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)

Prostaglandins E1, prostaglandin E2, 3-oxa-methano-prostaglandin I1 (SM-10906), a stable prostaglandin I2 analog, and dibutyryl cyclic AMP suppressed the production of tumor necrosis factor and interleukin-1 in lipopolysaccharide-stimulated rat pleural resident monocytic cells, whereas they enhanced the production of interleukin-6 and cytokine-induced neutrophil chemoattractant (CINC), a rat interleukin-8-like chemokine, in these cells. SM-10906 also inhibited the in vivo production of tumor necrosis factor and interleukin-1 in pleural exudates, when injected into the rat pleural cavity concomitantly with carrageenin. The cyclic AMP (cAMP) level in the lipopolysaccharide-stimulated resident cells was increased when the cells were incubated in the presence of prostaglandin E1, prostaglandin E2 or SM-10906. Prostaglandin I2 showed only slight effects. The addition of pentoxifylline, a phosphodiesterase inhibitor, to the incubation mixture increased the cAMP level and also enhanced the effect of prostaglandins, indicating that these regulating actions of prostaglandins may be exerted partly through a mechanism involving an increased intracellular cAMP level.
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PMID:Effects of prostaglandins and cyclic AMP on cytokine production in rat leukocytes. 873 16

Noradrenaline (NA) and adrenaline (Ad) are modulators of cytokine production. Here we investigated the role of these neurotransmitters in the regulation of macrophage inflammatory protein (MIP)-1alpha expression. Pretreatment of RAW 264.7 macrophages with NA or Ad decreased, in a concentration-dependent manner (1 nM-100 microM), MIP-1alpha release induced by bacterial lipopolysaccharide (LPS 10 ng ml(-1) LPS). The effect of NA was reversed by the selective beta-adrenoceptor antagonist propranolol (10 microM), but not by the alpha-adrenoceptor antagonist phentolamine (10 microM). In the concentration range of 10 nM-10 microM, isoproterenol, a beta-adrenoceptor agonist, but not phenylephrine (a selective alpha1-adrenoceptor agonist) or UK-14304 (a selective alpha2-adrenoceptor agonist) mimicked the inhibitory effects of catecholamines on MIP-1alpha production. Increases in intracellular cyclic adenosine monophosphate, elicited either by the selective type IV phosphodiesterase inhibitor rolipram (0.1 - 10 microM), or by prostaglandin E2, (10 nM-10 microM) decreased MIP-1alpha release, suggesting that increased cyclic AMP may contribute to the suppression of MIP-1alpha release by beta-adrenoceptor stimulation. Northern blot analysis demonstrated that NA (100 nM-10 microM), Ad, isoproterenol, as well as rolipram (100 nM-10 microM) decreased LPS-induced MIP-1alpha mRNA accumulation. NA and Ad (1-100 microM) also decreased MIP-1alpha production in thioglycollate-elicited murine peritoneal macrophages. Pretreatment of mice with either isoproterenol (10 mg kg(-1), i.p.) or rolipram (25 mg kg(-1), i.p.) decreased LPS-induced plasma levels of MIP-1alpha, while propranolol (10 mg kg(-1), i.p.) augmented the production of this chemokine, confirming the role of a beta-adrenoceptor mediated endogenous catecholamine action in the regulation of MIP-1alpha production in vivo. Thus, based on our data we conclude that catecholamines are important endogenous regulators of MIP-1alpha expression in inflammation.
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PMID:Exogenous and endogenous catecholamines inhibit the production of macrophage inflammatory protein (MIP) 1 alpha via a beta adrenoceptor mediated mechanism. 986 60

Crohn's disease and ulcerative colitis are two idiopathic inflammatory disorders of the GI tract. Manifestations of disease can be severe and lead to long term therapy with a variety of medications and/or surgery. Standard medical therapy consists of agents that either treat suppurative complications or modulate the inflammatory cascade in a nonspecific manner. Many specific chemokine and cytokine effectors that promote intestinal inflammation have been identified. Such work has led to experimental clinical trials with a variety of cytokine antagonists. Compounds directed against one such cytokine, tumor necrosis factor alpha (TNF), have demonstrated the greatest clinical efficacy to date. This is consistent with scientific observations that suggest a central role for TNF in the inflammatory cascade. Infliximab is a chimeric monoclonal antibody against TNF that has been demonstrated to be effective for the treatment of Crohn's disease. Infliximab is Food and Drug Administration approved for the treatment of Crohn's disease. There exist several other TNF antagonists in various phases of investigation, including the monoclonal antibody CDP 571, the fusion peptide etanercept, the phosphodiesterase inhibitor oxpentifylline, and thalidomide. The clinical efficacy of these agents and the role of TNF in the pathogenesis of inflammatory bowel disease is reviewed.
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PMID:Integrating anti-tumor necrosis factor therapy in inflammatory bowel disease: current and future perspectives. 1146 23

