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)

We have previously shown that recombinant interleukin 1 (IL-1) and recombinant tumour necrosis factor (TNF) synergistically stimulate phospholipase A2 release from mesangial cells. We now report that treatment of mesangial cells with the beta-agonist salbutamol, prostaglandin E2 (PGE2), cholera toxin or forskolin, which all activate adenylate cyclase, increased release of phospholipase A2 activity. Likewise, addition of a membrane-permeant cyclic AMP (cAMP) analogue or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine enhanced release of phospholipase A2 activity from mesangial cells. There was a lag period of about 8 h before a significantly enhanced secretion could be detected. Furthermore, actinomycin D or cycloheximide completely suppressed cAMP-stimulated secretion of phospholipase A2. Angiotensin II, the phorbol ester phorbol 12-myristate 13-acetate, the Ca2+ ionophore A23187 and a membrane-permeant cGMP analogue did not stimulate phospholipase A2 release from the cells. Treatment with indomethacin completely inhibited IL-1 beta- and TNF-stimulated PGE2 synthesis, without having any effect on phospholipase A2 secretion, thus excluding cytokine-induced PGE2 synthesis as the mediator of phospholipase A2 release. Neither IL-1 beta nor TNF induced any increase in intracellular cAMP in mesangial cells. Furthermore, incubation of the cells with 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, did not block cytokine-stimulated phospholipase A2 secretion. In addition, IL-1 beta and TNF synergistically interacted with forskolin to stimulate phospholipase A2 release from the cells. The protein kinase inhibitors H-8, staurosporine, K252a and amiloride inhibited IL-1 beta- and TNF-stimulated phospholipase A2 secretion. However, high concentrations that inhibit other protein kinases were needed. These observations suggest that IL-1 beta and TNF cause secretion of phospholipase A2 by a mechanism independent of cAMP. The signalling pathways used by IL-1 beta and TNF may involve a protein kinase that is probably different from protein kinase A or protein kinase C.
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PMID:Cyclic AMP mimics, but does not mediate, interleukin-1- and tumour-necrosis-factor-stimulated phospholipase A2 secretion from rat renal mesangial cells. 184 28

Recent reports have shown that phosphodiesterase (PDE) inhibitors suppress production of tumour necrosis factor-alpha (TNF-alpha) in mouse macrophages. In the present study we show that theophylline, pentoxifylline and 3-isobutyl-1-methylxanthine markedly suppress the lipopolysaccharide (LPS)-induced synthesis of TNF-alpha (also) in human mononuclear cells. This effect is selective for TNF-alpha since up to several-fold higher concentrations of these PDE inhibitors do not affect production of interleukin-1 beta (IL-1 beta) in the same system. The observed effect of PDE inhibitors appears to be mediated by accumulation of cAMP since (i) addition of PDE inhibitors increases cAMP while cGMP levels are only marginally elevated; (ii) raising cAMP by another mechanism (enhanced formation induced by prostaglandin E2; PGE2) leads to a similar suppression of TNF-alpha production; and (iii) raising cGMP by activating the soluble guanylate cyclase by 3-morpholinosydnonimine (SIN 1) does not inhibit TNF-alpha synthesis. However, SIN 1 suppressed the synthesis of IL-1 beta. Selective suppression of TNF-alpha synthesis by PDE inhibitors may contribute to their beneficial effects in animal models of septic shock or lung injury and may thus have clinical implications.
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PMID:Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-alpha and interleukin-1 beta by human mononuclear cells. 184 94

