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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine and adenosine analogues are potent inhibitors of the respiratory burst in neutrophils. Most investigators, however, have found little or no effect of these compounds on neutrophil degranulation from cytochalasin B-treated neutrophils in suspension. We have instead investigated the effect of adenosine and 2-chloroadenosine on degranulation in adherent neutrophils in the absence of cytochalasin B. Both adenosine and 2-chloroadenosine were effective inhibitors of lactoferrin secretion induced by the chemotactic peptide N-formyl-methionine-leucyl-phenylalanine (fMLP) [50% inhibitory concentration (IC50) of less than 10(-6) M]. Secretion induced by tumor necrosis factor (TNF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) was inhibited only at high concentrations (IC50 of approximately 10(-4) M). In the presence of cytochalasin B no inhibitory effect of 2-chloroadenosine was seen. The effect of cAMP-raising agents on secretion from adherent neutrophils was also investigated. Dibutyryl cAMP at 0.2 mM reduced secretion in response to fMLP by 50% but did not inhibit TNF- and GM-CSF-induced degranulation. At a concentration of 2.0 mM dibutyryl cAMP also inhibited exocytosis in response to the two cytokines. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) at 300 microM reduced fMLP-induced degranulation, whereas a concentration of 1 mM was required to inhibit TNF- and GM-CSF-mediated secretion. The adenylate cyclase activator forskolin (50 microM) alone did not inhibit secretion in response to TNF or fMLP. However, in combination with IBMX (300 microM), forskolin (50 microM) reduced both TNF- and fMLP-induced secretion to less than 10%. PMA-induced exocytosis was unaffected by all these agents. In conclusion, adenosine appears to be an effective inhibitor of neutrophil granule protein secretion induced by fMLP but only a weak inhibitor of exocytosis in response to TNF or GM-CSF. Secretion in response to fMLP was also found to be more susceptible to a rise in cAMP than degranulation induced by TNF and GM-CSF.
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PMID:Effect of adenosine analogues and cAMP-raising agents on TNF-, GM-CSF-, and chemotactic peptide-induced degranulation in single adherent neutrophils. 137 3

It has previously been demonstrated that interleukin-1 (IL-1) is expressed in a variety of fibroblast cell lines. In this study, we investigated the mechanisms involved in the regulation of IL-1 beta production by cultured human dermal fibroblasts. We have shown that IL-1 beta is constitutively expressed as a cell-associated form, with no soluble form detectable in control cell or in stimulated cell supernatants. IL-1 alpha and tumor necrosis factor-alpha (TNF-alpha) exerted a dose-dependent stimulation on the production of the cell-associated IL-1 beta, as estimated using a specific enzyme linked immunosorbent assay (ELISA). As expected, this effect was accompanied by a huge release of prostaglandin E2 (PGE2) and a transient rise in intracellular cyclic AMP. Furthermore, IL-1 beta production was elevated to a lesser extent by the addition of increasing concentrations of the protein kinase C activator phorbol myristate acetate or by low concentration (0.001 microgram/ml) of PGE2. In contrast, higher concentrations (0.1 and 1 micrograms/ml) of PGE2, as well as exogenous dibutyryl-cyclic AMP, were clearly inhibitory. H7, an inhibitor of protein kinases also reduced the stimulatory effect of IL-1 alpha and TNF-alpha. Together with the results obtained with phorbol myristate acetate, these data suggest that protein kinase C may play a role in the upregulation of IL-1 beta expression in normal skin fibroblasts. The addition of indomethacin not only suppressed prostaglandin synthesis, but also dramatically reduced cyclic AMP formation, probably because the PGE2-induced stimulation of adenylate cyclase was abolished. This resulted in a strong potentiation of the stimulatory effect of IL-1 alpha and TNF-alpha, supporting the role of both the cyclooxygenase and adenylate cyclase pathways in the endogenous downregulation of IL-1 beta induction by the two cytokines studied.
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PMID:Induction of interleukin-1 beta production in human dermal fibroblasts by interleukin-1 alpha and tumor necrosis factor-alpha. Involvement of protein kinase-dependent and adenylate cyclase-dependent regulatory pathways. 166 39

