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)

The ability of tumor necrosis factor-alpha (TNF-alpha) to attract lymphokine-activated killer (LAK) cells in vitro was examined. Utilizing modified Boyden chambers (BC), it was observed that TNF-alpha is not chemoattractant for LAK cells. On the other hand, TNF-alpha attracted both fresh and concanavalin A-activated T cells. However, when TNF-alpha was incubated in the upper compartments of BC and in the presence of LAK cells, it enhanced the random movement of these cells across the polycarbonate membranes. The effect of TNF-alpha was inhibited by incorporating anti-TNF-alpha antibody, or a high concentration (10 ng) of TFG-beta 1. The activity of TGF-beta 1 was reversed by anti-TGF-beta 1 antibody. Cholera toxin (CT), which is known to activate the endogenous level of cyclic adenosine monophosphate (cAMP) also inhibited TNF-alpha-induced LAK cell chemokinesis. The effect of CT was mimicked by the cAMP analog dibutyryl cAMP or by the phosphodiesterase inhibitors isobutyl methylxanthine or aminophylline. Measurement of the intracellular level of cAMP showed that cells incubated for 1, 2, or 4 hr with TNF-alpha have a lower level of cAMP, whereas those incubated with a high concentration of TGF-beta 1 produced significantly higher levels of this messenger. cAMP level was also increased in cells incubated with TGF-beta 1 plus TNF-alpha. This level was reduced to the background when anti-TGF-beta 1 antibody was added to the cultures. These results suggest that cAMP negatively regulates LAK cell chemokinesis.
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PMID:Tumor necrosis factor-alpha is chemokinetic for lymphokine-activated killer cells: regulation by cyclic adenosine monophosphate. 184 19

Previous studies have reported that the levels of pro-inflammatory cytokines, such as TNF-alpha and IFN-gamma, are elevated in the serum as well as in the cerebrospinal fluid of HAM/TSP patients. To evaluate the effect of the phosphodiesterase type IV inhibitor, rolipram on cytokine production, peripheral blood mononuclear cells (PBMCs) of HAM/TSP patients or HTLV-I infected T-cell lines (HUT102, MT2) were cultured in the presence of different doses of rolipram. The amount of cytokines in the supernatants of the cultured cells was determined by ELISA for TNF-alpha, IFN-gamma and TGF-beta. Rolipram inhibited TNF-alpha production by HUT102 and PBMCs from all the HAM/TSP patients in a dose-dependent manner. The suppression of IFN-gamma varied and was weaker in some HAM/TSP patients compared to that of TNF-alpha. The concentration of TGF-beta in the culture supernatants was not influenced by rolipram. The levels of TNF-alpha mRNA determined by competitive PCR were not changed in the cultured cells in the presence of rolipram, suggesting that rolipram inhibits TNF-alpha production at the post-transcriptional level. These findings suggest the possible benefit of rolipram as a therapeutic agent for HAM/TSP patients.
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PMID:The effect of rolipram on the production of cytokines in HTLV-I infected cell lines and peripheral blood mononuclear cells of patients with HTLV-I-associated myelopathy (HAM). 912 94

Pentoxifylline (PTX) is a methylxanthine derivative used in a wide range of dermatoses. As well as its hemorrheologic activity, PTX has anti-inflammatory properties. Buflomedil chlorhydrate (BC) is another hemorrheological drug with peripheral vasodilatory action, whose clinical uses are similar to those of PTX. Both drugs increase intracellular levels of cAMP, either secondary to phosphodiesterase inhibition (PTX) or adenyl-cyclase stimulation (BC). Long-term cultures of normal human keratinocytes were prepared in a free-serum medium, and stimulated with 1 mg/ml of phorbol 12-myristate 13-acetate (TPA) and PTX or BC (100-1000 micrograms/ml). Levels of TNF-alpha, IL-1 alpha, IL-1 beta, IL-8 and TGF-beta 1 using ELISA and Northern blot or RT-PCR techniques were measured. TPA-induced TNF-alpha and IL-8 release from keratinocytes. TPA did not induce IL-1 alpha or IL-1 beta release of keratinocytes. TPA increased RNA expression of the TNF-alpha, IL-1 alpha, IL-1 beta, IL-8 and TGF-beta 1. BC diminished TPA-induced TNF-alpha and IL-8 release from keratinocytes; in the case of IL-8 it is possible that this inhibition occur to transcriptional level. Moreover PTX was unable to inhibit TNF-alpha and IL-8 synthesis and expression. PTX and BC reduced TPA-induced IL-1 alpha and beta expression. It is possible that BC action is specifically exerted on keratinocytes, because we did not find similar results with TNF-alpha and IL-8 synthesis in mononuclear peripheral blood cells.
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PMID:Differential modulation of IL-8 and TNF-alpha expression in human keratinocytes by buflomedil chlorhydrate and pentoxifylline. 929 91

