Cyclic AMP inhibition of fMet-Leu-Phe-dependent metabolic responses in human neutrophils is not due to its effects on cytosolic Ca2+

Togni, P De; Cabrini, Giulio; Virgilio, Francesco Di

doi:10.1042/bj2240629

Cited by 76 publications

(21 citation statements)

References 34 publications

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“…3F), in accordance with previous reports (9,10). It is tempting to speculate that receptor-operated Ca 2ϩ channel is one of the targets of cAMP-dependent protein kinase, since cAMP-increasing agents were incapable of inhibiting thapsigargin-induced Ca 2ϩ influx (Fig.…”

Section: Different Signals Arising From Fmlp Receptor Stimulation Aresupporting

confidence: 79%

Cyclic AMP-increasing Agents Interfere with Chemoattractant-induced Respiratory Burst in Neutrophils as a Result of the Inhibition of Phosphatidylinositol 3-Kinase Rather than Receptor-operated Ca2+ Influx

Ahmed

Hazeki

et al. 1995

Journal of Biological Chemistry

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Superoxide anion and arachidonic acid were produced in guinea pig neutrophils in response to a chemotactic peptide formyl-methionyl-leucyl-phenylalanine (fMLP). Both responses were markedly, but the former response to a phorbol ester was not at all, inhibited when the cellular cAMP level was raised by prostaglandin E 1 combined with a cAMP phosphodiesterase inhibitor. Increasing cAMP was also inhibitory to fMLPinduced activation of phosphatidylinositol (PI) 3-kinase and Ca 2؉ influx without any effect on the cation mobilization from intracellular stores. The fMLP-induced respiratory burst was abolished when PI 3-kinase was inhibited by wortmannin or LY294002, but was not affected when Ca 2؉ influx was inhibited. On the contrary, fMLP released arachidonic acid from the cells treated with the PI 3-kinase inhibitors as well as from nontreated cells, but it did not so when cellular Ca 2؉ uptake was prevented. The chemotactic peptide activated PI 3-kinase even in cells in which the receptor-mediated intracellular Ca 2؉ mobilization and respiratory burst were both abolished by exposure of the cells to a permeable Ca 2؉ -chelating agent. Thus, stimulation of fMLP receptors gave rise to dual effects, activation of PI 3-kinase and intracellular Ca 2؉ mobilization; both effects were necessary for the fMLP-induced respiratory burst. Increasing cellular cAMP inhibited the respiratory burst and arachidonic acid release as a result of the inhibitions of PI 3-kinase and Ca 2؉ influx, respectively, in fMLP-treated neutrophils.The intracellular signaling pathways responsible for the formyl-methionyl-leucyl-phenylalanine (fMLP) 1 -induced respiratory burst in phagocytes remain to be fully understood as yet, although the activation mechanism of the respiratory burst oxidase is currently elucidated as an assembly of a number of membrane-bound and cytosolic components, including gp91 In general, one of the best strategies for identification of essential cellular signals involved in a cell response to a receptor stimulation is to search for the target with which an inhibitor interacts to abolish the response efficiently. Pertussis toxin was a good inhibitor and was successfully applied to the fMLPinduced respiratory burst. Prior exposure of guinea pig neutrophils to low concentrations of pertussis toxin for several hours prevented the cells from producing superoxide anion in response to the subsequent addition of fMLP (2). The prevention resulted from the toxin-induced ADP-ribosylation of G protein (Gi-2), the chemical modification by which the modified G protein is uncoupled from receptors. Evidence has been thus provided for involvement of the G protein in the fMLP-induced respiratory burst via phospholipase C activation (2-4).An additional example of useful inhibitors of the phagocytic respiratory burst is wortmannin, a fungal metabolite with hydrophobic sterol structure. Baggiolini and his colleagues (5, 6) first reported that incubation of human neutrophils with wortmannin or 17-hydroxywortmannin for 5 min inhibited fMLPinduced ...

