Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 (IL-1) is a potent stimulator of bone resorption. Induction of osteoclastic bone resorption by various endocrine or paracrine factors is mediated via the osteoblasts. We have therefore investigated the effects of IL-1 beta on cell signalling in isolated human osteoblasts. Special interest was focused on prostaglandin synthesis, since indomethacin, an inhibitor of prostaglandin synthesis, partly inhibits IL-1-induced bone resorption. IL-1 beta, at and above 0.3 pM, dose dependently stimulated PGE2 formation in isolated human osteoblasts, with half maximal stimulation, EC50, at 3 pM. Treatment with the calcium ionophore A23187 (1 microM), or with forskolin (30 microM), also stimulated PGE2 formation in human osteoblasts. The time-course for IL-1 beta-induced PGE2 formation was similar to that of forskolin, with a significant increase in the formation of PGE2 seen after 1 h. In contrast, A23187-induced PGE2 formation was seen within minutes. IL-1 beta stimulated the accumulation of cyclic AMP in isolated human osteoblasts incubated for 15 min. This increase in cyclic AMP formation was not secondary to PGE2 formation since it was not blocked by the addition of indomethacin (1 microM). Pretreatment with the phosphodiesterase inhibitor IBMX did not augment IL-1 beta-induced PGE2 formation, nor did the protein kinase A inhibitor Rp-cAMPs inhibit IL-1 beta-induced PGE2 formation, suggesting that cyclic AMP does not mediate the stimulatory effect of IL-1 on PGE2 formation. We conclude that IL-1 beta enhances the formation of cyclic AMP as well as PGE2 in primary cultures of isolated human osteoblasts. The IL-1 beta-induced cyclic AMP formation is, however, not related to the enhanced prostaglandin formation. The findings implicate that both cyclic AMP- and PGE2-formation in osteoblasts might be involved as independent mediators of IL-1 beta-induced bone resorption.
 ...
PMID:Interleukin-1 beta induces cyclic AMP formation in isolated human osteoblasts: a signalling mechanism that is not related to enhanced prostaglandin formation. 753 63

The marine natural products manoalide and scalaradial are potent anti-inflammatory agents that inactivate the enzyme phospholipase A2 (PLA2) in vitro. To study the mechanism of inhibition of prostaglandin E2 (PGE2) production in human monocytes by manoalide and scalaradial, lipopolysaccharide (LPS)-induced prostaglandin biosynthesis and induction of prostaglandin H synthase (PGHS) were evaluated. LPS (10 ng/mL) and interleukin-1 beta (IL-1 beta, 50-1000 ng/mL) but not tumor necrosis factor alpha (TNF alpha, 300 ng/mL) induced the expression of the PGHS-2 isoform as determined by immunoblot analysis with a specific polyclonal antibody for PGHS-2. Manoalide and scalaradial (1-10 microM) inhibited LPS-induced endogeneous PGE2 production, reduced the LPS-induced PGHS activity, and reduced the expression of PGHS-2. Indomethacin [a PGHS inhibitor (0.01 to 0.1 microM)], zileuton [a 5-lipoxygenase inhibitor (3-10 microM)], and WEB-2806 [a platelet-activating factor (PAF) antagonist (30 microM)] did not affect the LPS-induced expression of PGHS-2 in human monocytes. These results suggest that modulation of lipid mediator production by manoalide or scalaradial may not be involved in the observed effects on the expression of PGHS-2. Manoalide and scalaradial also inhibited the release of IL-1 beta and TNF alpha from LPS-stimulated monocytes. Expression of PGHS-2 induced by either LPS or IL-1 beta was blocked by the IL-1 receptor antagonist (IL-1ra, 2 micrograms/mL) but not by rolipram, a phosphodiesterase IV inhibitor that inhibits TNF alpha but not IL-1 beta release. Similar to LPS, IL-1 beta-induced PGHS-2 expression was apparently not regulated by lipid mediators such as prostaglandins, leukotrienes or PAF as determined with specific inhibitors and antagonists. Scalaradial and to some extent manoalide were capable of blocking the IL-1 beta-induced expression of PHGS-2. These results indicate that IL-1 beta is the predominant cytokine responsible for the induction of PGHS-2 in the human monocyte. Furthermore, marine natural products such as scalaradial have novel effects on the IL-1 beta-mediated induction of PGHS-2 in human monocytes, which appears to be independent of effects on lipid mediator production.
 ...
PMID:Regulation of prostaglandin H synthase 2 expression in human monocytes by the marine natural products manoalide and scalaradial. Novel effects independent of inhibition of lipid mediator production. 757 73

