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)

Elevation of cAMP downregulates certain functions of inflammatory cells, including the release of TNF alpha and IL-1 beta by macrophages. Intracellular cAMP levels can be modulated pharmacologically by adding cell-permeable cAMP analogs, by stimulating adenylate cyclase or by inhibiting degradation of cAMP by cAMP-phosphodiesterases (cAMP-PDE). Multiple forms of cAMP-PDEs have been identified in various tissues and cells using both biochemical characterization and selective inhibitors. Therefore, we wanted to determine which of these different PDE isoforms was present in human monocytes and whether this isoform could regulate cytokine release from human monocytes by a mechanism similar to that seen with dbcAMP or PGE1. Our results demonstrate that selective inhibitors of type IV cAMP-PDE, such as rolipram and Ro20-1724, are clearly the most effective compounds at enhancing cAMP levels and inhibiting the release of TNF alpha and IL-1 beta in these cells. The type III cAMP-PDE-selective inhibitors C1930 and cilostamide and the nonselective PDE inhibitors IBMX and pentoxifylline were significantly less potent. In agreement with these data, cAMP-PDE activity in cytosolic extracts from human monocytes was also much more sensitive to inhibition by rolipram than by cilostamide. Additionally, rolipram dramatically reduced TNF alpha mRNA accumulation, which supports previous findings that cAMP regulates TNF alpha at the transcriptional level. Surprisingly, rolipram, rolipram, dbcAMP or PGE1 increased IL-1 beta was reduced, which indicates that cAMP can have both positive and negative effects on the regulation of IL-1 beta.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential regulation of human monocyte-derived TNF alpha and IL-1 beta by type IV cAMP-phosphodiesterase (cAMP-PDE) inhibitors. 789 49

Activation of the enzyme adenylate cyclase or treatment with dibutyryl cyclic AMP (dbcAMP) stimulates prostaglandin biosynthesis in vitro and in vivo. Prior activation of adenylate cyclase has been shown to inhibit the stimulation of amnion cell prostaglandin E2 (PGE2) biosynthesis by substances such as epidermal growth factor (EGF) and phorbol 12-myristate 13-acetate (PMA). Little is known, however, concerning the effects of activation of the adenylate cyclase system on basal and stimulated prostaglandin biosynthesis in human chorion and decidual cells. Interleukin-1 beta (IL-1 beta), EGF, ionomycin (iono), and PMA are known to stimulate prostaglandin E2 production in human chorion and decidual cells. Hence, we have evaluated the effects of co-treatment of chorion and decidual cells with dbcAMP in the presence and absence of EGF, PMA, IL-1 beta, and iono on prostaglandin production. dbcAMP alone stimulated chorion and decidual PGE2 production. Coincubation of dbcAMP with all four test stimulants resulted in a further enhancement of decidual PGE2 production that was often more than additive. Thus activation of adenylate cyclase can have effects on prostaglandin production that have specificity with respect to tissue source, presence of other stimulants and relative time of exposure of the tissues to each of the substances involved.
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PMID:Protein kinase A interactions with prostaglandin biosynthesis at the chorio-decidual interface. 801 87

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

The effects of adenosine 3',5'-cyclic monophosphate (cAMP) on cardiac myocyte nitric oxide (NO) production were studied. Maximal nitrite (NO2(-)) production by cultured neonatal rat cardiac myocytes was achieved with 500 U/ml interleukin-1 beta (IL-1 beta) for 48 h (4.6 +/- 0.3 nmol/1.25 x 10(5) cells; n = 12). Cardiac myocytes exposed to 500 U/ml IL-1 beta for 48 h stained positively for inducible nitric oxide synthase (iNOS) by immunohistochemistry. Forskolin (FSK; adenylate cyclase stimulator) or dibutyryl cAMP (DBcAMP; membrane-permeable cAMP analogue) administration alone had no effect on NO2(-) production. The addition of FSK or DBcAMP to IL-1 beta significantly increased NO2-) levels vs. IL-1 beta alone (9.7 +/- 0.6 and 10.9 +/- 0.8 vs. 4.6 +/- 0.3 nmol/1.25 x 10(5) cells per 48 h, respectively; P < 0.01; n = 12). Semiquantitative reverse transcriptase-polymerase chain reaction revealed increased iNOS mRNA in myocytes treated with FSK+IL-1 beta or DBcAMP+IL-1 beta vs. those treated with IL-1 beta alone. The addition of FSK or DBcAMP to IL-1 beta increased iNOS mRNA half-life over IL-1 beta treatment alone (10.6, 11.7 vs. 2.4 h, respectively). Cardiac myocytes do not express iNOS in response to cAMP alone. Rather, cAMP enhances iNOS mRNA stability following cytokine exposure.
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PMID:cAMP enhances inducible nitric oxide synthase mRNA stability in cardiac myocytes. 859 15