We examined the role of augmented formation of intracellular cyclic AMP (cAMP) in the mediation of stromal cell growth factor production that occurs constitutively or upon cytokine stimulation. Clonal murine marrow adherent cell lines were stimulated under serum-free conditions by interleukin-1 (IL-1) or lipopolysaccharide (LPS) and one (+/+ -1.LDA11) was found to produce low quantities of granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF identity was confirmed by the ability of supernatants from stromal cells to promote proliferation of the factor-dependent cell line FDC-P1, neutralization of this activity by antiserum to GM-CSF, and by Northern blot analysis. However, optimal concentrations of IL-1 and tumor necrosis factor-alpha (TNF-alpha), in combination, led to synergistic (greater than 5-fold higher quantity) GM-CSF production compared with either stimulus alone in the +/+ -1. LDA11 cell line, capable of GM-CSF production after only single stimulation with IL-1 or LPS. In addition, synergistic stimulation by IL-1 and TNF-alpha led to equivalent high amounts of GM-CSF in another cell line incapable of GM-CSF production after induction with only IL-1 or LPS. Any of several means to raise intracellular cAMP levels, including addition of 8-bromo-cyclic AMP (8Br cAMP) (0.25-1mM), pertussis toxin (20-100 ng/ml), or addition of prostaglandin E1 (PGE1) (1 microM), failed to stimulate GM-CSF production alone and strongly inhibited GM-CSF production in stromal cells stimulated by IL-1, LPS, or the synergistic combination of IL-1 and TNF-alpha. In addition, PGE1 and pertussis intoxication were agonists of adenylate cyclase in membranes of marrow adherent cells, whereas IL-1 and LPS were not. The role for regulators of intracellular cAMP was specific because any of the cAMP agonists alone, or in the presence of cytokine stimulators of stromal cells, strongly enhanced IL-6 production, an event known to be cAMP-responsive. Thus, acute formation of intracellular cAMP is a negative regulator of stromal cell GM-CSF production mediated by cytokines, but positively regulates IL-6 production and may be an important determinant of cytokine-directed marrow microenvironmental function. These findings on the requirement for augmentation versus inhibition of cytokine-mediated production of hemopoietic growth factors might be applied to an analysis of marrow stromal cell heterogeneity.
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PMID:Role for cyclic AMP in the postreceptor control of cytokine-stimulated stromal cell growth factor production. 216 2

Platelet-activating factor (PAF or 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is the most potent lipid mediator yet discovered. It is known to stimulate a wide span of biological responses ranging from aggregation and degranulation of platelets and neutrophils to a variety of cellular effects involving the stimulation of chemotaxis; chemokinesis; superoxide formation; protein phosphorylation; activation of protein kinase C, arachidonic acid, and phosphoinositide metabolites; glycogenolysis; and tumor necrosis factor production. Obviously, with such a diversity of biological activities, it is not surprising that PAF has been considered to be a key component in numerous diseases related to hypersensitivity and inflammatory responses. Evidence has also been presented for the role of PAF in physiological processes, particularly those involving reproduction and fetal development. Furthermore, because of its potent hypotensive action, PAF has been implicated as a contributing factor in blood pressure regulation. PAF is produced by two independent enzymatic pathways. The remodeling route involves the structural modification of a membrane lipid (1-alkyl-2-acyl-sn-glycero-3-phosphocholine) by replacement of the acyl moiety with an acetate group. An alternate route is the de novo synthesis of PAF from an O-alkyl analogue of a lysophosphatidic acid that requires a reaction sequence of acetylation, dephosphorylation, and phosphocholine addition steps. Hypersensitivity and other pathophysiological reactions are thought to be caused by activation of the remodeling pathway, whereas the de novo route is believed to be the source of endogenous levels of PAF required for physiological functions. Inactivation of PAF occurs when the acetate group is hydrolyzed by an acetylhydrolase that is present in both extra- and intracellular compartments, although the catalytic activity of the two forms of acetylhydrolase are identical, some of their properties differ. The control of PAF metabolism is very complex, but acetylhydrolase, Ca2+, phosphorylation/dephosphorylation of enzymes, and fatty acids (especially polyunsaturates) appear to be important regulatory factors. Specific PAF receptors have clearly been demonstrated on several different types of cells, and although the mechanism of PAF actions is poorly understood, it appears that the PAF/receptor-induced responses are closely associated with the signal transduction process; both G proteins and adenyl cyclase appear to be involved. Because significant quantities of PAF are often retained within certain cells, the possibility of PAF serving as an intracellular mediator has also been proposed.
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PMID:Platelet-activating factor and related acetylated lipids as potent biologically active cellular mediators. 224 Jan 90