Compounds from two distinct pharmacological classes namely, SK&F 86002 and pentoxifylline, were examined for their effects on TNF alpha and IL-1 beta release by human monocytes stimulated with LPS or monoclonal antibodies to three cell surface glycoproteins, CD44, CD45 and LFA-3 (LFA-3 is also known as CD58). SK&F 86002, an inhibitor of 5-LO and CO in arachidonic acid metabolism, inhibited LPS-induced release of TNF alpha and IL-1 beta with an IC50 of 1 microM. At this dose, it also inhibited by > 50%, release of both cytokines induced by the three monoclonal antibodies. Pentoxifylline, a methylxanthine derivative with phosphodiesterase inhibitory activity, selectively inhibited LPS-induced TNF alpha release with an IC50 of 100 microM. TNF alpha and IL-1 beta release mediated by the monoclonal antibodies were inhibited by less than 30% in the presence of 100 microM pentoxifylline. These results suggest that (a) LPS induced cytokine release shares a common step with the physiologically relevant stimuli (involving cross-linking of cell surface receptors), and that this pathway is sensitive to inhibition by SK&F 86002 and, (b) SK&F 86002 is more potent than pentoxifylline in inhibiting TNF alpha and IL-1 beta release induced by both stimuli.
 ...
PMID:Inhibition of CD44, CD45 and LFA-3 mediated cytokine release from human monocytes by SK&F 86002 and pentoxifylline. 768 99

Prostacyclin analogues have been reported to inhibit the expression of tissue factor procoagulant activity in human monocytes, primarily by elevating intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP). The present studies have investigated whether prostacyclins can also inhibit tissue factor expression in endothelial cells. Iloprost, carbacyclin, and ciprostene had no effect on human umbilical vein endothelial tissue factor activity induced by lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), or interleukin-1 beta (IL-1 beta). Iloprost failed to elevate intracellular levels of cAMP, even when combined with a phosphodiesterase inhibitor. In contrast, forskolin increased endothelial cAMP and inhibited tissue factor expression. Conditioned medium from LPS-challenged monocytic THP-1 cells, which contained both TNF-alpha and IL-1 beta, induced endothelial cell procoagulant activity to levels 20-fold higher than those achieved in response to LPS alone. Iloprost abolished LPS-induced TNF-alpha secretion by THP-1 cells and inhibited IL-1 beta secretion by 45%. In keeping with this, iloprost reduced levels of TNF-alpha and IL-1 beta mRNA in LPS-challenged cells. Treatment of THP-1 cells with iloprost strongly inhibited the ability of conditioned medium to induce endothelial tissue factor expression, an effect that was mimicked by treating the medium with blocking antibodies to the cytokines. We conclude that although prostacyclin analogues do not directly suppress endothelial tissue factor expression due to their failure to elevate cAMP, they may do so indirectly by inhibiting the amplification produced by monocyte-derived cytokines.
 ...
PMID:Effects of prostacyclin analogues on human endothelial cell tissue factor expression. 768 94

Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the release of toxic factors from reticuloendothelial cells. One of the principal endogenous factors involved in this process is tumor necrosis factor alpha (TNF alpha). In this study, inhibitors selective for different classes of phosphodiesterases (PDE), were examined for their effects on LPS-induced TNF alpha production by human monocytes. The selective cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNF alpha production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC50 for inhibition of LPS-induced TNF alpha production by rolipram was 0.1 microM, whereas production of IL-1 beta or IL-6 was unaffected. Furthermore, rolipram was equally effective in inhibiting TNF alpha production by a number of other stimuli. Inhibition of TNF alpha production by rolipram was associated with an elevation of intracellular cAMP, consistent with a mechanism involving phosphodiesterase inhibition. Rolipram was efficacious in suppressing LPS-induced TNF alpha mRNA expression, and at the protein level was also active when added to cultures post-stimulated with LPS. This indicates that rolipram may act at both the transcriptional and translational levels. Rolipram inhibited TNF alpha production in vivo in a rat endotoxemia model. Collectively, these data suggest that the prototypic inhibitor of PDE IV isozyme, rolipram, can effectively and selectively inhibit LPS-induced TNF alpha production through elevation of intracellular cAMP.
 ...
PMID:Characterization of cAMP-dependent inhibition of LPS-induced TNF alpha production by rolipram, a specific phosphodiesterase IV (PDE IV) inhibitor. 784 52

