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 pro-inflammatory peptide tumor necrosis factor-alpha (TNF) stimulates production of the anti-inflammatory cytokine-interleukin-10 by monocytes which in turn inhibits the synthesis of TNF. This inhibitory effect of interleukin-10 may contribute to the balance of pro- and anti-inflammatory cytokines in several diseases, e.g., chronic inflammatory bowel disease. In the present study we addressed the question whether interleukin-10 in combination with other TNF-suppressing agents leads to enhanced suppression of TNF synthesis. We investigated the inhibitory potency of interleukin-10 in combination with rolipram, a specific type IV phosphodiesterase inhibitor, or with cicaprost, a stable prostacyclin analogue in lipopolysaccharide-stimulated human peripheral blood mononuclear cells. Peripheral blood mononuclear cells were stimulated with 10 ng/ml lipopolysaccharide in the absence or presence of interleukin-10 or one of the cAMP-elevating agents. First, we confirmed the TNF-suppressing effect of interleukin-10, rolipram and cicaprost alone and determined the IC50 for these substances. Second, for the combination of interleukin-10 with one of the cAMP-elevating substances we were able to demonstrate enhanced TNF inhibition. Of these, the combination of interleukin-10 and rolipram revealed an additive effect. The maximal TNF synthesis of 5.5 +/- 1.1 ng/ml after lipopolysaccharide stimulation alone was inhibited by 0.1 ng/ml interleukin-10 to 2.7 +/- 0.6 ng/ml TNF and by 100 nM rolipram to 3.1 +/- 0.6 ng/ml TNF. Both substances combined suppressed TNF synthesis to 1.5 +/- 0.3 ng/ml. After stimulation with Staphylococcus epidermidis we could demonstrate a more pronounced inhibition of TNF synthesis by interleukin-10 compared to rolipram which was more effective after stimulation with lipopolysaccharide. Finally, the additive inhibitory effect of interleukin-10 and rolipram could be confirmed on the level of TNF mRNA. The results obtained in the present investigation could form a prerequisite to study the combination of interleukin-10 and cAMP-elevating agents in in vivo models of acute or chronic inflammatory diseases.
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PMID:Suppression of tumor necrosis factor-alpha production by interleukin-10 is enhanced by cAMP-elevating agents. 906 93

The enhanced nitric oxide (NO) and prostaglandin (PG) generation of activated macrophages is controlled by glucocorticoid-sensitive inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. Negative feedback regulation of iNOS expression by the products of both pathways has been suggested, but their effects on COX-2 expression have not been examined. We hae investigated the effect of E- and l-series prostaglandins that activate adenylate cyclase (AC), forskolin (a direct activator of AC), and other agents that influence the cyclicAMP/cyclicGMP systems on the ability of E. coli endotoxin (lipopolysaccharide, LPS) to induce iNOS and COX-2 in the murine macrophage cell line J774. After a 2-hr pretreatment before adding endotoxin, PGE2, PGI2, forskolin, IBMX (isobutylmethylxanthine, a cyclicAMP/cyclicGMP phosphodiesterase inhibitor), 8-bromo cyclicAMP, and arachidonic acid itself all inhibited the expression of both iNOS and COX-2 (as shown by Western blotting) and reduced NO release and COX activity, whereas PGF2 alpha and 8-bromo cyclic GMP were only weakly effective. The effects of PGE2, PGI2, and forskolin were enhanced by cotreatment with IBMX. The suppression of LPS-induced iNOS induction by PGE2 was functionally significant, in that it protected against the mild cytotoxicity of the NO generated in response to endotoxin. These results provide the first direct evidence for the feedback regulatory suppression of COX-2 induction by a PG-driven cAMP-mediated process, and show that the modulation of iNOS and COX-2 induction shares common features. They also suggest that such modulation is normally held in check by high phosphodiesterase activity within these cells.
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PMID:Repression of inducible nitric oxide synthase and cyclooxygenase-2 by prostaglandin E2 and other cyclic AMP stimulants in J774 macrophages. 910