The process of signal transduction by interleukin 1 (IL-1) or tumor necrosis factor alpha (TNF alpha) for the production of hematopoietic growth factors by cultured fibroblasts was studied using inhibitors for protein kinase C, cyclic nucleotide-dependent protein kinases, calmodulin-dependent protein kinases, and the Na(+)-H+ antiport system. The protein kinase C inhibitor H-7 was shown to inhibit both IL-1 beta- and TNF alpha-induced granulocyte-macrophage colony-stimulating activity (GM-CSA) production and release from cultured fibroblasts in a dose-dependent manner, with 40 microM H-7 demonstrating maximum suppression of the GM-CSA response. In addition, 100-200 nM staurosporine, a more potent inhibitor of protein kinase C, also completely suppressed GM-CSA from IL-1 beta- and TNF alpha-induced fibroblasts. In contrast, a potent inhibitor of cyclic nucleotide-dependent protein kinases, HA1004, showed no effect when used at 10-40 microM. In addition, an inhibitor of calmodulin-induced protein kinases, W-7, also showed no effect when used at 10-30 microM. Prior incubation with H-7 did not inhibit the ability of fibroblasts to subsequently respond to IL-1 beta or TNF alpha, nor did H-7 directly inhibit the granulocyte-macrophage colony-forming assay. Both dibutyryl cyclic adenosine monophosphate (10-30 microM) and forskolin (1-100 nM), activators of adenylate cyclase, in the presence or absence of the phosphodiesterase inhibitor isobutylmethylxanthine, failed to stimulate a GM-CSA response from cultured fibroblasts, indicating a lack of effect of cyclic nucleotide-dependent protein kinases. Furthermore, the addition of H-7 30 min after induction with IL-1 beta or TNF alpha showed little effect on the synthesis of GM-CSA by cultured fibroblasts, indicating that the signal transduction process probably occurred within the first 30 min of ligand-receptor interaction. Finally, amelioride, an inhibitor of the Na(+)-H+ antiport, was shown to inhibit IL-1 beta-induced GM-CSA in a dose-dependent manner.
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PMID:The role of protein kinase C in interleukin 1 and tumor necrosis factor alpha induction of fibroblasts to produce and release granulocyte-macrophage colony-stimulating activity. 216 34

Peri-tumoral injection of recombinant human interleukin-1 beta in mice transplanted s.c. with Friend erythroleukemia cells (FLC) resulted in marked inhibition of tumor growth and increased survival. However, in vitro treatment of FLC (745 or 3Cl-8) with IL-1 beta barely inhibited cell multiplication. IL-1 beta, injected into established solid tumors, induced marked morphologic changes. Vascular congestion and focal extravasation of erythrocytes were observed as early as 6 hr after injection with IL-1 beta of FLC and L1210 tumors and HeJ16 fibrosarcomas. Focal areas of disaggregation of tumor cells and tumor necrosis were observed 6 and 24 hr after IL-1 injection. These morphologic changes were similar to those observed in FLC tumors or HeJ16 fibrosarcomas treated with TNF-alpha or beta. These cytokines determined morphological changes in tumor blood vessels of FLC tumors within 1 hr of injection. Freshly dissected FLC tumors and their tissue extracts were studied by Nuclear Magnetic Resonance (NMR) spectroscopy, shortly after peri-tumoral injection of IL-1 beta or TNF-beta. After 6 hr, both cytokines induced a 3-fold reduction in the levels of two catabolites, glycerophosphorylcholine and glycerophosphorylethanolamine, an accumulation of sn-glycerol 3-phosphate and a more than 10-fold increase in the choline/phosphorylcholine ratio. These results are similar to those reported for TNF-alpha, and can be interpreted on the basis of an activation of glycerophosphorylcholine phosphodiesterase (EC 3.1.4.2) and partial inhibition of choline kinase (EC 2.7.1.32). IL-1 beta and TNF-beta (like TNF-alpha) also induced alkaline shifts (0.10-0.25 units) in the average intratumoral pH value. We suggest that alterations of tumor blood vessels may be the primary events in solid tumors treated with IL-1 beta or TNF. Such alterations lead to early changes in tumor metabolism and subsequent tumor cell degeneration.
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PMID:Interleukin-1 beta induces tumor necrosis and early morphologic and metabolic changes in transplantable mouse tumors. Similarities with the anti-tumor effects of tumor necrosis factor alpha or beta. 278 94

