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

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines are soluble peptides that mediate cell-to-cell interactions via specific cell surface receptors. There is a growing body of evidence that cytokines may play an important role in the pathogenesis of heart failure, and the intriguing possibility has been postulated that anticytokine therapy may favorably alter the clinical outcome of heart failure. As cytokines are essentially pleiotropic and redundant in nature, elimination of a single cytokine from the biologic system often fails to have major consequences. Therefore, the prospect has been raised for developing immunomodulating therapy for heart failure, enabling the simultaneous modification of the actions of multiple cytokines. The recently observed clinical benefit of vesnarinone on mortality and morbidity in patients with heart failure has been attributed to this immunomodulation. In the murine model of myocarditis and heart failure, vesnarinone enhanced the cumulative survival rate without affecting virus replication on virus-induced cytopathic effects. Vesnarinone inhibited excessive cytotoxicity of natural killer cells presumably by suppressing activation mediated by K channel inhibition. Vesnarinone also inhibited the production of cytokines. Cytokine inhibitory effects were different from those of other phosphodiesterase inhibitors or direct elevation of intracellular cyclic adenosine monophosphate, suggesting that the effects did not appear to be derived solely from a cyclic adenosine monophosphate-elevating action. Such cytokine regulation also appeared to be different in normal patients and in patients with heart failure. In conclusion, vesnarinone exerts an immunomodulating effect by suppressing natural killer cell activity and inhibiting cytokine production. These findings may hold open the hope that immunomodulation could be a new therapeutic modality. However, further studies on the long-term safety and efficacy of vesnarinone are warranted to establish the eventual status of this agent in the treatment of heart failure.
...
PMID:Vesnarinone: a potential cytokine inhibitor. 889 63

This study was designed to determine the effects of interleukin-1 on basal and prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production by primary and first passage cultures of non-transformed rabbit pigmented and non-pigmented ciliary epithelial cells. Confluent cultures of rabbit pigmented and non-pigmented ciliary epithelial cells were incubated for varying periods of time in serum-free medium with or without interleukin-1 beta, tumor necrosis factor-alpha, bacterial lipopolysaccharide, transforming growth factor-beta 2, cycloheximide, indomethacin and combinations of these agents. Cells were then preincubated for 10 min with serum-free medium plus the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (for basal adenosine 3',5'-cyclic monophosphate production) or serum-free medium containing several concentrations of prostaglandin E2 and 3-isobutyl-1-methylxanthine. In certain experiments isoproterenol, vasoactive intestinal peptide, or forskolin was substituted for prostaglandin E2. Adenosine 3',5'-cyclic monophosphate was then extracted into ice-cold absolute ethanol and measured by radioimmunoassay. Prostaglandin E2 stimulated adenosine 3',5'-cyclic monophosphate production in pigmented and non-pigmented ciliary epithelial cells in a dose-dependent manner. Incubation with interleukin-1 beta (150 U ml-1) increased prostaglandin E2-stimulated, but not basal adenosine 3',5'-cyclic monophosphate production in pigmented ciliary epithelial cells. This interleukin-1 beta-induced enhancement of prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production, called the interleukin-1 effect, was not seen with non-pigmented ciliary epithelial cells. The interleukin-1 effect was dependent upon interleukin-1 beta concentration, time and de novo protein synthesis. The interleukin 1 effect could not be reproduced by replacing interleukin-1 beta with tumor necrosis factor-alpha or bacterial lipopolysaccharide and was specific for prostaglandin E2, since interleukin-1 beta did not enhance isoproterenol-, vasoactive intestinal peptide-, or forskolin-induced adenosine 3',5'-cyclic monophosphate production. Chronic exposure to prostaglandin E2 (during the 3 hr incubation period), with or without interleukin-1 beta in the incubation medium, reduced subsequent prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production. Inhibition of de novo prostaglandin synthesis with indomethacin increased the interleukin-1 effect. The interleukin-1 effect was inhibited by the immunosuppressive cytokine, transforming growth factor-beta 2, in a dose-dependent manner. This is the first report of prostaglandin E2-induced stimulation of adenosine 3',5'-cyclic monophosphate production by pigmented ciliary epithelial cells and of the unique ability of interleukin-1 to increase this effect. The results are consistent with interleukin-1-induced upregulation of prostaglandin E receptors. Since transforming growth factor-beta 2 inhibited this interleukin-1 effect, this immunosuppressive cytokine may exert negative feedback and thus regulate the physiological consequences of the interleukin-1 effect.
...
PMID:Interleukin-1 beta increases prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production in rabbit pigmented ciliary epithelium. 898 69