Neutrophils are recruited to the lungs of horses with chronic obstructive pulmonary disease (COPD) and exhibit increased activity after antigen challenge, which may contribute to inflammation and lung damage. Inhibition of phosphodiesterase isoenzymes (PDEs) has been shown to attenuate human neutrophil functions including superoxide production, leukotriene (LT)B4 biosynthesis, enzyme and chemokine release. As equine neutrophils contain predominantly the isoenzyme, PDE4, the present study was undertaken to investigate the effects of rolipram, a PDE4 inhibitor, on equine neutrophil function. For comparison, the effects of the nonselective PDE inhibitor, theophylline, were examined. Cells from both normal horses and COPD horses in remission were used. Superoxide production was significantly inhibited by both rolipram [32.2 +/- 2.6 vs. 10.1 +/- 1.1 nmol/10(6) cells and 49.8 +/- 6.8 vs. 22.7 +/- 2.2 nmol/10(6) cells for normal and COPD susceptible horses, respectively, in response to 10(-7) M human recombinant (hr) C5a] and theophylline (19.0 +/- 0.6 vs. 10.2 +/- 0.6 nmol/10(6) cells and 24.3 +/- 2.1 vs. 10.7 +/- 0.9 nmol/10(6) cells for normal and COPD susceptible horses, respectively, in response to 10(-7) M C5a). However, superoxide production induced by serum treated zymosan was inhibited only by theophylline (10(-3) M). Neither hrC5a- nor platelet activating factor (PAF)-induced neutrophil adherence to fibronectin coated plastic was reduced by rolipram (10(-5) M). These results demonstrate that the effects of PDE inhibitors on equine neutrophils are both stimulus and function dependent. The PDE4 inhibitors may reduce neutrophil activation in vivo in horses with COPD.
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PMID:Differential inhibition of equine neutrophil function by phosphodiesterase inhibitors. 1155 83

Phosphodiesterase inhibitors possess anti-inflammatory and immunomodulatory properties and seem to have a great potential in the treatment of inflammatory skin diseases; however, an overall study on the effects of specific phosphodiesterase inhibitors, such as rolipram on the processes involved in the extravasation of lymphoid cells has not been performed. In this work we have assessed the effect of rolipram on the adhesion, polarization, and migration of normal human T lymphocytes. We found that low concentrations of rolipram were able to inhibit significantly the adhesion of T cells to the beta1 and beta2 integrin ligands vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. Rolipram also interfered with the activation of integrins, and significantly inhibited the homotypic aggregation of T lymphocytes induced by anti-beta1 and anti-alpha4 integrin chain monoclonal antibodies. In addition, rolipram had a downregulatory effect on the activation of T cells, and significantly diminished the expression of the activation antigens CD69, CD25, and CD98 induced by phytohemagglutinin. Finally, this drug inhibited the polarization and transendothelial migration of T lymphocytes induced by the chemokine CXCL12 (SDF-1) and the chemotactic cytokine interleukin-15. The results indicate that rolipram, at low concentrations, exerts an important anti-inflammatory and immunomodulatory effect, and suggest that this selective phosphodiesterase inhibitor may be an effective tool for the therapy of immune-mediated diseases.
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PMID:Rolipram inhibits polarization and migration of human T lymphocytes. 1283 67

Atherosclerosis involves cellular immune responses and altered vascular smooth muscle cell (VSMC) function. Nitric oxide (NO)/cGMP is uniquely capable of inhibiting key processes in atherosclerosis. In this study, we determined the effects of NO/cGMP and their molecular mechanisms in the regulation of NF-kappaB-dependent gene expression in VSMCs. We found that cGMP-elevating agents such as the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and C-type natriuretic peptide (CNP), reduced TNF-alpha-induced NF-kappaB-dependent reporter gene expression in rat aortic VSMCs in a cGMP-dependent manner. The effects of SNAP and CNP on NF-kappaB are mediated by cAMP-dependent protein kinase (PKA) but not cGMP-dependent protein kinase (PKG) based on the findings that the selective PKA inhibitor, PKI, abolished the effects of SNAP and CNP on NF-kappaB, whereas the PKG inhibitor Rp-8-Br-PET-cGMP had no effect. Inhibition of cGMP-inhibited cAMP-hydrolyzing phosphodiesterase 3 (PDE3) blocked SNAP- and CNP-elicited effects on NF-kappaB-dependent transcription. Furthermore, cGMP analogues such as 8-pCPT-cGMP, which selectively activates PKG but does not inhibit PDE3, had no effect on NF-kappaB-mediated transcription. Activation of PKA by SNAP or cAMP-elevating agents not only inhibited TNF-alpha-induced NF-kappaB-dependent reporter gene expression but also reduced endogenous NF-kappaB-dependent adhesion molecule and chemokine expression. These results suggest that SNAP and CNP exert inhibitory effects on NF-kappaB-dependent transcription by activation of PKA via cGMP-dependent inhibition of PDE3 activity. Therefore, PDE3 is a novel mediator of inflammation in VSMCs.
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PMID:Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells. 1291 48

