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)

Human papillary thyroid carcinoma (PTC) has a relatively benign prognosis despite a high frequency of lymphatic metastasis. This suggests that local anticancer factors, generated in lymph nodes, control PTC progression. The cytokine, tumor necrosis factor-alpha (TNF-alpha), may be one such factor. We have previously shown that a human PTC cell line (NP-PTC) has high affinity TNF-alpha receptors. We now report on the action of TNF-alpha in these cells. TNF-alpha decreased [3H]thymidine incorporation as well as cellular DNA content and cell number in a dose-dependent manner. The abundance of phosphodiesterase and manganous superoxide dismutase mRNA species was increased in a time- and dose-dependent manner in the NP-PTC cells after TNF-alpha treatment. TNF-alpha activated NF-kappa B, a nuclear factor thought to mediate multiple actions of TNF-alpha, in these cells with a maximum effect observed after 30 min of treatment. Thus, TNF-alpha has an antiproliferative action on NP-PTC cells, despite its ability to induce the accumulation of mRNA that encodes an enzyme (manganous superoxide dismutase), thought to be cytoprotective. The net antiproliferative effect must therefore be explained by a balance of protective and tumoricidal or static effects that ultimately result in control of tumor spread. These antiproliferative effects may be in part mediated by NF-kappa B and PDE.
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PMID:Tumor necrosis factor-alpha activates nuclear factor kappa B and induces manganous superoxide dismutase and phosphodiesterase mRNA in human papillary thyroid carcinoma cells. 132 6

Adenosine and adenosine analogues are potent inhibitors of the respiratory burst in neutrophils. Most investigators, however, have found little or no effect of these compounds on neutrophil degranulation from cytochalasin B-treated neutrophils in suspension. We have instead investigated the effect of adenosine and 2-chloroadenosine on degranulation in adherent neutrophils in the absence of cytochalasin B. Both adenosine and 2-chloroadenosine were effective inhibitors of lactoferrin secretion induced by the chemotactic peptide N-formyl-methionine-leucyl-phenylalanine (fMLP) [50% inhibitory concentration (IC50) of less than 10(-6) M]. Secretion induced by tumor necrosis factor (TNF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) was inhibited only at high concentrations (IC50 of approximately 10(-4) M). In the presence of cytochalasin B no inhibitory effect of 2-chloroadenosine was seen. The effect of cAMP-raising agents on secretion from adherent neutrophils was also investigated. Dibutyryl cAMP at 0.2 mM reduced secretion in response to fMLP by 50% but did not inhibit TNF- and GM-CSF-induced degranulation. At a concentration of 2.0 mM dibutyryl cAMP also inhibited exocytosis in response to the two cytokines. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) at 300 microM reduced fMLP-induced degranulation, whereas a concentration of 1 mM was required to inhibit TNF- and GM-CSF-mediated secretion. The adenylate cyclase activator forskolin (50 microM) alone did not inhibit secretion in response to TNF or fMLP. However, in combination with IBMX (300 microM), forskolin (50 microM) reduced both TNF- and fMLP-induced secretion to less than 10%. PMA-induced exocytosis was unaffected by all these agents. In conclusion, adenosine appears to be an effective inhibitor of neutrophil granule protein secretion induced by fMLP but only a weak inhibitor of exocytosis in response to TNF or GM-CSF. Secretion in response to fMLP was also found to be more susceptible to a rise in cAMP than degranulation induced by TNF and GM-CSF.
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PMID:Effect of adenosine analogues and cAMP-raising agents on TNF-, GM-CSF-, and chemotactic peptide-induced degranulation in single adherent neutrophils. 137 3

Increased expression of tissue factor procoagulant by peripheral blood monocytes has been implicated in a number of thrombotic disorders. The present studies were undertaken to determine whether stable analogues of prostacyclin, a potent endothelium-derived platelet inhibitor and vasodilator, could inhibit tissue factor expression by human monocytic cells. Exposure of monocytic tumor THP-1 cells to 100 ng/ml endotoxin, 2 units/ml interleukin-1 beta, or 5 ng/ml tumor necrosis factor-alpha for 4 hours led to increased tissue factor procoagulant activity. Preincubation for 30 minutes with iloprost, ciprostene, and carbacyclin led to a dose-dependent inhibition of tissue factor expression induced by all three challenging agents. Iloprost was the most potent: 50% inhibition occurred at 5 nM, a concentration close to the reported dissociation constant for iloprost binding to the platelet prostacyclin receptor. An orally active analogue, cicaprost, was equally effective against endotoxin-induced tissue factor expression. Carbacyclin and ciprostene were 100 times less potent. Iloprost prevented the endotoxin-induced expression of tissue factor antigen on the surface of THP-1 cells, as determined by flow cytometry. Iloprost (500 pM-50 nM) increased intracellular levels of cyclic AMP. This effect was potentiated by isobutylmethylxanthine, an inhibitor of phosphodiesterase. The inhibitory effects of iloprost on tissue factor expression were also potentiated by isobutylmethylxanthine and mimicked by forskolin and dibutyryl cyclic AMP but not dibutyryl cyclic GMP. These results suggest that prostacyclin may play a role in downregulating tissue factor expression in monocytes, at least in part via elevation of intracellular levels of cyclic AMP.
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PMID:Prostacyclin analogues inhibit tissue factor expression in the human monocytic cell line THP-1 via a cyclic AMP-dependent mechanism. 137 7

