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)

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

Pentoxifylline (PTX), a methylxanthine derivative and phosphodiesterase inhibitor, is known to influence production and/or function of some cytokines. We examined the effect of PTX on the in vitro expression of cytokine genes using endotoxin- or phytohaemagglutinin (PHA)-stimulated human blood mononuclear cells. The expression of tumour necrosis factor (TNF)alpha, TNF beta interleukin (IL)-2 and interferon (IFN)gamma was inhibited by PTX in a dose-dependent manner, whereas expression of IL-1 alpha, IL-1 beta, and IL-6 was unaffected at concentrations up to 300 microM of PTX. The amount of TNF beta mRNA in PHA-stimulated blood mononuclear cells was reduced by PTX. Finally, PTX stimulated PHA-induced cell proliferation whereas antigen-induced cell proliferation was inhibited in the presence of PTX. The PTX analogues HWA-138 and A-802715 inhibited TNF alpha mRNA expression from endotoxin-stimulated mononuclear cells. These data suggest that PTX-analogues affect the in vitro immune response at different target points and that the response depends upon the respective triggering mechanism(s).
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PMID:In vitro immunomodulatory effects of pentoxifylline. 750

We have recently shown that PGE2 inhibits the release of TNF-alpha from LPS-stimulated murine peritoneal macrophages via a feedback mechanism involving IL-10. Here we demonstrate that a rolipram-sensitive phosphodiesterase (PDE) type IV participates in the regulation of IL-10 synthesis. Selective PDE IV inhibitors (rolipram and RO-20-1724), but not selective inhibitors of other types of PDE, significantly augment marcrophage IL-10 production and contribute to the inhibition of TNF-alpha and IL-6 release. The addition of rolipram to LPS-stimulated macrophages results in the accumulation of cAMP and in the significant augmentation of IL-10 release. Competitive PCR analysis reveals that the drug dramatically increases IL-10 mRNA, but does not affect TNF-alpha mRNA. The inhibitory effect of rolipram on TNF-alpha can be significantly but incompletely reversed by anti-IL-10 Ab, whereas the effect of the drug on IL-6 can be completely reversed by anti-IL-10. In endotoxemic mice, the administration of rolipram increases serum IL-10 and reduces TNF-alpha and IL-6 levels. Northern blot analysis of spleens from these mice shows that rolipram increases IL-10 mRNA, whereas TNF-alpha mRNA remains largely unchanged. These results suggest that a rolipram-sensitive PDE type IV is involved in the production of IL-10 and in turn contributes to the inhibition of TNF-alpha and IL-6 release.
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PMID:Cyclic nucleotide phosphodiesterase type IV participates in the regulation of IL-10 and in the subsequent inhibition of TNF-alpha and IL-6 release by endotoxin-stimulated macrophages. 759 95

The immunologic aberrations associated with atopic dermatitis include the paradox of reduced cell-mediated immune responses in the setting of increased cell-mediated immunity features that resemble allergic contact dermatitis. In this review, we present evidence that abnormalities in monocytes and Langerhans cells alter the function of T-helper-cell subpopulations to cause the immunologic defects associated with atopic dermatitis. Increased monocyte prostaglandin E2 production inhibits Th1 responses, accentuating interleukin (IL)-4 secretion by Th2 cells. Elevated prostaglandin E2 secretion correlates with abnormally increased cyclic adenosine monophosphate-phosphodiesterase activity in monocytes and this, along with other defective inflammatory cell responses, can be normalized in vitro by phosphodiesterase inhibitors. It appears that in addition to prostaglandin E2, IL-10 acts to regulate the balance between Th1 and Th2 functional responses accounting for many atopic features, including increased IL-4, IL-5, and IL-6 production by T cells; increased IgE synthesis; decreased interferon-gamma production; and impaired cell-mediated immune responses. All of these abnormalities can be related to increased phosphodiesterase activity in atopic monocytes, and inhibition of this key enzyme appears to reverse atopic dermatitis inflammatory abnormalities in vitro and in vivo.
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PMID:Monocyte phosphodiesterase abnormalities and dysregulation of lymphocyte function in atopic dermatitis. 761 4

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.
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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.
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PMID:Effects of rolipram on responses to acute and chronic antigen exposure in monkeys. 817 55