Autotaxin (ATX/NPP2) is a tumor cell motility-stimulating factor that displays both a nucleotide pyrophosphatase/phosphodiesterase activity and a recently described lysophospholipase D (lysoPLD) activity. The precise function of ATX in tumor cells and the role of ATX in thyroid carcinoma remains unclear. We have quantified ATX mRNA expression in thyroid carcinoma cell lines and in tissues of patients with thyroid carcinomas. ATX gene activity was significantly higher in undifferentiated anaplastic thyroid carcinoma cell lines (UTC) and tumor tissues as compared to follicular thyroid carcinoma (FTC) cell lines, FTC tissues or goiter tissues that were used as a control. In the thyroid carcinoma cell line 1736, EGF and bFGF stimulated ATX mRNA expression, whereas the cytokines IL-4, IL-1beta and TGF-beta reduced ATX transcriptional levels. FTC-133 cells, stably transfected with an expression vector for ATX, showed a higher lysoPLD activity, a higher proliferation rate and an increased migratory behavior. In addition, ATX also displayed a paracrine stimulatory effect on the motility of different thyroid carcinoma cell lines. Overexpression of ATX in the stably transfected FTC-133 resulted in down-regulation of CD54/ intercellular adhesion molecule-1 (ICAM-1) gene expression and augmented gene activity of the pro-angiogenic chemokine IL-8. We conclude that ATX may be regarded as a new tissue marker for undifferentiated human thyroid carcinoma cells. ATX increases the proliferation and migration of thyroid carcinoma cell lines and may also affect the angiogenic potential of thyroid carcinoma cells. Further studies are needed to provide insight into the role of ATX in the normal and neoplastic thyroid gland.
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PMID:Expression, regulation and function of autotaxin in thyroid carcinomas. 1502 16

No currently available treatments reduce the progression or suppress the inflammation of chronic obstructive pulmonary disease (COPD). However, with a better understanding of the inflammatory and destructive process, several targets have been identified and new treatments are in clinical development. Several specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, including adhesion molecule and chemokine-directed therapy, as well as therapies to inhibit tumour necrosis factor-alpha. Several broad-spectrum anti-inflammatory drugs are also in development, and include inhibitors of phosphodiesterase-4, p38 mitogen-activated protein kinase and nuclear factor-kappaB. There is a need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.
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PMID:COPD: is there light at the end of the tunnel? 1514 Apr 18

Although long-acting bronchodilators have been an important advance for the management of chronic obstructive pulmonary disease (COPD), these drugs do not deal with the underlying inflammatory process. No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflammatory process are now in clinical development. Some therapies, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, whereas others target inflammatory cytokines such as tumour necrosis factor-alpha. Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kappaB and phosphoinositide-3 kinase-gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase and leukotriene B(4) antagonists. Other treatments have the potential to combat mucus hypersecretion, and there is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema. More research is needed to understand the cellular and molecular mechanisms of chronic obstructive pulmonary disease and to develop biomarkers and monitoring techniques to aid the development of new therapies.
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PMID:COPD: current therapeutic interventions and future approaches. 1592 66

By 2020 chronic obstructive pulmonary disease (COPD) will be the third leading cause of mortality and fifth leading cause of morbidity. Research over the past two decades has shed important insights on the pathobiology of COPD, leading to the development of novel drugs. In the past, symptomatic treatment with bronchodilators was the predominant focus of COPD management. With increased awareness of the importance of airway inflammation in COPD progression, there has been a shift in emphasis to drugs that attack various targets in the inflammatory cascade. These drugs include phosphodiesterase 4 inhibitors, leukotriene modifiers and TNF antagonists, which are poised to enter the COPD market in the very near future. Tyrosine kinase antagonists, inhibitors of NF-kappaB, neutrophil elastase inhibitors, chemokine antagonists, mucolytics and novel antibiotics are being evaluated for possible effectiveness in COPD. Many of these drugs may enter the COPD market within the next decade. This paper reviews the molecular rationale for these emerging drugs and their potential efficacy in COPD.
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PMID:Emerging drugs for the treatment of chronic obstructive pulmonary disease. 1663 2


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