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)

Ligation of the antigen receptors on both T and B lymphocytes induces phosphoinositide (PI) hydrolysis, Ca(2+)-mobilization and protein kinase C activation. The activation of the phosphoinositide-specific phosphodiesterase (PPI-PDE) following crosslinking of surface Ig receptors on B cells is controlled by an uncharacterized guanine nucleotide-regulatory (G) protein. Here we have used permeabilized murine T cells (both resting T cells and a conalbumin-specific CD4-positive T cell clone) to investigate a role for G protein(s) in coupling the TCR to the PPI-PDE. We found that anti-TCR McAb (or processed antigen)-induced PI hydrolysis cannot be uncoupled by permeabilizing T cells, as occurs with classical G protein-linked receptors. Furthermore, the TCR-mediated release of inositol phosphates in permeabilized T cells was not enhanced by non-hydrolyzable analogs of GTP, nor inhibited by GDP analogs. These findings therefore argue strongly against the concept that TCR-mediated PI hydrolysis is G-protein controlled.
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PMID:Antigen receptor-mediated phosphoinositide hydrolysis in murine T cells is not initiated via G-protein activation. 165 2

Atopic dermatitis is a genetically determined inflammatory condition in which the primary defect is expressed in one or more hematopoietic cells that infiltrate the skin. It is a multifactorial disease with inflammation triggered by a variety of factors. Among these, atopic dermatitis has been experimentally induced and reproduced by emotional-stress interviews and food challenges only. The inflammatory events of atopic dermatitis appear to initiated by mast cells, but eosinophils, monocytes, and T lymphocytes (predominantly CD4) also are present in lesions. The secondary effects of inflammation are a dry, brittle stratum corneum and pruritus, causing excoriation and a lichenified epidermal layer resulting from chronic rubbing. Therapeutic approaches to atopic dermatitis may be directed at several points in the evolution of the disease. Agents including emollients are needed to preserve and restore the stratum corneum barrier, and effective antipruritics are required to reduce the self-inflicted damage to the involved skin. Various other agents may be needed to antagonize mediators or cytokines and to inhibit cytokine expression and release from lesional, immune-effector cells. Likewise, new phosphodiesterase inhibitors, calcium-active agents, and antiallergic drugs may be used to reduce the quantity and pathologic functioning of inflammatory infiltrating cells in the skin.
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PMID:Atopic dermatitis: new therapeutic considerations. 167 14

Rolipram is a type IV phosphodiesterase inhibitor that suppresses inflammation and TNF-alpha production. As anti-TNF-alpha therapy is effective in rheumatoid arthritis, we investigated the effect of rolipram on collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. Rolipram was administered after the onset of clinical arthritis at doses of 0.5, 3, 5, or 10 mg/kg twice daily, with a dose-dependent therapeutic effect on clinical severity and joint erosion. Immunohistochemical analysis of joints of rolipram-treated mice revealed 67% reduction in TNF-alpha-expressing cells compared with control arthritic mice. In vitro studies using bone marrow-derived macrophages confirmed that rolipram directly suppressed TNF-alpha and IL-12 production following stimulation with IFN-gamma and LPS. The effect of rolipram on T cell activity was studied by measuring Th1/Th2 cytokine production by collagen-stimulated draining lymph node cells from arthritic mice treated in vivo with rolipram. Rolipram reduced IFN-gamma production and increased IL-10, indicating that rolipram down-regulated the ongoing Th1 response to type II collagen. Finally, the effect on CIA of combination therapy was studied using rolipram plus either anti-TNF-alpha or anti-CD4 mAbs. Rolipram plus anti-TNF-alpha was not therapeutically additive, whereas rolipram plus anti-CD4 mAb was clearly additive. This result indicates that the therapeutic effects of rolipram overlap with TNF-alpha blockade, but are complementary to anti-CD4 treatment. It is therefore proposed that a major mechanism of action of rolipram in CIA is suppression of TNF-alpha activity. These findings suggest that type IV phosphodiesterase inhibitors may be effective in pathologic conditions, such as RA, with overexpression of TNF-alpha.
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PMID:Suppression of TNF-alpha expression, inhibition of Th1 activity, and amelioration of collagen-induced arthritis by rolipram. 955 Apr 29

