Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although several cytokines have been demonstrated to exert pleiotropic responses, there is little information on cytokine regulation of renal tubular epithelial cell function. In the present studies, we find that both T cell-derived (tumor necrosis factor-beta and interleukins 2 and 3) and monocyte/macrophage derived (tumor necrosis factor alpha and interleukin 1 beta) cytokines promote basal, arginine vasopressin- and forskolin-stimulated adenylate cyclase activity in cultured LLC-PK1 cells. No effect of TNF, IL-1 beta, and IL-2 to stimulate protein kinase C activity was observed. TNF-beta, IL-1 beta and IL-2 also modestly stimulated 3H release from 3H-arachidonic acid labeled cells. Mepacrine, a phospholipase A inhibitor, prevented TNF-beta stimulation of 3H release from 3H-arachidonic acid labeled cells and TNF-beta potentiation of adenylate cyclase activity. TNF-beta potentiation of adenylate cyclase activity and stimulation of 3H release from 3H arachidonic acid labeled cells was not prevented by pertussis toxin. These results demonstrate that several cytokines can stimulate adenylate cyclase activity while not affecting protein kinase C activity in cultured renal tubular epithelial cells. The effect of TNF-beta to stimulate adenylate cyclase appears to occur independent of pertussis toxin-sensitive substrate and may involve activation of phospholipase A.
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PMID:Cytokine regulation of adenylate cyclase activity in LLC-PK1 cells. 140 34

In the present study we evaluated the effect of interleukin 1-beta on adenylate cyclase activity in 235-1 pituitary cell line. The dose-response curve of interleukin 1 beta effect on adenylate cyclase activity showed a significant inhibition of basal enzyme activity at 1 pM concentration, while the inhibition of forskolin stimulated adenylate cyclase activity was more pronounced and evident at both 0.01 and 1 pM concentrations. The action of the monokine on basal enzyme activity was almost completely reverted by polyclonal anti interleukin 1 beta antibody. The incubation of the cells for 48h with interleukin 1 beta showed a different pattern of response. The inhibitory effect of interleukin 1 beta on adenylate cyclase activity disappeared, while the highest concentration of interleukin 1 beta tested, caused a meaningful stimulation of adenylate cyclase activity which is not present in acute condition. These data show that interleukin 1-beta interacts with the cAMP-generating system in the 235-1 clonal pituitary cells.
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PMID:Effect of interleukin 1 beta on transducing mechanisms in 235-1 clonal pituitary cells. Part I: Modulation of adenylate cyclase activity. 326 20

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

The inflammatory cytokine interleukin 1 beta (IL-1 beta) induces both cyclooxygenase (COX) and nitric oxide synthase (NOS) with increases in the release of prostaglandin (PG) and nitric oxide (NO) by mesangial cells. Recently, activation of the COX enzyme by NO has been described. However, the effects of COX products (PGs) on the NO pathway have not been fully clarified. Thus we determined the effect of COX inhibition and exogenous PGs on NO production and NOS induction in rat mesangial cells. A COX inhibitor, indomethacin, enhanced IL-1 beta-induced steady-state level of the inducible NOS (iNOS) mRNA and nitrite production. The effect of indomethacin was dose dependently reversed by the replacement of endogenous PGE2 with exogenous PGE2, which is the predominant product of the COX pathway in rat mesangial cells. In contrast to PGE2, a stable analog of PGI2, carba prostacyclin, enhanced IL-1 beta-induced iNOS mRNA levels and nitrite production. Forskolin, an activator of the adenylate cyclase, mimicked the effect of carba prostacyclin but not PGE2. These data suggest that (i) endogenous PGE2 downregulates iNOS induction, (ii) this inhibitory effect of PGE2 on iNOS induction is not mediated by activation of adenylate cyclase, and (iii) exogenous PGI2 stimulates COX induction possibly by activation of adenylate cyclase.
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PMID:Cross-talk between cyclooxygenase and nitric oxide pathways: prostaglandin E2 negatively modulates induction of nitric oxide synthase by interleukin 1. 752 54