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

Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured cardiac myocytes in the presence of culture supernatants from activated immune cells. We observed that these culture supernatants inhibit beta-adrenergic agonist-mediated increases in cultured cardiac myocyte contractility and intracellular cAMP accumulation. The myocyte contractile response to increased extracellular Ca2+ concentration is unaltered by prior exposure to these culture supernatants, as is the increase in myocyte intracellular cAMP concentration in response to stimulation with forskolin, a direct adenyl cyclase activator. Inhibition occurs in the absence of alteration in beta-adrenergic receptor density or ligand binding affinity. Suppressive activity is attributable to the macrophage-derived cytokines interleukin 1 and tumor necrosis factor. Thus, these observations describe a role for defined cytokines in regulating the hormonal responsiveness and function of contractile cells. The effects of interleukin 1 and tumor necrosis factor on intracellular cAMP accumulation may be a model for immune modulation of other cellular functions dependent upon cyclic nucleotide metabolism. The uncoupling of agonist-occupied receptors from adenyl cyclase suggests that beta-receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.
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PMID:Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. 254 46

Nuclear protein IRF-1 (interferon regulatory factor 1) was earlier shown to bind to cis-acting regulatory elements present on interferon (IFN)-alpha/beta genes and some IFN-inducible genes. Here we show that in both human FS-4 and murine L929 cells, steady-state levels of IRF-1 mRNA were increased by treatment with tumor necrosis factor (TNF), interleukin 1 (IL-1), poly(I).poly(C), or IFN-beta. IRF-1 mRNA induction was also demonstrated in cells treated with calcium ionophore A23187 or with phorbol 12-myristate 13-acetate, but not with epidermal growth factor, dibutyryl-cAMP, or the adenylate cyclase activator forskolin. To determine whether stimulation of IRF-1 mRNA levels correlates with IFN-beta induction, we compared IRF-1 and IFN-beta mRNA levels in cells exposed to various stimuli. In L929 cells, treatment with poly(I).poly(C) under conditions that failed to induce significant levels of IFN-beta mRNA led to a very low induction of IRF-1 mRNA, but "priming" cells with IFN prior to the addition of poly(I).poly(C) greatly increased both IRF-1 and IFN-beta mRNAs. In FS-4 cells an increase in IFN-beta mRNA (examined by the polymerase chain reaction) was seen after treatment with TNF, IL-1, A23187, or poly(I).poly(C), but not with IFN-beta, epidermal growth factor, dibutyryl-cAMP, or forskolin. Thus, all treatments that increased steady-state levels of IFN-beta mRNA also enhanced IRF-1 mRNA levels. However, treatment with IFN-beta, which caused a marked stimulation in IRF-1 mRNA, failed to produce a detectable increase in IFN-beta mRNA. It appears that IRF-1 may be necessary but not sufficient for IFN-beta induction. The ability of TNF and IL-1 to increase both IRF-1 and IFN-beta mRNAs may be responsible for some similarities in the actions of TNF, IL-1, and the IFNs.
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PMID:Induction of the transcription factor IRF-1 and interferon-beta mRNAs by cytokines and activators of second-messenger pathways. 255 35