Rolipram, a phosphosdiesterase type IV-specific inhibitor, prevented p24 antigen release from anti-CD3-activated human immunodeficiency virus (HIV)-infected T cells and CD4(+)-cell depletion associated with viral replication in a dose-responsive manner but minimally inhibited T-cell proliferation. Moreover, rolipram reduced the production of tumor necrosis factor alpha (TNF-alpha) and interleukin-10 (IL-10) by HIV-infected T cells. The transcriptional ability of a luciferase reporter gene under control of the HIV long terminal repeat, induced by phorbol myristic acetate plus ionomycin or by TNF-alpha, in primary T and Jurkat cells was also inhibited by rolipram. Rolipram inhibited NF-kappaB and NFAT activation induced by T-cell activation in Jurkat and primary T cells, as measured by transient transfection of reporter genes and electrophoretic mobility shift assays. Exogenous addition of TNF-alpha in the presence of rolipram restored NF-kappaB but not NFAT activation or p24 release. Addition of dibutyryl-cyclic AMP (dBcAMP) mimicked the effects of rolipram on p24 antigen release, NF-kappaB activation, and TNF-alpha secretion, but it did not affect NFAT activation or IL-10 production. The protein kinase A inhibitor KT5720 prevented the inhibition of TNF-alpha secretion but not that of HIV type 1 (HIV-1) replication caused by rolipram. Our data indicate that blockade of phosphodiesterase type IV could be of benefit against HIV-1 disease by modulating cytokine secretion and transcriptional regulation of HIV replication, and they suggest an important role of NFAT in HIV replication in primary T cells. Some of those activities cannot be ascribed solely to its ability to increase cAMP.
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PMID:Inhibition of phosphodiesterase type IV suppresses human immunodeficiency virus type 1 replication and cytokine production in primary T cells: involvement of NF-kappaB and NFAT. 957 35

Asthma is an inflammatory condition of the airways. First-line therapy involves the use of inhaled corticosteroids as anti-inflammatory agents to control the underlying process. Bronchodilators are used for symptom relief. Short-acting beta-agonists provide rapid relief of bronchoconstriction, whereas long-acting beta-agonists control the symptoms and reduce the frequency of exacerbations when combined with inhaled corticosteroids. Anticholinergic bronchodilators have a minor role in acute exacerbations and in patients troubled by adverse effects from beta-agonists. Theophylline has a bronchodilator action in asthma, but its role as an anti-inflammatory agent needs to be examined further. Because of their toxicity, corticosteroid-sparing agents have a limited role, being restricted to patients with severe uncontrolled asthma. New selective phosphodiesterase IV inhibitors show both anti-inflammatory and bronchodilator characteristics with fewer adverse effects. Other new approaches to the control of inflammation come from the antileukotriene drugs, which improve pulmonary function in patients with chronic asthma. The antileukotrienes have shown promising results, especially in the treatment of asthma caused by aspirin (acetylsalicylic acid), exercise and cold air. Other new therapies being studied include anti-immunoglobulin E, antitryptase and anti-CD4 agents. These newer possibilities suggest that the range of available treatment options will expand significantly over the next decade.
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PMID:Drug treatment of asthma in the 1990s: achievements and new strategies. 995 47

There is increasing interest in the use of combination therapy for rheumatoid arthritis and in the possibility of combining the conventional drug approach with newer biological therapies. Animal models of arthritis provide important tools for evaluating novel forms of therapy and for eludicating mechanisms of drug action. In this paper, we review the results of our own research into combination therapy in collagen-induced arthritis using biological therapies such as anti-tumor necrosis factor alpha, anti-CD4, and anti-interleukin 12 monoclonal antibodies, and small molecular weight compounds such as cyclosporin and the phosphodiesterase IV (PDE IV) inhibitor rolipram.
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PMID:Combination therapy with DMARDs and biological agents in collagen-induced arthritis. 1058 69

We show here that HIV type 1 (HIV-1) Tat protein, in combination with anti-CD3/CD28 mAbs, promotes IL-2 production and proliferation of primary CD4(+) T lymphocytes, obtained from HIV-1-seronegative donors. This effect was observed when Tat was immobilized on a solid support, but it was not observed with soluble Tat. Such hyperactivation was accomplished by recruiting the rolipram-sensitive cyclic nucleoside phosphodiesterase 4 and resulted in increased susceptibility to HIV-1 infection. Accordingly, rolipram potently inhibited HIV-1 replication in cultures stimulated by anti-CD3/CD28 +/- Tat. These results add to the concept that decreasing Tat activity is an important addition to anti-HIV-1 therapy, and they suggest a target for anti-HIV-1 chemotherapy, phosphodiesterase 4.
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PMID:Pivotal role of cyclic nucleoside phosphodiesterase 4 in Tat-mediated CD4+ T cell hyperactivation and HIV type 1 replication. 1111 67