Injection of the T cell mitogens concanavalin A (Con A) into nonsensitized or of staphylococcal enterotoxin B (SEB) into D-galactosamine (GalN)-sensitized mice is known to cause fulminant liver failure via a cytokine response syndrome with tumor necrosis factor-alpha (TNF) as the plvotal mediator. We examined in vivo whether the phosphodiesterase (PDE) inhibitors motapizone (PDE3-selective) and rolipram (PDE4-selective) affected cytokine release and hepatic injury after T cell activation. Both motapizone as well as rolipram dose-dependently (0.1-10 mg/kg) attenuated the systemic release of TNF and interferon-gamma as initiated by injection of Con A (25 mg/kg) or SEB (2 mg/kg). Although interleukin-4 production was not affected by motapizone or decreased by rolipram, circulating levels of interleukin-10, however, were significantly increased in PDE inhibitor-treated mice compared with controls. Associated with the suppression of the central mediator TNF, motapizone and rolipram protected mice from liver injury in the Con A as well as in the SEB model. Moreover, the combined administration of motapizone plus rolipram at doses which were ineffective when given alone completely protected mice from GalN/SEB toxicity. These data demonstrate that PDE inhibitors effectively attenuate an inflammatory T cell response in vivo and strongly suggest a therapeutic potential as anti-inflammatory drugs in T cell-related disorders. We conclude that cAMP-elevating drugs shift the balance of T cell-derived cytokines from a proinflammatory to an enhanced anti-inflammatory factor release, thus protecting mice from TNF-mediated hepatic failure.
...
PMID:Protection from T cell-mediated murine liver failure by phosphodiesterase inhibitors. 899 81

Elevations of intracellular cyclic AMP, achieved with the use of phosphodiesterase (PDE) inhibitors, cause functional downregulation of most inflammatory cells. Rolipram, an inhibitor selective for the PDE4 isozyme, can markedly downregulate antigen-driven proliferation and cytokine gene expression of unfractionated human peripheral blood mononuclear cells. However, it is unclear whether PDE4 inhibitors in a mixed-cell system exert their immunosuppressive effect on the lymphocyte or on the monocyte fraction. We have used an adherence-based protocol for separating peripheral blood mononuclear cells, isolated from atopic individuals, into lymphocyte and monocyte fractions and have selectively treated these populations with rolipram prior to reconstituting the cell cultures to their original lymphocyte/monocyte proportions. Cellular responses to both ragweed and tetanus toxoid were analyzed for both proliferation and gene expression of proinflammatory cytokines. A dose-dependent downregulation of ragweed- and tetanus toxoid-driven proliferative responses was achieved by pretreatment of lymphocytes from peripheral blood with rolipram. This downregulation was significantly greater than that achieved with pretreatment of monocytes. Pretreatment of both populations failed to show synergistic downregulation of proliferation. Lymphocyte pretreatment with rolipram also resulted in marked downregulation of gene expression for IL-4, IL-5, and interferon-gamma compared to monocyte pretreatment in both ragweed- and tetanus toxoid-driven systems. Interestingly, monocyte pretreatment in these systems resulted in significant downregulation of IL-2 gene expression compared to lymphocyte pretreatment. Flow cytometric analysis failed to show alterations in any of a panel of surface activation and signal transducing molecules by rolipram treatment with or without antigen stimulation. We conclude that, in a mixed cell system, PDE4 inhibitors downregulate antigen-driven proliferation and gene expression of proinflammatory cytokines predominantly through their effects on lymphocytes rather than monocytes.
...
PMID:Differential efficacy of lymphocyte- and monocyte-selective pretreatment with a type 4 phosphodiesterase inhibitor on antigen-driven proliferation and cytokine gene expression. 900 8

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

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.
...
PMID:Suppression of tumor necrosis factor-alpha production by interleukin-10 is enhanced by cAMP-elevating agents. 906 93