Interleukin-1 beta (IL-1 beta) increased the production of cyclic AMP and prostaglandin E2 (PGE2) by cultured human decidual cells during 24 h of stimulation, but not over short incubation times (< 6 h). At concentrations of IL-1 beta ranging from 1 to 100 pg/ml, there were parallel changes in cyclic AMP and PGE2 levels, but 1000 pg of IL-1 beta/ml inhibited cyclic AMP production while still stimulating PGE2 synthesis. The possible link between cyclic AMP and PGE2 was therefore studied further. Inhibition of IL-1 beta-stimulated PGE2 synthesis by indomethacin and direct addition of PGE2 had no effect on cyclic AMP levels, indicating that PGE2 did not increase cyclic AMP production by human decidual cells and confirming the independent synthesis of cyclic AMP and PGE2. The increase in cyclic AMP production induced by IL-1 beta is dependent on protein synthesis, but it is not known which component of the adenylate cyclase is increased. A phosphodiesterase inhibitor potentiated the effects of IL-1 beta on cyclic AMP synthesis, indicating that the cytokine may increase cyclic AMP metabolism. We suggest that high concentrations of IL-1 beta activate phosphodiesterase activity more than adenylate cyclase, which gives rise to the low levels of cyclic AMP noted above. IL-1 beta also decreased forskolin-stimulated cyclic AMP production, which again indicates increased cyclic AMP metabolism. Since most concentrations of IL-1 beta alone increased cyclic AMP levels, this stimulation must out-weigh the increase in metabolism apparent in the presence of forskolin, phosphodiesterase inhibitor or high levels of interleukin. It is clear that IL-1 beta increased decidual PGE2 production independently of cyclic AMP, and that other second messenger must mediate the action of this cytokine.
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PMID:Interleukin-1 beta independently stimulates production of prostaglandin E2 and cyclic AMP from human decidual cells. 748 46

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

Exposure of human monocytes (HM) to E. coli lipopolysaccharide (LPS) results in measurable production of both IL-1 beta and TNF alpha in culture supernatants. It has previously been reported that the elevation of cAMP levels in HM selectively suppresses the LPS-induced TNF alpha but not IL-1 beta production. In this study we investigated whether the novel anti-inflammatory drug, SK&F 86002 [5-4(-pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazole(2,1-b)thi azol] and related analogs of the pyridinyl imidazole class, inhibit IL-1 and TNF production via a cAMP-dependent mechanism. These compounds, when added together with LPS result in inhibition of IL-1 and TNF production with equal-rank-order potency. Although the pyridinyl imidazole compounds were found to be generally weak phosphodiesterase inhibitors, they did not affect cAMP levels in HM, alone or in the presence of LPS. In contrast, PGE2, which significantly elevated intracellular cAMP levels, inhibited TNF but not IL-1 production at the transcriptional level. Taken together, these results suggest that the pyridinyl imidazoles inhibit the production of IL-1 beta and TNF alpha through pathways independent of cAMP elevating mechanisms.
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PMID:Inhibition of interleukin-1 (IL-1) and tumor necrosis factor (TNF) production by pyridinyl imidazole compounds is independent of cAMP elevating mechanisms. 750 4