A combination therapy was tested consisting of chloroquine and interferon-gamma (IFN-gamma) in the late phase of blood-stage Plasmodium vinckei malaria in BALB/c mice. When mice were treated with three times 300 micrograms chloroquine at 24-h intervals starting at a parasitemia of 30%-50%, only 5 of 14 mice (36%) died 2-4 days after initiation of therapy. However, when infected mice received chloroquine plus 1 microgram IFN-gamma at the same time, 14 of 18 mice (78%) died 0.5-3 days after start of therapy (p < 0.05) despite clearance of parasitemia. The histopathology from mice dying after combination therapy revealed interstitial leukocyte infiltration of lung tissue, severe liver cell necrosis and kidney tubular necrosis. Pretreatment of P. vinckei-infected mice with pentoxifylline, a phosphodiesterase inhibitor, led to a significant decrease of IFN-gamma-induced lethality (p < 0.05). In contrast, pretreatment with neutralizing antibodies to tumor necrosis factor or with L-N-monomethyl arginine, the latter an inhibitor of the nitric oxide synthase, significantly increased lethality (p < 0.05).
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PMID:Interferon-gamma induced lethality in the late phase of Plasmodium vinckei malaria despite effective parasite clearance by chloroquine. 142 13

Recombinant human granulocyte/macrophage colony-stimulating factor (GM-CSF) induced significant superoxide production in human neutrophils within 30 minutes after addition of stimulus and the response was complete within 2 hr. Other agents known to prime neutrophils, including LPS and tumor necrosis factor-alpha, lacked activity under the experimental conditions employed. Using a panel of pharmacologic inhibitors, we sought to compare GM-CSF-induced neutrophil superoxide to that produced by cells exposed to N-formyl methionyl-leucyl-phenylalanine (fMet-Leu-Phe) and phorbol 12-myristate 13-acetate (PMA). Each stimulant displayed a different profile. Rolipram, a peak IV phosphodiesterase inhibitor, specifically inhibited neutrophil activation by GM-CSF and fMet-Leu-Phe, while superoxide production stimulated by PMA was unaffected. Staurosporine, a protein kinase C (PK-C) inhibitor, suppressed superoxide production induced by all three neutrophil stimulants. Cytochalasin B totally inhibited superoxide induced by GM-CSF under conditions that promote the fMet-Leu-Phe-induced response. Cytochalasin B did not markedly affect PMA-induced superoxide. The results are consistent with the hypothesis that intact PK-C activity is essential for neutrophil superoxide production, but that differences exist in the initial pathways induced by these neutrophil activators. Superoxide secretion from GM-CSF-treated neutrophils appears to be a direct, delayed response that requires assembly of microfilaments during exposure to the cytokine.
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PMID:Effect of recombinant human granulocyte/macrophage colony-stimulating factor on neutrophil superoxide production. 166 43

The expression of the 55 kD human tumor necrosis factor (TNF) receptor gene was investigated. By use of a 1.2 kb cDNA we demonstrated a constitutive expression of a single 2.3 kb transcript in cell lines and fresh blood cells. The TNF receptor gene expression was not affected by phorbol esters, dibutyryl cAMP (dbcAMP), interleukin-1 (IL-1), interferon-gamma (IFN-gamma) or by TNF, agents known to modulate functional TNF receptors. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX) showed a dose dependent inhibition of the TNF receptor gene expression. This inhibition is not mediated by cAMP, since neither dbcAMP nor forskolin had any effects on the expression of the 55 kD receptor gene. The results suggest that the effects of phorbol diesters, IL-1, IFN-gamma, TNF and dbcAMP previously observed on binding of TNF to cells are limited to posttranscriptional regulation of the 55 kD TNF receptor.
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PMID:Modulation of the constitutive gene expression of the 55 kD tumor necrosis factor receptor in hematopoietic cells. 170 Jul 5