1. During in vitro culture in 10% human AB serum, human peripheral blood monocytes acquire a macrophage-like phenotype. The underlying differentiation was characterized by increased activities of the macrophage marker enzymes unspecific esterase (NaF-insensitive form) and acid phosphatase, as well as by a down-regulation in surface CD14 expression. 2. In parallel, a dramatic change in the phosphodiesterase (PDE) profile became evident within a few days that strongly resembled that previously described for human alveolar macrophages. Whereas PDE1 and PDE3 activities were augmented, PDE4 activity, which represented the major cyclic AMP-hydrolysing activity of peripheral blood monocytes, rapidly declined. 3. Monocytes and monocyte-derived macrophages responded to lipopolysaccharide (LPS) with the release of tumour necrosis factor-alpha (TNF). In line with the change in CD14 expression, the EC50 value of LPS for induction of TNF release increased from approximately 0.1 ng ml-1 in peripheral blood monocytes to about 2 ng ml-1 in macrophages. 4. Both populations of cells were equally susceptible towards inhibition of TNF release by cyclic AMP elevating agents such as dibutyryl cyclic AMP, prostaglandin E2 (PGE2) or forskolin, which all led to a complete abrogation of TNF production in a concentration-dependent manner and which were more efficient than the glucocorticoid dexamethasone. 5. In monocytes, PDE4 selective inhibitors (rolipram, RP73401) suppressed TNF formation by 80%, whereas motapizone, a PDE3 selective compound, exerted a comparatively weak effect (10-15% inhibition). Combined use of PDE3 plus PDE4 inhibitors resulted in an additive effect and fully abrogated LPS-induced TNF release as did the mixed PDE3/4 inhibitor tolafentrine. 6. In monocyte-derived macrophages, neither PDE3- nor PDE4-selective drugs markedly affected TNF generation when used alone (< 15% inhibition), whereas in combination, they led to a maximal inhibition of TNF formation by about 40-50%. However, in the presence of PGE2 (10 nM), motapizone and rolipram or RP73401 were equally effective and blocked TNF release by 40%. Tolafentrine or motapizone in the presence of either PDE4 inhibitor, completely abrogated TNF formation in the presence of PGE2. Thus, an additional cyclic AMP trigger is necessary for PDE inhibitors to become effective in macrophages. 7. Finally, the putative regulatory role for PDE1 in the regulation of TNF production in macrophages was investigated. Zaprinast, at a concentration showing 80% inhibition of PDE1 activity (100 micromol l-1), did not influence TNF release. At higher concentrations (1 mmol l-1), zaprinast became effective, but this inhibition of TNF release can be attributed to a significant inhibitory action of this drug on PDE3 and PDE4 isoenzymes. 8. In summary, the in vitro differentiation of human peripheral blood monocytes to macrophages is characterized by a profound change in the PDE isoenzyme pattern. The change in the PDE4 to PDE3 ratio is functionally reflected by an altered susceptibility towards selective PDE inhibitors under appropriate stimulating conditions.
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PMID:In vitro differentiation of human monocytes to macrophages: change of PDE profile and its relationship to suppression of tumour necrosis factor-alpha release by PDE inhibitors. 915 31

Intracellular cyclic nucleotide levels play an important role in the regulation of several immunological processes. Since elevation of intracellular cyclic adenosine monophosphate and/or cyclic guanosine monophosphate concentration by inhibition of phosphodiesterase (PDE) is known to modulate the inflammatory response, we compared the effect of amrinone, an inhibitor of the PDE III isoenzyme, and of theophylline, a nonspecific PDE inhibitor, on the plasma tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), and nitric oxide response in mice to intraperitoneal injection of bacterial lipopolysaccharide (LPS). Intraperitoneal treatment of animals with amrinone (100 mg/kg) 30 min before LPS administration decreased both plasma IL-6 and IL-10 concentrations in the first phase of the response, but enhanced plasma levels of these cytokines in the second part. In contrast, pretreatment of the animals with theophylline (100 mg/kg) enhanced LPS-induced plasma IL-6 and IL-10 levels during the whole response. However, pretreatment with both PDE inhibitors resulted in a marked inhibition of LPS-evoked plasma concentrations of TNF-alpha and nitrite/nitrate (breakdown products of nitric oxide) throughout the response. This study demonstrates for the first time that amrinone and theophylline possess differential, but primarily anti-inflammatory, properties during LPS-induced systemic inflammation in the mouse.
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PMID:Amrinone and theophylline differentially regulate cytokine and nitric oxide production in endotoxemic mice. 916 73