Increased 'oxidative stress' resulting in the activation of nuclear factor kappa B (NF-kappa B) is thought to play a crucial role in the cytokine-mediated expression of the inducible isoform of nitric oxide synthase (iNOS) in different cell types. Therefore, the effects of four different antioxidants, carbocromen, chrysin, 3,4-dichloroisocoumarin (DCI) and N-acetylserotonin (NAS), on iNOS expression were investigated in vascular smooth muscle cells (VSMC). All antioxidants strongly reduced the phorbol ester-stimulating superoxide anion formation in native VSMC. Carbocromen (200 microM) and chrysin (50 microM) had no effect, while NAS (1 mM) abolished the increase in nitrine production and iNOS protein abundance in cultured VSMC exposed to interleukin-1 beta (IL-1 beta, 60 U/ml) or the adenyl cyclase activator forskolin (10 microM). DCI also revealed a marked inhibitory effect in IL-1 beta-stimulated VSMC, but was less effective in cells treated with forskolin. DCI, but not NAS, also suppressed the activation of NF-kappa B in VSMC exposed to IL-1 beta, while no significant NF-kappa B activation was detected in forskolin-treated cells. These findings demonstrate that antioxidants differentially affect iNOS expression in VSMC both at the transcriptional level by preventing the activation of NF-kappa B and at the post-transcriptional level, presumably by promoting iNOS mRNA or protein degradation. They also suggest that reactive oxygen intermediates do not play a role in the activation of NF-kappa B by IL-1 beta in VSMC, and that transcription factors other than NF-kappa B mediate the induction of iNOS expression by elevating the intracellular concentration of cyclic AMP.
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PMID:Antioxidants differentially affect nuclear factor kappa B-mediated nitric oxide synthase expression in vascular smooth muscle cells. 860 29

Cholera toxin (CT) is a potent mucosal adjuvant and is widely used for vaccine studies in animal models. However, there have been few studies that describe the immunomodulating effects of CT on cells of the human immune system. In this study, the immunomodulatory properties of CT on human peripheral blood mononuclear cells (PBMC) were examined to gain insights to its effects on cells of the human immune system. CT induced production of immunostimulating (IL-1 beta and IL-6) and immunosuppressive (IL-10) cytokines by PBMC. However, the dose-response curve of its cytokine-inducing activity did not correlate well with the concentrations of intracellular cAMP generated by varying doses of CT. the CT mode of action on human PBMC, regarding induction of these cytokines, was clarified by the use of inhibitors of adenyl cyclase, protein kinase A (PKA), and protein kinase C (PKC). 2',3'-Dideoxyadenosine, which inhibits adenyl cyclase activity, reduced IL-1, IL-6, and IL-10 levels by 29, 15, and 28% respectively. HA1004, an inhibitor of PKA, reduced the IL-1 and IL-6 levels by 29 and 27%, respectively. The PKC inhibitor, H7, completely blocked the induction of all three cytokines by CT, suggesting a cAMP-independent mode of action for CT on human PBMC. These observations suggest that CT induces immunomodulating cytokines from human PBMC via the PKC pathway.
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PMID:Evidence for protein kinase C pathway in the response of human peripheral blood mononuclear cells to cholera toxin. 896 84

Activation of cAMP signaling pathway was shown to inhibit some pathobiologic processes in mesangial cells (MC). We investigated whether adrenomedullin (ADM), a potent agonist of adenylate cyclase, is synthesized in MC and whether it can, via cAMP, suppress the generation of reactive oxygen metabolites (ROM) and proliferation of cells in glomeruli. With the use of an immunohistologic technique ADM was detected in mesangial and microvascular areas of rat glomeruli. MC grown in primary culture synthesized ADM, and the synthesis was stimulated by TNF alpha and IL-1 beta but not by PDGF and EGF. ADM inhibited ROM generation in MC dose-dependently and caused in situ activation of protein kinase A (PKA). In macrophages (cell line J774) ROM generation was about four times higher than in MC and was inhibited by ADM in a similar way as in MC. The rate of MC proliferation, measured by [3H]-incorporation, and the activity of mitogen-activated protein kinase (MAPK) stimulated by PDGF and EGF were dose-dependently inhibited by ADM; the maximum inhibition (at 10 nM ADM) was about -80%. Mitogenesis of MC and MAPK activity when stimulated to a similar extent by endothelin (ET-1) was inhibited by ADM to a significantly (P < 0.01) lesser degree (-30%). Further, ADM inhibited PDF-stimulated mitogenesis and activation of MAPK in cultured vascular smooth muscle cells (VSMC). The inhibition of PDGF-activated MAPK by ADM in VSMC was reversed by the protein kinase A (PKA) inhibitor, H89. Taken together, results indicate the adrenomedullin (ADM) generated in mesangial cells (MC) can suppress, via activation of the cAMP-protein kinase A (PKA) signaling pathway, reactive oxygen metabolites (ROM) generation in MC and infiltrating macrophages as well as mitogen-activated protein kinase (MAPK)-mediated mitogenesis in MC and vascular smooth muscle cells (VSMC). We suggest that introglomerular ADM may serve as a cytoprotective autoacoid that suppresses pathobiologic processes evoked by immuno-inflammatory injury of glomeruli.
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PMID:Cytoprotective effects of adrenomedullin in glomerular cell injury: central role of cAMP signaling pathway. 932 30