Breast cancer cells secrete endothelin-1 (ET-1), which may act as a paracrine mitogen in breast tumours. The paracrine factors and signal transduction pathways responsible for regulating ET-1 production in breast cancer are unknown. In this study we have examined the involvement of the protein kinase A (PKA) signalling pathway in the control of ET-1 secretion in the human breast cancer cell line MCF-7. Treatment of MCF-7 cells with various agents that activate protein kinase A (PKA) through increases in intracellular cAMP levels including forskolin, cholera toxin (ChT), the cAMP analogue 8-Br-cAMP, or the cAMP phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX) all markedly increased ET-1 release. Prostaglandin E2 (PGE2) while stimulating cAMP production, but not inositol lipid hydrolysis also significantly stimulated ET-1 release. Activation of PKC by 2-O-tetradecanoyl phorbol 13-acetate (TPA) also stimulated ET-1 secretion in MCF-7 cells. The PKA inhibitor H-89 attenuated the ET-1 response to PGE2, forskolin and ChT, but not that due to the PKC agonist TPA. The possibility that human breast fibroblasts (HBFs) are a target for ET-1 action with regard to PGE2 production was also investigated, and revealed that while HBFs were unresponsive to ET-1 alone, pretreatment with the cytokine IL-beta greatly potentiated PGE2 release in response to ET-1. In conclusion our results show that activation of either the PKA or PKC signalling pathways in human breast cancer cells increases ET-1 secretion. We also found that HBFs release PGE2 after treatment with ET-1 and that PGE2 itself stimulates ET-1 production in MCF-7 cells. The implication of this potential novel paracrine loop may be significant in view of the high levels of PGE2 and ET-1 found in malignant breast tissues.
...
PMID:Stimulation or endothelin-1 secretion by human breast cancer cells through protein kinase A activation: a possible novel paracrine loop involving breast fibroblast-derived prostaglandin E2. 908 52

Depression of myocardial contractility plays an important role in the development of heart failure; therefore, intensive interest and passion have been generated to develop cardiotonic agents to improve the contractile function of the failing heart. Inotropic agents that increase cyclic AMP, either by increasing its synthesis or reducing its degradation, exert dramatic short-term hemodynamic benefits, but these acute effects cannot be extrapolated into long-term improvement of the clinical outcome in patients with advanced heart failure. Administration of these agents to an energy-starved failing heart would be expected to increase myocardial energy use and could accelerate disease progression. The role of digitalis in the management of heart failure has been controversial, but ironically the drug has now been proved to favorably affect the neurohormonal disorders and its reevaluation is now being intensively investigated. More recently, attention has been focused on other inotropic agents that have a complex and diversified mechanism. Recent clinical studies have demonstrated that they are potentially useful in the long-term treatment of heart failure patients. These agents have some phosphodiesterase-inhibitory action but also possess additional effects, including acting as cytokine inhibitors, immunomodulators, or calcium sensitizers. However, their therapeutic ratio is narrow and further studies are warranted to establish their optimal doses and their eventual status in the treatment of heart failure.
...
PMID:Inotropic agents in the treatment of heart failure: despair or hope? 911 Jan 13

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.
...
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

T cell activation in vivo results in proliferation and generation of effector cytokine-secreting cells, as also in development of memory cells that mount enhanced responses upon restimulation. However, differences in the signals promoting generation of effector vs memory T cells are not yet characterized. In this study, using various strategies to modulate an allorecognition system for priming human T cells in vitro, we show that there are indeed differences between the signaling requirements for a first proliferative response and those for priming T cells for enhanced recall proliferative responses. Using APCs fixed with varying concentrations of paraformaldehyde, we show that the loss of ability of these APCs to generate a first response is not matched by a similar loss in their ability to prime responder T cells for recall responses. Prevention of DNA replication during T cell priming with aphidicolin, a DNA polymerase inhibitor, is not inimical to successful T cell priming. Thus, clonal expansion during priming is less crucial than the primed activation status of T cells for the enhanced recall response. We also show that pentoxifylline, a phosphodiesterase inhibitor, inhibits the primary proliferative response, but its presence during priming enhances the recall response capabilities of T cells. On the other hand, the presence of the calcineurin inhibitor cyclosporin A during priming reduces the efficiency of priming, but at low concentrations it induces, like pentoxifylline, enhancement in recall response capability. These findings have significant implications in designing immunosuppressive therapy and in the analysis of signals for T cell memory commitment.
...
PMID:Differential regulation of T cell activation for primary versus secondary proliferative responses. 912 70


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---