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Section: Different Signals Arising From Fmlp Receptor Stimulation Aresupporting

confidence: 79%

Cyclic AMP-increasing Agents Interfere with Chemoattractant-induced Respiratory Burst in Neutrophils as a Result of the Inhibition of Phosphatidylinositol 3-Kinase Rather than Receptor-operated Ca2+ Influx

Ahmed

Hazeki

et al. 1995

Journal of Biological Chemistry

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“…Changes in plasma membrane potential were measured with the fluorescent dye bis [l1,3-diethylthiobarbiturate) trimethineoxonal (bisoxonol; Molecular Probes, Inc., Eugene, OR) at the wavelength pair 540/580 nm, as previously described (25). Experiments were performed in a spectrofluorometer (model LS50, Perkin-Elmer Ltd., Beaconsfield, UK) equipped with a thermostat-controlled (37°C) cuvette holder and magnetic stirTer.…”

Section: Methodsmentioning

confidence: 99%

“…Chemotaxis was measured in the chamber previously described containing the chemoattractant in the bottom compartment. The chemotactic factors used were as follows: casein "Hammarsten" (Merck, Darmstadt, Germany) at a concentration of 2 mg/ml in KrebsRinger phosphate containing 0.1% (wt/vol) glucose and 0.5 mg/ml BSA, pH 7.4; fMet-Leu-Phe (FMLP) at a concentration of 10-8 M; and pooled fresh serum (15%) activated with LPS (25 The first phase is due mainly to Ca2' release from intracellular stores; the second reflects Ca2+ influx across the plasma membrane, probably via the newly identified but still poorly characterized Ca2' release-activated plasma membrane Ca2+ channels (32). As shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

The purinergic P2Z receptor of human macrophage cells. Characterization and possible physiological role.

Falzoni¹,

Munerati²,

Ferrari³

et al. 1995

J. Clin. Invest.

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228

212

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We have investigated responses of human monocyte/macrophage cells to extracellular ATP (ATPe). Freshly isolated peripheral blood monocytes showed responses linked to P2Y but not P2Z purinergic receptors; however, during in vitro macrophage differentiation, these cells also exhibited responses suggestive of the presence of the membrane-permeabilizing P2z receptor. In fact, in human macrophages a brief (15-min) exposure to ATPe, but not other nucleotides, caused (1) a rapid and long-lasting plasma membrane depolarization; (2) a large increase in intracellular Ca2+ concentration followed by efflux of the Ca2+ indicator; (3) uptake of low molecular weight hydrophilic molecules such as Lucifer yellow and ethidium bromide; and (4) cell rounding, swelling, and eventual release of the cytoplasmic enzyme lactate dehydrogenase. rIFN-y enhanced both membranepermeabilizing and cytotoxic ATPe effects. Membrane permeabilization and cytotoxicity were fully blocked by pretreatment of the cells with oxidized ATP, a compound recently shown to block P2z receptors covalently in macrophages. Blocking of the P2z receptor by oxidized ATP also inhibited multinucleated giant cell generation stimulated by concanavalin A or rIFN-y without decreasing monocyte migration or membrane adhesion molecule expression. These data suggest that human macrophages express rIFN-ymodulated purinergic P2z receptors in vitro and hint at a role for these plasma membrane molecules in the generation of macrophage polykarions. (J. Clin. Invest. 1995Invest. . 95:1207Invest. -1216

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“…At least three different intracellular messenger systems are involved in these events: (a) An increase in [Ca 2+ ] i activates various neutrophil functions (3-5); (b) Protein kinase C probably has a dual regulatory role, stimulating and inhibiting neutrophil functions (6)(7)(8); (c) cyclic adenosine monophosphate, cAMP, is an intracellular inhibitor of neutrophil function (9)(10)(11). The involvement of other intracellular messenger systems is likely, but unproven.…”

Section: Introductionmentioning

confidence: 99%

The calcium signal and neutrophil activation

Krause

Campbell

Welsh

et al. 1990

Clinical Biochemistry

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Cyclic AMP inhibition of fMet-Leu-Phe-dependent metabolic responses in human neutrophils is not due to its effects on cytosolic Ca2+

Cited by 76 publications

References 34 publications

Cyclic AMP-increasing Agents Interfere with Chemoattractant-induced Respiratory Burst in Neutrophils as a Result of the Inhibition of Phosphatidylinositol 3-Kinase Rather than Receptor-operated Ca2+ Influx

Cyclic AMP-increasing Agents Interfere with Chemoattractant-induced Respiratory Burst in Neutrophils as a Result of the Inhibition of Phosphatidylinositol 3-Kinase Rather than Receptor-operated Ca2+ Influx

The purinergic P2Z receptor of human macrophage cells. Characterization and possible physiological role.

The calcium signal and neutrophil activation

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