The inflammatory nature of multiple sclerosis (MS) implicates the participation of cytokines as immune response mediators. Targeting the cytokine balance by downregulating proinflammatory cytokines and/or upregulating immunosuppressive cytokines could benefit patients with MS. This article reports on the in vitro effects of the phosphodiesterase i.v. inhibitor Rolipram on the production of pro- and anti-inflammatory cytokines in MS and, for reference, in myasthenia gravis (MG). Blood mononuclear cells (MNC) were cultured in the presence of the organ-specific autoantigens myelin basic protein (MBP) or acetylcholine receptor (AChR), and in the absence of antigens, with and without Rolipram. In situ hybridization with synthetic oligonucleotide probes was used to detect and enumerate blood MNC expressing IFN-gamma, TNF-alpha, LT, TGF-beta, IL-4, and IL-10 mRNA. Numbers of MNC-secreting IFN-gamma and IL-4 in blood blood were examined by ELISPOT assays. Rolipram reduced the numbers of MBP-reactive IFN-gamma- and TNF-alpha mRNA-expressing blood MNC in MS, and numbers of AChR-reactive IFN-gamma-, TNF-alpha-, and LT mRNA-positive cells in MG. In contrast, expression of the Th2 cell related IL-4 and the anti-inflammatory IL-10, and TGF-beta was not affected. These data support a role for Rolipram in the treatment of diseases such as MS.
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PMID:The phosphodiesterase i.v. inhibitor rolipram in vitro reduces the numbers of MBP-reactive IFN-gamma and TNF-alpha mRNA expressing blood mononuclear cells in patients with multiple sclerosis. 970 65

Interstitial myofibroblasts (MF) are cells with features of both smooth muscle cells and fibroblasts. They have been universally recognized in situations of tubulointerstitial injury, where their presence has been shown to be a marker of disease progression. The objective of this study was to determine if functions of MF relevant to fibrogenesis can be modified in vitro by the phosphodiesterase inhibitor pentoxifylline (PTX). MF were obtained from sub-culture of normal rat kidney explant outgrowths maintained in DMEM + 20% fetal calf serum (FCS), supplemented with antibiotics. Cells were characterized on the basis of growth characteristics and immunohistochemistry. MF constituted >95% of cells at passage 3. Cell culture media was supplemented with the potential antagonist PTX alone (0, 1, 10, 100 microg/ml) and in combination with TGFbeta(1) (5 ng/ml). Population kinetics, proliferation and collagen production were determined from cell growth, [(3)H]thymidine incorporation and [(3)H]proline incorporation in collagenous proteins, respectively. Both serum-stimulated population growth and proliferation were reduced in a linear fashion by 1, 10 and 100 microg/ml PTX (all p < 0.05 versus 0 microg/ml). Effect of PTX on cell population growth was however reversible when PTX was removed. Basal collagen secretion was decreased by PTX at 10 and 100 microg/ml (p < 0.05 versus 0 microg/ml although layer collagen remained unchanged. Collagen production (secreted and cell layer) was augmented by 5 ng/ml TGFbeta(1). These effects on collagen production were partially reduced when 100 microg/ml PTX was added. The authors conclude that myofibroblast function can be altered with agonists/antagonists. Attempts to down-regulate fibrogenic functions of MF may therefore offer a valuable therapeutic strategy.
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PMID:Pentoxifylline reduces in vitro renal myofibroblast proliferation and collagen secretion. 1064 75

Matrix metalloproteinases (MMPs) and transforming growth factor (TGF)-beta are involved in airway remodeling associated with the inflammatory process. In this study, we investigated the effect of RP 73-401 (piclamilast), a selective phosphodiesterase-4 inhibitor, on MMP-9 activity and TGF-beta production in two murine models of acute inflammation. In the first model, the lipopolysaccharide (LPS)-induced increase in neutrophils, MMP-9 activity, and tumor necrosis factor (TNF)-alpha and TGF-beta release in bronchoalveolar lavage (BAL) was significantly reduced by RP 73-401 pretreatment. In contrast, the BAL interleukin (IL)-10 level was decreased by LPS but restored by RP 73-401. IL-10 administration in LPS-exposed mice elicited a significant reduction in BAL neutrophilia, MMP-9 activity, and TNF-alpha release but not in TGF-beta production. In the second model, RP 73-401 inhibited BAL neutrophils but not MMP-9 activity and TGF-beta production that were induced by intranasal TNF-alpha. We demonstrated that RP 73-401 might modulate the expression of airway remodeling-associated mediators such as MMP-9 and TGF-beta and that this effect seemed to be at least partially mediated by the balance between TNF-alpha and IL-10.
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PMID:The selective phosphodiesterase 4 inhibitor RP 73-401 reduced matrix metalloproteinase 9 activity and transforming growth factor-beta release during acute lung injury in mice: the role of the balance between Tumor necrosis factor-alpha and interleukin-10. 1190 82

