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)

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

Human neutrophils were incubated with granulocyte-macrophage (GM)-CSF and examined for changes in second messenger systems. Twofold increases in cGMP but not cAMP were measured after 5 to 20 min with 100 U/ml GM-CSF. Guanylate cyclase activities in membrane and cytosol fractions were increased to the same extent whether measured in the presence of Mg2+ or Mn2+, or in the cytosol with Mg2+ + N-methyl-N'-nitro-N-nitroso-guanidine. Kinetic studies of the cytosol enzyme showed no changes in the Km values for Mg2+ and Mn2+dependent guanylate cyclase activities (0.91 and 0.022 mM, respectively), whereas Vm values were increased after treating intact cells with GM-CSF. Two peaks of guanylate cyclase activity were observed, one at 10 and another at 60 min after adding 100 U/ml GM-CSF, whereas only one peak at 5 min occurred with 1 U/ml. Adenylate cyclase activity was reduced by nearly 50% after adding 100 U/ml GM-CSF for 10 to 30 min. These effects were also seen in the presence of several hormonal and nonhormonal adenylate cyclase stimulators. In contrast, small increases in adenylate cyclase activity occurred after adding 1 U/ml GM-CSF. In experiments to examine the pathway of guanylate cyclase activation by GM-CSF, we observed no changes in inositol phosphates, intracellular calcium ion, or cytosolic protein kinase C. The augmentation of chemotactic peptide-induced superoxide production by GM-CSF concentrations, may be related to the effects of the higher levels of GM-CSF to stimulate late increases in guanylate cyclase or decreases in adenylate cyclase.
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PMID:Stimulation of guanylate cyclase activity and reduction of adenylate cyclase activity by granulocyte-macrophage colony-stimulating factor in human blood neutrophils. 289 92

Ouabain has been shown to increase the number of clonally derived erythroid stem cells, CFUE and BFUE, from normal murine bone marrow. We report here that digoxin and theophylline also enhance erythroid stem cell colony formation, in the presence of suboptimal concentrations of erythropoietin (Ep) (0.01 IU/ml) in methylcellulose culture. Both digoxin and theophylline increased CFUE colony formation optimally at 10(-8) M (29-81% respectively). The increase in BFUE colony formation occurred at 10(-10) M (35-76% respectively), suggesting that BFUE are more sensitive to the enhancing properties of these compounds. In addition, digoxin theophylline and ouabain were effective inhibitors of clonally derived granulocyte-macrophage progenitor cells, CFUC, from normal murine marrow plated in double layer agar in the presence of 10% L-cell conditioned medium (LCM). The degree of reduction in colony formation by CFUC ranged from 11% to 100%. Digoxin and theophylline were inhibitory for CFUC in the range of 10(-2) to 10(-12) M; however, ouabain was inhibitory over a broader concentration range of 10(-4) to 10(-18) M, suggesting that ouabain has a greater influence on committed hematopoietic progenitor cell colony formation. Both ouabain and digoxin have the property of binding to Na+/K+ATPase. This may mediate the alteration of hematopoietic differentiation. Theophylline, an adenyl cyclase inhibitor, may act through alterations in cyclic nucleotide levels. These studies further indicate that digoxin, theophylline and ouabain may serve as useful tools in elucidating the underlying mechanisms of how specific growth factors influence hematopoietic growth and differentiation.
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PMID:Modulation of murine in vitro erythroid and granulopoietic colony formation by ouabain, digoxin and theophylline. 629 70

The signaling mechanisms that regulate lymphokine gene expression in the murine Th2 clone D10.G4.1 were investigated by comparing the steady state mRNA levels of six lymphokine genes in response to cellular treatment with various activators and inhibitors of several key signaling pathways. A surprising degree of differential regulation was found. All of the genes studied (IL-3, IL-4, IL-5, IL-6, IL-10, and granulocyte-macrophage (GM)-CSF) were induced by the lectin Con A and the TCR idiotype-specific mAb 3D3. However, the induction of the IL-3, IL-4, and GM-CSF genes, but not the IL-5, IL-6, and IL-10 genes, was strongly inhibited by cyclosporin A. Furthermore, IL-5, IL-6, and IL-10 genes were independently induced by IL-1 alpha, the phorbol ester PMA, and by forskolin, an activator of adenylate cyclase. Results of studies performed with use of the Ca2+ ionophore A23187 indicated that elevation of intracellular Ca2+ levels is sufficient to fully induce IL-3 and IL-4 gene expression. Protein kinase C activation was also required for full induction of the GM-CSF gene and seemed to be obligatory for maximal IL-5 gene expression. The patterns of mRNA induction by the different stimuli broadly correlated with increased rates of transcription. In addition to their induction by IL-1 alpha, the IL-5, IL-6, and IL-10 genes were also induced by mAbs to CD2 and to CD45. In contrast, adding CD45 mAb strongly inhibited the induction of IL-3, IL-4, and GM-CSF genes through TCR stimulation. These results indicate that distinct groups of lymphokine genes may be differentially regulated by signaling pathways that are activated by stimulation of the TCR and other cell surface molecules.
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PMID:TCR-dependent and -independent signaling mechanisms differentially regulate lymphokine gene expression in the murine T helper clone D10.G4.1. 791 89

Suppressed granulocyte and macrophage growth after burn infection or endotoxicosis appears to be mediated by macrophage-derived products. In this study, we found that after burn, burn plus infection, or endotoxicosis, peritoneal-elicited macrophages or bone marrow cells released increased amounts of prostaglandin E2 (PGE2) and inhibited growth of granulocyte-macrophage progenitor cells (GM-CFC). PGE2, when added in culture, inhibited in vitro GM-CFC growth in a dose-dependent manner. Pretreatment of bone marrow cells with either dibutyryl cyclic adenosine monophosphate or Forskolin in vitro mimicked the PGE2 inhibition, further aggravated the inhibition induced by burn, burn plus infection, or endotoxicosis, and was not blocked by co-culture with indomethacin. Pretreatment of bone marrow cells with SQ22536, an adenylate cyclase inhibitor, significantly restored the suppressed GM-CFC growth found after burn, burn plus infection, or endotoxicosis. Alterations in myeloid production after burn infection appear to be related in part to the level of intracellular cyclic adenosine monophosphate for the GM-CFC and are responsive to PGE2.
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PMID:Burn wound infection-induced myeloid suppression: the role of prostaglandin E2, elevated adenylate cyclase, and cyclic adenosine monophosphate. 952 73