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

In cultured vascular smooth muscle cells, interferon gamma (IFN-gamma) induced the accumulation of nitrite, a stable metabolite of nitric oxide, in a dose- and time-dependent manner. In parallel with this reaction, this cytokine increased the mRNA and protein levels of an inducible macrophage-type of nitric oxide synthase (iNOS). Forskolin, a direct activator of adenylate cyclase, or dibutyryl cAMP alone caused small increases in nitrite accumulation and iNOS mRNA and protein levels and synergistically enhanced the IFN-gamma-stimulated reactions. 8-Bromo-cGMP neither increased by itself nor synergized with IFN-gamma to increase the same reactions. Prostaglandin E1 and beraprost, a stable analogue of prostaglandin I2, which by themselves showed only marginal effects on these reactions, also synergized with IFN-gamma to stimulate the reactions. Interleukin 1 beta or tumor necrosis factor alpha stimulated the same reactions which were similarly enhanced by forskolin. These results indicate that an elevation of intracellular cAMP, particularly in combination with inflammatory cytokines, positively regulates nitric oxide production at the level of iNOS mRNA expression in vascular smooth muscle cells.
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PMID:Cyclic AMP-elevating agents induce an inducible type of nitric oxide synthase in cultured vascular smooth muscle cells. Synergism with the induction elicited by inflammatory cytokines. 769 10

We have recently shown that interleukin 1 beta (IL-1 beta) directly reduces the number of adipocytes in cultures of human bone marrow (BM) stromal cells. The aim of the present study was to establish the mechanisms involved in the IL-1 effect and thereby assess its importance in BM pathophysiology. Direct morphological observation showed that individual adipocytes lost their fat in the presence of IL-1 beta and regained it when the cytokine was withdrawn. These morphological observations were supported by metabolic studies using [14]acetate as a precursor of storage fat. These metabolic studies showed that IL-1 beta inhibited the incorporation of label into triglycerides. In addition, the cytokine enhanced the release of radioactivity from prelabelled adipocytes and reduced their triglyceride stores. It was therefore concluded that IL-1 beta can both inhibit lipogenesis and stimulate lipolysis in BM adipocytes. Forskolin (an adenylate cyclase activator) produced lipolytic effect similar to those of IL-1 beta, while indomethacin (an inhibitor of prostaglandin [PG] production) fully blocked the release of radioactivity induced by IL-1 beta and greatly increased triglyceride synthesis. However, IL-1 beta was still able to decrease triglyceride synthesis in the presence of indomethacin. These results indicate that a prostaglandin-dependent increase in cAMP is important to in the lipolytic effects of IL-1 beta but that the anti-lipogenic effects of the cytokine are, at least in part, independent of PG synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The metabolic effects of interleukin 1 beta on human bone marrow adipocytes. 858 64

Addition of lipopolysaccharide plus interferon gamma, tumour necrosis factor alpha and interleukin 1 beta to cultured hepatocytes resulted in the induction of inducible nitric oxide synthase (iNOS) activity as measured by NO3(-)+NO2- formation, the conversion of L-[U-14C]arginine into citrulline and Western blotting of the iNOS protein. The inclusion of 1 microM glucagon during the induction period significantly decreased the effect of the cytokines on iNOS activity, the major effect being at the level of the total amount of protein, rather than alterations in substrate supply or covalent modification of the existing protein. In contrast, 1 microM insulin was without effect. The effect of glucagon was mediated via cAMP and could be mimicked by the presence of either dibutyryl cAMP or forskolin to activate adenylate cyclase directly. It was rapid in onset and long-lived, a 30 min pretreatment period protecting the cells from the induction of NO synthesis over the next 21 h in the presence of cytokines. Addition of glucagon at any time point up to 9 h after treatment of the cells with lipopolysaccharide plus the cytokines resulted in a significant inhibition of iNOS activity, glucagon being most potent when added during the first 3 h.
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PMID:Inhibition of cytokine-induced inducible nitric oxide synthase expression by glucagon and cAMP in cultured hepatocytes. 933 67