1. Treatment of rat mesangial cells with interleukin 1 beta (IL-1 beta) or tumour necrosis factor alpha (TNF alpha) has been shown to induce a macrophage-type of nitric oxide (NO) synthase. Here we report that adenosine 3':5'-cyclic monophosphate (cyclic AMP) is another mediator that triggers induction of NO synthase in mesangial cells. 2. Incubation of mesangial cells with the beta-adrenoceptor agonist, salbutamol, forskolin or cholera toxin, which all activate adenylate cyclase and increase intracellular cyclic AMP concentration, increased nitrite formation in a dose-dependent manner. Likewise, the addition of the membrane-permeable cyclic AMP analogue, N6, 0-2'-dibutyryladenosine 3',5'-phosphate (Bt2 cyclic AMP) or the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine enhanced NO synthase activity in a dose-dependent manner. 3. There was a lag period of about 8 h before a significantly enhanced secretion of nitrite could be detected upon exposure of cells to forskolin and for maximal stimulation, forskolin had to be present during the whole incubation period. 4. Treatment of mesangial cells with actinomycin D, cycloheximide or dexamethasone completely suppressed forskolin-stimulated NO-synthase activity, thus demonstrating that transcription and protein synthesis are necessary for nitrite formation. 5. Bt2 cyclic AMP, the most potent inducer of nitrite production, increased NO synthase mRNA levels in mesangial cells in a time- and dose-dependent fashion. Dexamethasone completely inhibited the increase of NO synthase mRNA in response to Bt2 cyclic AMP. 6. Combination of Bt2 cyclic AMP and IL-1 beta or TNF alpha revealed a strong synergy in terms of nitrite formation. Time-course studies indicated that cyclic AMP needed to be increased during the whole period of IL-1 Beta stimulation for maximal nitrite production.7. These observations suggest that cyclic AMP controls NO synthase expression in mesangial cells.Furthermore, the signalling cascades triggered by IL-1 Beta and TNF alpha synergize with the cyclic AMP pathway to stimulate NO synthase activity.
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PMID:Expression of nitric oxide synthase in rat glomerular mesangial cells mediated by cyclic AMP. 751

1. Interleukin-1 beta (IL-1 beta) is a potent stimulant of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production in vascular smooth muscle (VSM) cells in culture. These studies investigate the role of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in this process. 2. Dibutyryl cyclic AMP (db cyclic AMP, 0.1-1 mM), forskolin (1-10 microM) and the phosphodiesterase inhibitor, Ro 20-1724 (1-10 microM), all of which increase intracellular cyclic AMP, had no effect on NO production when added alone but markedly enhanced NO production by IL-1 beta-stimulated VSM cells in a dose-dependent manner. Consistent with a cyclic AMP-mediated action, isoprenaline (1-10 microM) increased NO production from IL-1 beta-stimulated cells. Dibutyryl cyclic GMP (db cyclic GMP) had no effect at concentrations up to 1 mM. 3. Pursuing these observations, iNOS protein levels were examined by Western blot analysis and iNOS mRNA levels were measured by reverse transcription and amplification of the resultant cDNA using the polymerase chain reaction. In addition to enhancing NO production, db cyclic AMP increased iNOS protein and mRNA above that produced by IL-1 beta alone. 4. These data demonstrate a major effect of cyclic AMP on cytokine-induced NOS activity in VSM cells, mediated at least in part by regulating synthesis of iNOS, and has implications for the pathogenesis and management of septic shock.
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PMID:Induction of nitric oxide synthase in cultured vascular smooth muscle cells: the role of cyclic AMP. 752 Dec 56

We have previously shown that activation of the phosphatidyl-inositol/phospholipase C pathway could induce interleukin 6 (IL-6) release from U373MG human astrocytomes cells. We also found that, although interleukin 1 beta (IL-1 beta) did not activate phosphatidy-linositol turnover, it induced, a robust release of IL-6. In the present study, we examined the role of adenylate cyclase/cyclic 3',5'-adenosine monophosphate (cAMP) pathway in IL-6 release. Agents which mimicked (dibutyryl cAMP) or stimulated (isoproterenol and forskolin) cAMP formation were found to induce IL-6 release and their effects could be potentiated by 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor. On the other hand, in spite of its robust action on IL-6 release, IL-1 beta did not stimulate cAMP formation. Other possible signal transduction mechanisms involved in IL-1 beta-induced IL-6 release are discussed.
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PMID:cAMP is not involved in interleukin-1-induced interleukin-6 release from human astrocytoma cells. 752 12


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