Previous studies from our laboratories demonstrated that human decidual macrophages and peripheral mononuclear cells express renin. In the present study, we found that U-937 monocytes, induced to differentiate into macrophage-like cells by treatment with phorbol dibutyrate (PDBU), express renin mRNA and release renin (95%, of which is in the form of prorenin). Treatment of these PDBU-exposed cells with dibutyryl-cAMP (1 mM) caused a 20-fold increase in renin mRNA and a 10-fold increase in prorenin release. Forskolin (10 microM), an activator of adenylyl cyclase, and terbutaline (100 microM), a beta2-adrenergic agonist known to increase cAMP levels, also increased renin mRNA and prorenin release. The secretory response to terbutaline was potentiated by the type IV cyclic AMP-phosphodiesterase (PDE) inhibitor Ro 20-1724 (50 microM). Angiotensin II agonist inhibited the stimulatory effect of terbutaline on renin secretion as did the cytokines tumor necrosis factor-alpha and lipopolysaccharide plus interferon-gamma. Since other studies have shown that U-937 cells possess beta2-adrenergic receptors and express mainly the type IV PDE, the present findings strongly suggest that beta-adrenergic receptors in mononuclear cells are coupled to renin expression via the cAMP transduction pathway. The results support a possible role for the renin-angiotensin system in macrophage function and suggest potential autocrine regulatory mechanisms in prorenin expression.
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PMID:Beta-adrenergic regulation of renin expression in differentiated U-937 monocytic cells. 925 63

Tumor necrosis factor alpha (TNF-alpha), a major product of alveolar macrophages (AM), has been implicated in many pulmonary diseases. Histamine, a mediator important in pulmonary inflammation, has been demonstrated to regulate the production of TNF-alpha by monocytes. In this study, we show that human AM and monocytes differ in their responses to histamine. Whereas histamine suppressed lipopolysaccharide (LPS)-stimulated TNF-alpha production by monocytes through a cAMP-dependent mechanism, it had no effect on either cAMP levels or TNF-alpha production by AM. In contrast, both PGE2 and IL-10 suppressed LPS-stimulated TNF-alpha production by AM and monocytes. The lack of response of AM to histamine appears unique, as histamine suppressed LPS-stimulated TNF-alpha production by mononuclear cells isolated from sites of acute and chronic inflammation, as well as from noninflammatory tissues, and by macrophages differentiated in vitro. In the presence of the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine, histamine increased cAMP levels in AM. Freshly isolated monocytes and AM did not differ in PDE activity. However, PDE activity in AM, but not in monocytes, was increased 15 min after culture with histamine and may, in part, be responsible for the inability of histamine to suppress TNF-alpha production by AM. However, this increase was small and we hypothesize that additional mechanisms may contribute to the unresponsiveness of AM to histamine. We suggest that the lack of response of AM to histamine may be important in the host defense function of AM in the distal lung.
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PMID:Inability of histamine to regulate TNF-alpha production by human alveolar macrophages. 927 10

Heparin-binding EGF-like growth factor (HB-EGF) is a mitogen for smooth muscle cells (SMC) and is detected in SMC and macrophages in atherosclerotic plaques, suggesting that HB-EGF may be associated with the pathogenesis of atherosclerosis. The present study indicates that cilostazol, a phosphodiesterase III inhibitor, suppresses the expression of HB-EGF in rat aortic SMC and in U-937 cells, a macrophage-like cell line, stimulated by lipopolysaccharide. Further, cilostazol diminished the induction of HB-EGF mRNA by methylglyoxsal, which is a reactive dicarbonyl metabolite produced as the result of a glycation reaction and which might be associated with macroangiopathy caused by hyperglycemia. Cilostazol suppressed the production of HB-EGF protein in the conditioned medium of SMC. These data suggest that cilostazol might act by suppressing the progression of atherogenesis by means of suppressing the expression of HB-EGF in SMC and macrophages.
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PMID:The effect of cilostazol, a cyclic nucleotide phosphodiesterase III inhibitor, on heparin-binding EGF-like growth factor expression in macrophages and vascular smooth muscle cells. 929 35