The phosphodiesterase inhibitor pentoxifylline (POX), which is known to have pharmacological effects in animal models of multiorgan failure and endotoxin-mediated shock, was tested for its immunosuppressive potential on T lymphocyte activation in vitro and in vivo. POX was found to have a profound inhibitory effect on both mitogen- and antigen-induced proliferation of CD4+ T cells in vitro. This inhibitory activity of the drug could be reproduced by treating T lymphocytes with cAMP analogues during stimulation. Responses of repeatedly in vitro stimulated cells were much more strongly inhibited by the drug and by cAMP analogues than responses of fresh resting lymphocytes. Furthermore, POX could drastically down-regulate tumor necrosis factor regulate production and to a lesser extent interleukin (IL)-2 secretion in activated T cells, but an excess of exogenous IL-2 did not override the antiproliferative effect of the drug. In contrast, the same doses of POX had no inhibitory effect on spontaneous or induced IL-4 and IL-6 production by short-term cultured T lymphocytes, indicating a selective sparing of T helper type 2 (Th2)-associated lymphokine functions by the drug. To test a potential use of POX as an antiinflammatory agent in T cell-mediated autoimmune disease, the influence of POX on myelin basic protein (MBP)-induced experimental autoimmune encephalomyelitis (EAE) was assessed. The onset of EAE in Lewis rats could almost completely be abrogated by oral administration of POX during the induction phase of disease. Lack of clinical symptoms in POX-treated animals coincided with a marked suppression of MBP-specific T cell reactivity in vitro, without any evidence for a generalized impairment of T cell activity. Collectively, our data suggest the potential use of xanthine derivatives of the POX type as a supporting antiinflammatory therapeutic agent in Th1 CD4+ T cell-mediated autoimmune diseases in animal models and possibly in man.
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PMID:Phosphodiesterase inhibitor pentoxifylline, a selective suppressor of T helper type 1- but not type 2-associated lymphokine production, prevents induction of experimental autoimmune encephalomyelitis in Lewis rats. 839 96

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.
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PMID:Differential modulation of cytokine production by drugs: implications for therapy in heart failure. 900 65

Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. We have recently compared the effects on cytokine production of drugs for therapy of heart failure that have different effects on survival. Amrinone, pimobendan and vesnarinone, phosphodiesterase III inhibitors that have been shown to have short term haemodynamic benefits, inhibited TNF-alpha production. Differential modulation of the production of IL-1beta and IL-6 was observed; amrinone and pimobendan enhanced the production of IL-1beta, whereas vesnarinone did not. As inotropic agents differentially modulate cytokine production, these agents may interfere with induction of inducible nitric oxide (NO) synthase through an inhibition of cytokine formation. Although differential modulation of the production of NO by inotropic agents may explain their different effect in patients with heart failure, further study is necessary to reach this conclusion. We have shown that amlodipine increases the survival of mice with viral myocarditis and inhibits expression of inducible NO synthase and production of NO in vivo and in vitro. The therapeutic effect of amlodipine may in part result from inhibition of overproduction of NO. As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure, it should be possible to design better and more targeted pharmacological agents. Furthermore, the investigation of inotropic agents that are effective against the production of cytokines may help in the classification of these agents.
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PMID:The use of cytokine inhibitors. A new therapeutic insight into heart failure. 946 76

The immunomodulatory drug thalidomide has been shown to be clinically useful in a number of situations due to its ability to inhibit TNF-alpha synthesis. However, its use is restricted by potentially serious side effects, including teratogenicity and neuorotoxicity; furthermore, insolubility may present problems in terms of systemic bioavailability. Recently, structural modifications of thalidomide have been designed enabling greatly enhanced anti-TNF-alpha activity in LPS-treated mice. In contrast to thalidomide (LPS-induced TNF-alpha IC50 approximately 200 microM in DMSO) and other analogs tested, one of these compounds, CC-3052 (IC50 approximately 1 microM in water), is water soluble. Furthermore, this analog exhibits increased stability in human plasma (t(1/2) approximately 17.5 vs 1.5 h for thalidomide) and appears to be nontoxic, nonmutagenic, and nonteratogenic. At pharmacologically active levels, cellular proliferation and LPS-induced IL-6 mRNA and IL-12p40 mRNA (as well as IL-1beta and IL-6 protein levels) in whole blood cultures were not affected; apparent inhibition of NK activity by CC-3052 was reversed upon addition of exogenous rTNF-alpha. In addition, IL-10 mRNA and protein levels were increased. These properties are consistent with results indicating inhibition of phosphodiesterase type IV activity by CC-3052. Furthermore, CC-3052 did not increase the degradation rate of macrophage TNF-alpha transcripts nor inhibit LPS-induced primary macrophage NF-kappaB activation. Taken together, the potency of selective TNF-alpha inhibition, water solubility, and increased plasma stability make CC-3052 an excellent candidate for further development and clinical evaluation for the treatment of TNF-alpha-mediated disease.
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PMID:CC-3052: a water-soluble analog of thalidomide and potent inhibitor of activation-induced TNF-alpha production. 978 Jan 98


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