We related the effects of c-myc expression on the ability of growth inhibitors to block the cells in the G0/G1 phase of the cell cycle. In two different B-cell lines, there was an association between the accumulation of cells in the middle to late G1 phase of the cell cycle and a rapid transient downregulation of c-myc mRNA levels. The phorbol ester TPA and the adenylate cyclase activator forskolin reduced the c-myc RNA, levels and after 3 days of treatment a proportion of the cells accumulated in G1. In contrast, neither interferon-gamma, tumor necrosis factor-alpha nor the monoclonal antibody 33-1 against DQ major histocompatibility antigens changed the cell-cycle distribution or regulated the c-myc RNA levels. Yet, all five growth inhibitors reduced the proliferation to approximately the same extent. The growth reduction was not accompanied by definite differentiation, as judged by the absence of the B-cell differentiation marker B1 (CD20).
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PMID:Downregulation of c-myc RNA is not a prerequisite for reduced cell proliferation, but is associated with G1 arrest in B-lymphoid cell lines. 311 97

A functioning rat thyroid cell line (FRTL5) was used to study interactions of thyrotropin (TSH) and various cytokines on expression of class I and II major histocompatibility complex (MHC) antigens and on growth stimulation. Only gamma-interferon (gamma-IFN) affected MHC antigen expression, i.e., to enhance class I, that was constitutive, and to induce class II. A concomitant, but probably not directly related, effect of gamma-IFN was to diminish growth stimulation, as effected by TSH and other activators of adenylate cyclase and measured by DNA increase and enhanced incorporation of [3H]thymidine into DNA. Stimulation of growth by tetradecanoylphorbol ester was also decreased by gamma-IFN. These effects of gamma-IFN were mimicked to some degree by tumor necrosis factor but there was major synergism between the two cytokines. Enhanced accumulation of cAMP by TSH and other agents was not diminished in these experiments. Flow cytometry analysis showed that inhibition of growth stimulation involved blocking of the passage of cells from the G0/1 phase to the S phase. The data may have relevance to goiter size in autoimmune thyroid disease.
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PMID:Effects of gamma-interferon and tumor necrosis factor alpha on thyroid cells: induction of class II antigen and inhibition of growth stimulation. 314 28

The effect of prostaglandin (PG) E2 on macrophage activation by interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) was evaluated. Murine macrophages infected with Leishmania enriettii or Leishmania major were activated by exposure to IFN-gamma (10-50 U/ml) and TNF-alpha (30-3000 U/ml), leading to intracellular parasite destruction within 24-48 h. Leishmanicidal activity was markedly increased when activation was performed in the presence of PGE2 (10(-9)-10(-7) M) or arachidonate (10(-5) M, a PG precursor), concomitant with enhanced nitrite release and glucose oxidation through the hexose monophosphate shunt pathway. Conversely, activation was reduced by indomethacin and hydrocortisone, two inhibitors of PG synthesis. Parasite killing and nitrite production were fully restored by exogenous PGE2, indicating that inhibition by these drugs was related to their ability to block PG production. PG can stimulate adenylate cyclase, thus raising intracellular cAMP levels. Accordingly, dibutyryl-cAMP, theophylline (which prevents cAMP breakdown), and forskolin (an activator of adenylate cyclase) all stimulated macrophage activation. Finally, PGE2 and cAMP enhanced expression of inducible nitric oxide synthase mRNA in response to IFN-gamma and TNF-alpha, and this effect was inhibited by the cAMP antagonist 2'-O-methyl adenosine. These findings are consistent with the hypothesis that PGE2 acts as a positive agonist in macrophage activation by IFN-gamma and TNF-alpha via its capacity to modulate intracellular cAMP levels.
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PMID:Effect of PGE2 and of agents that raise cAMP levels on macrophage activation induced by IFN-gamma and TNF-alpha. 754 22


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