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

Endothelial cells (EC) secrete platelet-derived growth factor (PDGF)-like protein, which is a potent mitogen to smooth muscle and connective tissue cells. The purpose of this study was to determine if amrinone, a phosphodiesterase inhibitor, could inhibit PDGF-like protein secretion on the basis of its ability to increase cAMP. Human umbilical artery endothelial cells (HUAEC) (n = 7) were preincubated for 4 h with amrinone (10 micrograms/mL) before coincubation with thrombin (10 IU/mL) and amrinone (10 micrograms/mL) for 18 h. The supernatant was then assayed for the presence of both PDGF-like protein by using a competitive 125I-PDGF radioreceptor inhibition assay, and cAMP by using an RIA. Thrombin-induced PDGF-like protein secretion from HUAEC was significantly inhibited by amrinone (7.8 +/- 1.6 fmol/10(6) EC) when compared with thrombin alone (12.1 +/- 2.4 fmol/10(6) EC) (p less than 0.05). Amrinone alone had no effect on baseline PDGF-like protein secretion. Amrinone inhibition of thrombin-induced PDGF-like protein secretion was comparable whether amrinone was added to HUAEC 4 or 0 h before thrombin, and it was dose dependent with a maximal inhibition of 82.7% by amrinone (160 micrograms/mL). In contrast, IL-1 alpha (10 micrograms/mL) and tumor necrosis factor (100 ng/mL) induced less secretion of PDGF-like protein from HUAEC, and this secretion was not inhibited by amrinone. Amrinone (10 micrograms/mL) significantly increased secretion of cAMP from HUAEC from a baseline value of 6.4 +/- 0.4 pmol/10(6) EC to 10.6 +/- 0.1 pmol/10(6) EC (p less than 0.01). We conclude that amrinone inhibits thrombin-induced PDGF-like protein secretion from HUAEC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of amrinone on thrombin-induced platelet-derived growth factor-like protein secretion from endothelial cells. 195 18

Tibenelast (LY186655), 5,6,-diethoxybenzo(b)thiophene-2-carboxylic acid, sodium salt, is an orally active anti-anaphylactic compound in guinea pigs, and has been shown to prevent bronchospasm in moderately severe asthmatic patients. Pharmacological studies with tibenelast demonstrated that it is a selective phosphodiesterase (PDE) inhibitor in that it is moderately active against the lung and stomach enzyme while being a very weak inhibitor of the heart enzyme. The compound was without cardiovascular effects at anti-anaphylactic doses. In contrast to theophylline, tibenelast did not have a direct inotropic effect in the cat papillary muscle system. The concentration that inhibited 50% of the enzymatic activity (IC50) for tibenelast was 20- to 30-fold lower for neutrophil PDE than for PDE of other tissues. It was 100 times more potent than aminophylline in inhibiting superoxide generation from platelet-activating factor (PAF)-primed polymorphonuclear leukocytes (PMNL) challenged with chemotactic factor, N-formyl-methionyl-leucyl-phenylalanine. However, tibenelast was less effective in the tumor necrosis factor-primed system, and did not inhibit superoxide generation during phagocytosis or when other soluble stimuli, such as phorbo-12-myristate-13-acetate or the calcium ionophore A23187, were used. Furthermore, tibenelast did not inhibit enzymes involved in arachidonic acid metabolism. These results suggest that tibenelast probably inhibits superoxide release from PMNL via a selective inhibition on PDE.
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PMID:Cardiovascular effect and stimulus-dependent inhibition of superoxide generation from human neutrophils by tibenelast, 5,6-diethoxybenzo(b)thiophene-2-carboxylic acid, sodium salt (LY186655). 217 1

Interleukin 6 (IL-6; also referred to as interferon-beta 2, 26-kDa protein, and B cell stimulatory factor 2) is a cytokine whose actions include a stimulation of immunoglobulin synthesis, enhancement of B cell growth, and modulation of acute phase protein synthesis by hepatocytes. Synthesis of IL-6 is stimulated by interleukin 1 (IL-1), tumor necrosis factor (TNF), or platelet-derived growth factor. We examined the role of the cyclic AMP (cAMP)-dependent signal transduction pathway in IL-6 gene expression. Several activators of adenylate cyclase, including prostaglandin E1, forskolin, and cholera toxin, as well as the phosphodiesterase inhibitor isobutylmethylxanthine and the cAMP analog dibutyryl cAMP, shared the ability to cause a dramatic and sustained increase in IL-6 mRNA levels in human FS-4 fibroblasts. Actinomycin D treatment abolished this enhancement. Treatments that increased intracellular cAMP also stimulated the secretion of the IL-6 protein in a biologically active form. Increased intracellular cAMP appears to enhance IL-6 gene expression by a protein kinase C-independent mechanism because down-regulation of protein kinase C by a chronic exposure of cells to a high dose of 12-O-tetradecanoylphorbol 13-acetate did not abolish the enhancement of IL-6 expression by treatments that increase cAMP. IL-1 and TNF too increased IL-6 mRNA levels by a protein kinase C-independent mechanism. Our results suggest a role for the cAMP-dependent pathway(s) in IL-6 gene activation by TNF and IL-1.
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PMID:Synthesis of interleukin 6 (interferon-beta 2/B cell stimulatory factor 2) in human fibroblasts is triggered by an increase in intracellular cyclic AMP. 245 59


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