Chronic hepatitis C progresses to cirrhosis within 20 years in an estimated 20-30% of patients, while running a relatively uneventful course in most others. Certain HCV proteins, such as core and NS5A, can induce derangement of lipid metabolism or alter signal transduction of infected hepatocytes which leads to the production of reactive oxygen radicals and profibrogenic mediators, in particular TGF-beta1. TGF-beta1 is the strongest known inducer of fibrogenesis in the effector cells of hepatic fibrosis, i.e. activated hepatic stellate cells and myofibroblasts. However, fibrogenesis proceeds only when additional profibrogenic stimuli are present, e.g. alcohol exposure, metabolic disorders such as non-alcoholic steatohepatitis, or coinfections with HIV or Schistosoma mansoni that skew the immune response towards a Th2 T cell reaction. Furthermore, profibrogenic polymorphisms in genes that are relevant during fibrogenesis have been disclosed. This knowledge will make it possible to identify those patients who are most likely to progress and who need antiviral or antifibrotic therapies most urgently. However, even the best available treatment, the combination of pegylated interferon and ribavirin, which is costly and fraught with side effects, eradicates HCV in only 50% of patients. While the suggestive antifibrotic effect of interferons (IF-gamma>alpha,beta), irrespective of viral elimination, has to be proven in randomised prospective studies, additional, well tolerated and cost-effective antifibrotic therapies have to be developed. The combination of cytokine strategies, e.g. inhibition of the key profibrogenic mediator TGF-beta, with other potential antifibrotic agents appears promising. Such adjunctive agents could be silymarin, sho-saiko-to, halofuginone, phosphodiesterase inhibitors, and endothelin-A-receptor or angiotensin antagonists. Furthermore, drug targeting to the fibrogenic effector cells appears feasible. Together with the evolving validation of serological markers of hepatic fibrogenesis and fibrolysis an effective and individualised treatment of liver fibrosis is anticipated.
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PMID:Hepatitis C and liver fibrosis. 1265 47

The ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP) multigene family contains five members. NPP1-3 are type II transmembrane metalloenzymes characterized by a similar modular structure composed of a short intracellular domain, a single transmembrane domain and an extracellular domain containing a conserved catalytic site. The short intracellular domain of NPP1 has a basolateral membrane-targeting signal while NPP3 is targeted to the apical surface of polarized cells. NPP4-5 detected by database searches have a predicted type I membrane orientation but have not yet been functionally characterized. E-NPPs have been detected in almost all tissues often confined to specific substructures or cell types. In some cell types, NPP1 expression is constitutive or can be induced by TGF-beta and glucocorticoids, but the signal transduction pathways that control expression are poorly documented. NPP1-3 have a broad substrate specificity which may reflect their role in a host of physiological and biochemical processes including bone mineralization, calcification of ligaments and joint capsules, modulation of purinergic receptor signalling, nucleotide recycling, and cell motility. Abnormal NPP expression is involved in pathological mineralization, crystal depositions in joints, invasion and metastasis of cancer cells, and type 2 diabetes. In this review we summarize the present knowledge on the structure and the physiological and biochemical functions of E-NPP and their contribution to the pathogenesis of diseases.
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PMID:Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family. 1275 29

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

Pulmonary arterial hypertension (PAH) is a rare condition characterised by elevated pulmonary arterial resistance leading to right heart failure. PAH can be sporadic (idiopathic PAH, or primary pulmonary hypertension), familial (caused by germline BMPR2 mutations, a type II member of the TGFbeta receptor superfamily), or related to other conditions including connective tissue disease, congenital heart disease, human immunodeficiency virus infection, portal hypertension, appetite suppressant exposure... Idiopathic PAH has a prevalence of 2 per million per year in France. The lack of specificity of PAH symptoms (mostly dyspnea) presumably lead to underdiagnosis of this condition. Echocardiography is the investigation of choice for non-invasive screening. Measurement of hemodynamic parameters during right-heart catheterism is mandatory to establish the diagnosis (mean pulmonary artery pressure >25 mmHg and pulmonary artery wedge pressure <12 mmHg). Acute pulmonary vasodilator testing should be performed with nitric oxide or prostacyclin during right-heart catheterization. Recent advances in the management of PAH including continuous intravenous prostacyclin infusion and endothelin receptor antagonists have improved markedly the patients' prognosis. Novel treatments such as inhaled iloprost and type 5 phosphodiesterase inhibitors have to be further evaluated in this setting. Lung transplantation is the last option for patients deteriorating despite medical treatment.
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PMID:[Pulmonary arterial hypertension]. 1504 92


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