Despite the anti-TNF alpha based progress in the treatment of RA, it is necessary to further optimize study designs and reports (Etanercept/MTX combination with results of radiological progression; publication of D2E7 trials; combination of D2E7 with MTX). Moreover, innovative immunobiologicals (PEG-TNFRI, PEG-TNF alpha antibody fragments, soluble TNFRI, CTLA4-Ig, CD40 ligand antibody, antibodies against IFN-gamma, IL-6, IL-12, IL-15, IL-18, complements), inhibitors of TNF alpha translation (peptides, anti-sense constructs) or TNF alpha synthesis (targeting NF kappa B, p38 MAP-kinase, phosphodiesterase IV, TNF alpha converting enzyme) are forthcoming. Principally different are inhibitors of complement convertases or collagenase as well as vaccination studies or trials trying to induce T cell anergy. Furthermore, for patients with MTX side effects, alternative DMARDs need to be tested along with TNF alpha blockers. Combination studies of TNF alpha constructs with other immunobiologicals (anti-CD4, IL-4, IL-10, IL-1RA) should be evaluated. To date, TNF alpha blockers have been evaluated in very early RA. Finally, a step-down trial will test whether--after induction of remission with a TNF alpha blocker plus MTX--replacement of the TNF alpha blocker with MTX alone or in combination with leflunomide will be able to keep disease activity suppressed for a longer duration.
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PMID:[New therapy developments in rheumatoid arthritis]. 1175 32

Modalities for inducing long-lasting immune responses are essential components of vaccine design. Most currently available immunological adjuvants empirically used for this purpose cause some inflammation, limiting clinical acceptability. We show that pentoxifylline (PF), a phosphodiesterase (PDE) inhibitor in common clinical use, enhances long-term persistence of T cell responses, including protective responses to a bacterial immunogen, Salmonella typhimurium, via a cAMP-dependent protein kinase A-mediated effect on T cells if given to mice for a brief period during immunization. PF inhibits activation-mediated loss of superantigen-reactive CD4 as well as CD8 T cells in vivo without significantly affecting their activation, and inhibits activation-induced death and caspase induction in stimulated CD4 as well as CD8 T cells in vitro without preventing the induction of activation markers. Consistent with this ability to prevent activation-induced death in not only CD4 but also CD8 T cells, PF also enhances the persistence of CD8 T cell responses in vivo. Thus, specific inhibition of activation-induced T cell apoptosis transiently during immune priming is likely to enhance the persistence of CD4 and CD8 T cell responses to vaccination, and pharmacological modulators of the cAMP pathway already in clinical use can be used for this purpose as immunological adjuvants.
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PMID:Pentoxifylline functions as an adjuvant in vivo to enhance T cell immune responses by inhibiting activation-induced death. 1237 Mar 57

Incubation of purified C57BL/6 murine CD4(+) T lymphocytes with anti-CD3 mAb serves as a model of TCR-mediated activation and results in increased IFN-gamma production and cell surface expression of CD25 and CD69. We demonstrate here that signaling through the TCR causes a rapid (4-h) 5-fold increase in A(2A) adenosine receptor (AR) mRNA, which is correlated with a significant increase in the efficacy of A(2A)AR-mediated cAMP accumulation in these cells. A(2A)AR activation reduces TCR-mediated production of IFN-gamma by 98% with a potency order of 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]prop-2-ynyl}cyclohexanecarboxylic acid methyl ester (ATL146e; EC(50) = 0.19 +/- 0.03 nM) > 4-{3-[6-amino-9-(5-cyclopropyl-carbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]prop-2-ynyl}piperidine-1-carboxylic acid methyl ester (ATL313; 0.43 +/- 0.06 nM) > 5'-N-ethylcarboxamidoadenosine (3.5 +/- 0.77 nM) > 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680; 7.2 +/- 1.4 nM) >> N(6)-cyclohexyladenosine (110 +/- 33 nM) > 2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarboxamide (390 +/- 160 nM), similar to the potency order to compete for radioligand binding to the recombinant murine A(2A)AR but not the A(3)AR. The selective A(2A)AR antagonist, 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM241385), inhibits the effect of ATL146e with a pA(2) of 0.34 nM and also inhibits the effects of N(6)-cyclohexyl-adenosine and 2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarboxamide. In CD4(+) T cells derived from A(2A)AR(-/-) and A(2A)AR(+/-) mice, the IFN-gamma release response to ATL146e is reduced by 100 and 50%, respectively, indicative of a gene dose effect. The response of T cells to the phosphodiesterase inhibitor, 4-(3'-cyclopentyloxy-4'-methoxyphenyl)-2-pyrrolidone (rolipram), is not affected by A(2A)AR deletion. We conclude that the rapid induction of the A(2A)AR mRNA in T cells provides a mechanism for limiting T cell activation and secondary macrophage activation in inflamed tissues.
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PMID:A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells. 1563 32


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