The following study was performed to test the hypothesis that treatment with rolipram, a specific inhibitor of phosphodiesterase (PDE) IV, should inhibit many pulmonary responses to acute and chronic antigen challenge in atopic monkeys by elevating intracellular cAMP and subsequently inhibiting leukocyte function. Monkeys received subcutaneous injections of either vehicle (2% DMSO) or 10 mg/kg of rolipram 1 h before exposure to Ascaris suum antigen (Ag). Acute responses to Ag, including bronchoconstriction, pulmonary leukocyte infiltration, and cytokine production, were monitored before and 4 h after single Ag aerosol administration. To monitor the effects of rolipram on chronic Ag exposure, a 10-d, multiple-Ag protocol, previously demonstrated to induce airway hyperresponsiveness (AHR) to methacholine (MCh), was performed. Ag exposure increased respiratory system resistance (Rrs) 221.7 +/- 31.88% (n = 5). This increase in Rrs was not significantly altered by rolipram. Rolipram significantly (p < 0.002) increased cAMP levels in bronchoalveolar lavage (BAL) leukocytes 1 h after administration (n = 5). Ag-induced increases in BAL IL-8 and TNF were significantly reduced by rolipram, but IL-1 beta and IL-6 increases were unaffected (n = 9). Ag-induced increases in BAL eosinophils and neutrophils were significantly reduced by rolipram (n = 9). In the multiple-Ag protocol (n = 7), rolipram significantly reduced both the number of BAL eosinophils (p < 0.02) and the development of AHR (p < 0.002). Despite its inability to inhibit acute Ag-induced bronchoconstriction, rolipram was protective against acute and chronic inflammatory responses to Ag and prevented the development of AHR, suggesting that selective PDE-IV inhibition is a relevant target for asthma therapy.
 ...
PMID:Effects of rolipram on responses to acute and chronic antigen exposure in monkeys. 817 55

Several in vitro and in vivo studies have demonstrated suppression of tumour necrosis factor-alpha (TNF-alpha) synthesis by pentoxifylline. In the present study we compared the effect of pentoxifylline with that of five other xanthine derivatives. We addressed two questions. First, what is the relative potency of those chemically related compounds in suppressing the lipopolysaccharide (LPS)-induced production of TNF-alpha in human mononuclear cells? Second, does suppression of TNF-alpha production by these xanthine derivatives correlate with their capacity to inhibit 3',5'-cAMP phosphodiesterase (PDE) activity? The experimental drug A 80 2715 [1-(5-hydroxy-5-methylhexyl)-3-methyl-7-propylxanthine] was identified as the most potent agent with an IC50 (concentration exerting 50% suppression of LPS-induced TNF-alpha production) of 41 microM (mean of 13 individuals). The IC50 values of the other substances ranged between 106 microM for HWA 138 and 419 microM for theophylline. The LPS-induced interleukin-1 beta (IL-1 beta) production was not influenced by all substances tested at comparable concentrations. Inhibition of PDE activity was determined in a cell-free system using PDE isolated from bovine heart. All xanthine derivatives dose-dependently inhibited PDE activity. Furthermore, with the exception of theophylline, there was a high degree of correlation between the potency to suppress TNF-alpha production in the cell culture system and the potency to inhibit PDE activity in the cell-free enzymatic assay. This argues for a crucial role of PDE inhibition in the suppression of TNF-alpha synthesis by xanthine derivatives.
 ...
PMID:Xanthine derivatives: comparison between suppression of tumour necrosis factor-alpha production and inhibition of cAMP phosphodiesterase activity. 838 63

Isolated rat islets or RINm5F insulinoma cells treated with interleukin-1 beta (IL-1 beta) for 18 h show reduced glucose-sensitive insulin release and increased nitrite formation as a result of nitric oxide synthase induction. Although a phosphodiesterase inhibitor, isobutylmethylxanthine, potentiated insulin release in response to glucose stimulation, the secretory response was not restored to normal in IL-1 beta-treated islets. Islets that were cultured for 18 h in the presence of IL-1 beta and epiandrosterone (EA) or dehydroepiandrosterone (DHEA) and then washed responded with a concentration-dependent reversal of the effects of IL-1 beta on insulin release in the presence of a glucose or glucose plus isobutylmethylxanthine stimulus. In contrast, when EA and DHEA were not washed from the islets before determination of insulin release, the presence of EA or DHEA inhibited insulin release in both freshly isolated and cultured islets. Nitrite formation in islets and RINm5F cells in response to IL-1 beta was also significantly reduced during culture with EA or DHEA, although nitrite levels were still elevated above control values. Neither steroid affected cell growth or DNA or protein content. Pyrrolidine dithiocarbamate also reduced IL-1 beta-induced nitrite formation. EA and DHEA inhibited [U-14C]glucose oxidation in islets and RINm5F cells. Comparison of [1-14C]glucose and [6-14C]glucose oxidation in islets and RINm5F cells when EA was present during culture and metabolic determination indicated that EA inhibited glycolysis and the pentose shunt contribution to glucose utilization. Neither IL-1 beta in islets nor DHEA in RINm5F cells inhibited pentose shunt activity, although total glucose oxidation and utilization were inhibited. The effects of DHEA and EA on glucose oxidation were rapidly reversible. EA and DHEA reduced glucose-6-phosphate dehydrogenase activity only when added directly to tissue homogenates. Thus, EA and DHEA antagonize the effects of IL-1 beta on beta-cells. Inhibition of glucose metabolism and pentose shunt activity may protect the cells from nitric oxide synthase activation and related toxicities.
 ...
PMID:Epiandrosterone and dehydroepiandrosterone affect glucose oxidation and interleukin-1 beta effects in pancreatic islets. 875 64