1. The effects of cAMP-phosphodiesterase (PDE) isozyme inhibitors on the production of tumor necrosis factor alpha (TNF-alpha), and interleukins 1 beta 8 (IL-1 beta and IL-8) by lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMC) were evaluated. In addition, we investigated the effects of dibutyryl cAMP (dbcAMP) and beta-adrenergic receptor agonist on the production of these cytokines. 2. Type IV PDE inhibitors were more effective at inhibiting the production of TNF-alpha and IL-1 beta by LPS-stimulated PBMC than a nonselective, type III or type III/IV inhibitor. In contrast, these agents had no effect on IL-8 production. 3. Increasing concentrations of dbcAMP progressively reduced the production of TNF-alpha and IL-1 beta but not IL-8. 4. The addition of beta-agonist increased the inhibitory effect of PDE inhibitors tested on the production of TNF-alpha and IL-1 beta. 5. Type IV PDE inhibitors could be potent pharmacological agents for the treatment of diseases in which TNF-alpha and IL-1 beta are important etiological factors.
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PMID:Effects of cAMP-phosphodiesterase isozyme inhibitor on cytokine production by lipopolysaccharide-stimulated human peripheral blood mononuclear cells. 935 14

1. We have investigated the effects of the phosphodiesterase (PDE) type IV inhibitor rolipram and of the glucocorticoid methylprednisolone on the induction of tumour necrosis factor alpha (TNF-alpha) mRNA and protein in brains of rats after peripheral administration of lipopolysaccharide (LPS). 2. After intravenous administration of LPS, a similar time-dependent induction of both TNF-alpha mRNA and protein was observed in rat brain. Peak mRNA and protein levels were found 7 h after administration of LPS. 3. In situ hybridization experiments with a specific antisense TNF-alpha riboprobe suggested that the cells responsible for TNF-alpha production in the brain were microglia. 4. Intraperitoneal administration of methylprednisolone inhibited the induction of TNF-alpha protein in a dose-dependent manner. A maximal inhibition of TNF-alpha protein production by 42.9+/-10.2% was observed at a dose regimen consisting of two injections of each 30 mg kg(-1) methylprednisolone. 5. Intraperitoneal administration of rolipram also inhibited the induction of TNF-alpha protein in a dose-dependent manner. The maximal inhibition of TNF-alpha protein production was 96.1+/-12.2% and was observed at a dose regimen of three separate injections of each 3 mg kg(-1) rolipram. 6. In situ hybridization experiments showed that the level of TNF-alpha mRNA induced in rat brain by LPS challenge was reduced by intraperitoneal administration of methylprednisolone (2 x 15 mg kg(-1)) and of rolipram (3 x 3 mg kg(-1)). 7. We suggest that peripheral administration of LPS induces a time-dependent expression of TNF-alpha in rat brain, presumably in microglial cells, and that methylprednisolone and rolipram inhibit LPS-induced expression of TNF-alpha in these cells via a decrease of TNF-alpha mRNA stability and/or TNF-alpha gene transcription.
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PMID:Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain: inhibition by methylprednisolone and by rolipram. 942 Dec 99

Postinjury deficits in monocyte tumor necrosis factor receptors (moTNFR) activity may alter beneficial functions during an inflammatory response. Several counter-regulatory hormones elicited during inflammation may modulate tumor necrosis factor (TNF) activity, but little is known about their influence on moTNFR. Also, catecholamines inhibit TNF production, but the adrenoreceptor mechanism of this effect has not been fully clarified. To determine the effect of catecholamines and corticosteroids on moTNFR, whole blood was coincubated for up to 8 (moTNFR) or 24 h (cytokines) in the presence of lipopolysaccharide (100 ng/ml) and 1) epinephrine (Epi, 10(-6) M), dexamethasone (Dex, 10(-6) M) or both (EpiDex, 10(-6) M) to assess the expression of total moTNFR, moTNFR-I, and moTNFR-II. 2) Epi and norepinephrine (EpiNE, 10(-6) M) and the alpha 1 + 2-, beta 1 + 2-, beta 1-, or beta 2-adrenergic antagonists were used to assess the role of such adrenoreceptors on total moTNFR and TNF production, and N6,2'-O-dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) alone or in combination with the phosphodiesterase inhibitor Ro-20-1724/000, to study the cAMP-dependent pathway on total moTNFR. We found that Epi upregulated total moTNFR and moTNFR-II. Dex did not significantly influence total moTNFR or moTNFR-II. Also, EpiNE increased total moTNFR and inhibited TNF by a beta 2-dependent mechanism. DBcAMP (10(-5) M) modestly enhanced total moTNFR. This suggests a common mechanism for acutely enhancing moTNFR and attenuation of soluble TNF appearance during conditions of severe stress.
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PMID:Catecholamines increase monocyte TNF receptors and inhibit TNF through beta 2-adrenoreceptor activation. 943 37


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