Adrenomedullin (AM) has very recently been demonstrated to be produced and secreted from fibroblasts. The production of AM in the fibroblasts is augmented by inflammation-related substances, and Swiss 3T3 fibroblast cells express AM specific receptors coupled with adenylate cyclase. To assess the functions of AM secreted from fibroblasts, we measured the effect of AM on production in Swiss 3T3 cells of interleukin-6 (IL-6), a typical cytokine involved in the general inflammatory reactions. AM stimulated basal secretion of IL-6 5.5-fold, while other peptides elicited much weaker stimulatory effects. The effect of AM was inhibited with an AM receptor antagonist and a cAMP-dependent protein kinase (PKA) inhibitor. Furthermore, AM remarkably potentiated stimulatory effects of tumor necrosis factor-alpha, IL-1 beta and lipopolysaccharide on IL-6 production. This stimulatory effect of AM was induced through activation of gene transcription, which reached maximum within 30 min. These findings verify that AM is a rapid and extraordinarily potent regulator of IL-6 production in Swiss 3T3 cells acting through the cAMP-PKA pathway. The data thus obtained suggest that AM is a peptidergic regulator of inflammation.
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PMID:Adrenomedullin stimulates interleukin-6 production in Swiss 3T3 cells. 951 21

1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia. 7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase. 8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP. 9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations. 10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways. 11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.
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PMID:Inflammatory mediators and modulation of blood-brain barrier permeability. 1069 6

Blastocyst implantation in the baboon usually occurs between 8 and 10 days post ovulation. Changes that occur within this window of receptivity and immediately following implantation can be divided into three distinct phases. The first phase, regulated by estrogen and progesterone, is characterized primarily by changes in both the luminal and glandular epithelial cells in preparation for blastocyst apposition and attachment. The second phase is the further modulation of these steroid induced changes in both epithelial and stromal cells by embryonic signals. The final phase is associated with trophoblast invasion and the remodeling of the endometrial stromal compartment. During the initial phase, the actions of estrogen and progesterone are dependent on the presence of specific receptors. Estrogen up-regulates both its own receptor (ER) and the progesterone receptor (PR), while progesterone down-regulates this expression pattern. However, the pattern of progesterone-induced down-regulation of ER and PR is confined to the epithelial cells and demonstrates a gradient effect from the functionalis to the basalis. What is most intriguing is that the loss of epithelial PR is closely correlated with the establishment of uterine receptivity. Coincident with the changes in ER and PR expression, epithelial cells undergo alterations in their cytoskeletal architecture and secretory profile. These changes can be counteracted by PR antagonist treatment during the luteal phase. Although estrogen and progesterone play a critical role in establishing the initial phase of uterine receptivity, it is becoming increasingly evident that the embryo induces functional receptivity in ruminants and rodents. In our studies in the primate, we demonstrate that chorionic gonadotrophin when infused in a manner that mimics blastocyst transit, has physiological effects on the three major cell types in the uterine endometrium. The luminal epithelium undergoes endoreplication and distinct epithelial plaques are evident. The glandular epithelium responds by inducing transcriptional and post-translational modifications in the major secretory product, glycodelin. The stromal fibroblasts initiate their differentiation process into a decidual phenotype and are characterized by the expression of actin filaments. In phase three, blastocyst attachment to the surface epithelium and subsequent implantation is associated with local remodeling of the maternal stroma, smooth muscle, and endothelium of the blood vessels by the trophoblast. In addition, there is a gradual diminution of the epithelial plaques on the luminal surface although the glandular epithelium remains highly secretory. The most dramatic effect is on the stromal fibroblasts, which in response to embryonic stimuli, differentiate into decidual cells, the major cell type of the gestational endometrium. This differentiation is characterized by the expression of insulin-like growth factor binding protein-1 (IGFBP-1) in these cells. The cytokine IL-1 beta is one possible embryonic signal. COX-2 is the rate-limiting enzyme for prostaglandin biosynthesis and transcription of this enzyme in response to the embryonic stimulus (IL-1 beta) results in an increase in prostaglandin biosynthesis in stromal fibroblasts at the site of implantation. Prostaglandins and PGE2 in particular, binds to its specific receptor (EP2 or EP4) and activates adenyl cyclase. The resulting increase in intracellular levels of cAMP can now activate IGFBP-1 gene transcription at the site of implantation. In summary, our studies have demonstrated that chorionic gonadotrophin, when infused into non-pregnant baboons during the window of uterine receptivity can induce epithelial responses that are similar to those observed in a fertile cycle. Stromal differentiation is initiated; however, decidualization requires a signal from the conceptus.
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PMID:Implantation in the baboon: endometrial responses. 1079 44


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