The closely related cytokines bFGF and aFGF regulate the function of bone cells and mineralization. Osteoblasts express PPi-generating nucleoside triphosphate pyrophosphohydrolase (NTPPPH)/nucleotide phosphodiesterase I activity. bFGF and aFGF (10 ng/ml) up-regulated NTPPPH in human SaOS-2 and U2OS osteosarcoma cells, which express osteoblast-like features in culture. The induction was selective as alkaline phosphatase activity was down-regulated and specific as insulin-like growth factor-1 (IGF-1) and interleukin-1 beta (IL-1 beta) were not active. Furthermore, IL-1 beta but not IGF-1 inhibited bFGF-induced up-regulation of NTPPPH. The induced NTPPPH remained predominantly associated with cells. bFGF can induce signaling through pathways including protein kinase A (PKA) and protein kinase C (PKC)-mediated transduction. An activator of the PKA pathway (8-bromo cyclic adenosine monophosphate [cAMP]) induced NTPPPH. Furthermore, pretreatment with the PKC activator phorbol myristate acetate (PMA) (80 nM) markedly increased subsequent NTPPPH induction by both bFGF and cAMP. The PMA effect was associated with morphologic changes characterized by long, thin intercellular extensions. PKC desensitization also potentially contributed to this effect because the PKC inhibitors staurosporine and H-7 enhanced bFGF-induced and cAMP-induced NTPPPH expression in the absence of morphologic changes. We observed that bFGF induced expression of PC-1, a member of the NTPPPH gene family. The majority of NTPPPH activity was depleted by immunoadsorption using a monoclonal antibody to native human PC-1. bFGF- and aFGF-induced production of PC-1/NTPPPH in osteoblastoid cells may contribute to the effects of FGFs on bone metabolism.
 ...
PMID:Expression of the nucleoside triphosphate pyrophosphohydrolase PC-1 is induced by basic fibroblast growth factor (bFGF) and modulated by activation of the protein kinase A and C pathways in osteoblast-like osteosarcoma cells. 882 42

We studied the effects of various phosphodiesterase (PDE) III inhibitors: amrinone, pimobendan and vesnarinone: a PDE IV inhibitor (Ro 20-1724) and a PDE V inhibitor (E-4021) on the production of cytokines which have been shown to depress myocardial function. Recently developed inotropic agents which inhibit PDE III activity have produced short-term hemodynamic benefits in patients with advanced heart failure, but long-term treatment with these agents has an adverse effect on survival. However, vesnarinone, which has been shown to improve survival dramatically, has an immunomodulating effect and inhibits the production of cytokines. Peripheral blood mononuclear cells obtained from healthy human subjects were stimulated with lipopolysaccharide and each PDE inhibitor was added. After 24 h of incubation, tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and IL-6 in the culture supernatants were measured by an enzyme-linked immunosorbent assay. All three PDE III inhibitors, amrinone, pimobendan and vesnarinone, inhibited TNF-alpha production, but vesnarinone's inhibitory effect was the most prominent. Amrinone and pimobendan enhanced IL-1 beta production, whereas vesnarinone had no effect. Vesnarinone inhibited IL-6 production and pimobendan slightly decreased IL-6 production, whereas amrinone had no significant effect on IL-6 production. The PDE IV inhibitor, Ro 20-1724, decreased the production of IL-1 beta and TNF-alpha and also tended to inhibit IL-6 production; its modulation of cytokine production was similar to the effects of vesnarinone. Because 8Br-cAMP or 8Br-cGMP did not suppress cytokine production, the modulating effects were not considered to result from an increase in cAMP or cGMP. Differential modulation of cytokine production may play a role in the therapeutic effect in heart failure patients who are treated with drugs that have PDE-inhibitory actions. It may be important to study whether the use of dual inhibitors of PDE III and PDE IV is therapeutically more useful for the treatment of heart failure due to their immunomodulating properties.
 ...
PMID:Differential modulation of cytokine production by drugs: implications for therapy in heart failure. 900 65


<< Previous 1 2 3 Next >>