the generation of cytokines from basophils. The nonselective PDE inhibitors, isobutyl-methylxanthine (IBMX) and theophylline, attenuated the IgE-mediated generation of IL-4 and IL-13 and, also, the release of histamine from basophils. The effects of the isoform-selective inhibitors, 8-methoxymethyl-IBMX (PDE 1 inhibitor), siguazodan (PDE3 inhibitor), rolipram (PDE4 inhibitor), denbufylline (PDE4 inhibitor), Org 30029 (mixed PDE3 and 4 inhibitor) and zaprinast (PDE5 inhibitor), were studied. Of these selective compounds, only rolipram, denbufylline and Org 30029 inhibited the IgE-dependent generation of IL-4, IL-13 and histamine from basophils to a statistically significant (P<0.05) degree. The effects of isoform-selective inhibitors on basophils activated by IL-3 were evaluated. The IL-3-induced generation of IL-4, IL-13 and histamine was inhibited to a statistically significant (P<0.05) extent, only by compounds that act as inhibitors of PDE4. These data suggest that inhibition of PDE4 can regulate the generation of cytokines from human basophils.
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PMID:Effects of phosphodiesterase inhibitors on interleukin-4 and interleukin-13 generation from human basophils. 1526 10

Mortality in dialysis patients is greater than that in the general population across all age groups. The disparity in mortality is greatest among patients aged under 35 years. Chronic kidney disease (CKD) is associated with the malnutrition, inflammation and atherosclerosis (MIA) syndrome, which helps to explain the high mortality rates among patients with CKD. Paradoxically, CKD patients exhibit signs of immune suppression as well as immune system activation. Chronic inflammation and immune system activation are not only integral to the MIA syndrome, but also may underlie resistance to erythropoietin treatment in patients with anaemia. Chronic immune system activation is reflected by abnormally raised T-lymphocyte and monocyte expression of both pro- and anti-inflammatory cytokines. Patients who respond well to erythropoietin treatment exhibit fairly normal expression of these cytokines. Patients who persistently fail to respond, however, express abnormally raised levels of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), which are also known to inhibit erythropoiesis. Paradoxically, these patients also express abnormally high levels of the anti-inflammatory cytokines interleukin (IL)-10 and IL-13. Although anti-inflammatory in nature, these cytokines might also affect erythropoiesis. One strategy to overcome the problem of chronic inflammation in anaemic patients with CKD may be treatment with the phosphodiesterase inhibitor, pentoxifylline. Preliminary results suggest that once-daily treatment with 400 mg of pentoxifylline orally not only can reduce T-cell expression of TNF-alpha and IFN-gamma, but can also restore the response to erythropoietin and improve haemoglobin levels. Ongoing studies will investigate further the use of pentoxifylline in erythropoietin resistance.
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PMID:Could anti-inflammatory cytokine therapy improve poor treatment outcomes in dialysis patients? 1528 64

Hand, foot, and mouth disease and herpangina are the major clinical manifestations of enterovirus 71 (EV71) infections. Brain-stem encephalitis and pulmonary edema are severe complications that can lead to death. This study was designed to evaluate the potential therapeutic effect of milrinone, a phosphodiesterase (PDE) inhibitor, in the treatment of patients with EV71-induced pulmonary edema. We conducted a historically controlled trial of 24 children with severe EV71-induced pulmonary edema from April 1998-June 2003 in southern Taiwan. Patients were divided into groups treated before and after the introduction of milrinone therapy. Etiological diagnosis was established by viral cultures and confirmed by specific immunofluorescence and neutralization tests. All 24 patients were below 5 years of age. The mortality was lower in the milrinone-treated vs. nontreated group (36.4% vs. 92.3%, P=0.005). Sympathetic tachycardia was decreased in patients treated with milrinone compared to controls (144 +/- 17/min vs. 206 +/- 26/min, P=0.004). A marked decrease in IL-13 (77 +/- 9 pg/ml vs. 162 +/- 88 pg/ml, P=0.001) was observed in milrinone-treated patients compared to controls. There was a significant reduction in white blood cell (10,838 +/- 4,537/mm3 vs. 19,475 +/- 7,798/mm3, P=0.009) and platelet (257 +/- 45 x 10(3)/mm3 vs. 400 +/- 87 x 10(3)/mm3, P=0.001) counts in milrinone-treated patients compared to controls. These results were associated with improvement in sympathetic regulation and decrease in IL-13 production. Milrinone therapy may provide a useful therapeutic approach for this highly lethal disorder.
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PMID:Therapeutic efficacy of milrinone in the management of enterovirus 71-induced pulmonary edema. 1563 19


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