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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of polymorphonuclear leukocytes (PMNL) by most soluble stimulants is associated with a marked increase in cytosolic free Ca2+ ([Ca2+]i). Interleukin-8 (IL-8), a monocyte-derived neutrophil chemotactic factor and potent neutrophil-activating cytokine, effectively enhanced the resting free [Ca2+]i within human PMNL in a dose-dependent manner (maximal effect with 100 ng/mL). The increase in [Ca2+]i was substantially (55%) inhibited in the absence of extracellular Ca2+. Thus, the increase was due to extra- and intracellular cooperative mobilization of Ca2+, as supported by the reduced effect of IL-8 on [Ca2+]i after quenching with Mn2+. Granulocyte-macrophage colony-stimulating factor and interferon-gamma failed to induce a change in [Ca2+]i, suggesting that they may operate through different signal pathways. Pretreatment with Bordetella pertussis toxin largely inhibited the IL-8-induced change in [Ca2+]i. Thus, IL-8-induced cooperative mobilization of intra- and extracellular Ca2+ leads to a net Ca2+ influx into the cytoplasm through a process mediated by a guanosine triphosphate-binding protein.
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PMID:Recombinant interleukin-8 induces changes in cytosolic Ca2+ in human neutrophils. 140 20

The addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to human peripheral blood neutrophils primes phospholipase D (PLD) to subsequent stimulation by N-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol myristate acetate (PMA). The present investigation was directed at the elucidation of the pathway(s) involved in the regulation of the activity of PLD in untreated as well as in GM-CSF-primed neutrophils. Pretreatment with pertussis toxin (PT) totally inhibited fMLP-induced activation of PLD in control or GM-CSF-treated cells. PT did not affect the activation of PLD by PMA but inhibited the priming effect of GM-CSF. Activation of PLD by fMLP was dose-dependently inhibited by erbstatin, an inhibitor of tyrosine kinases. Furthermore, pre-incubation with GM-CSF accelerated the tyrosine phosphorylation response to fMLP (as analysed by protein immunoblot with antiphosphotyrosine antibodies). In PMA-stimulated neutrophils, erbstatin antagonized the priming effect of GM-CSF on PLD without affecting the direct effects of the phorbol ester. Buffering cytoplasmic calcium with the chelator BAPTA inhibited fMLP-induced activation of PLD as monitored by the formation of phosphatidylethanol. The stimulation of PLD by PMA was partially attenuated in BAPTA-loaded cells while the priming effect of GM-CSF was abolished. Thus, priming of human neutrophil PLD by GM-CSF may be mediated by G-proteins, by increases in the levels of cytosolic free calcium, and by stimulation of protein kinase C and/or tyrosine kinase(s).
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PMID:Granulocyte-macrophage colony-stimulating factor primes phospholipase D activity in human neutrophils in vitro: role of calcium, G-proteins and tyrosine kinases. 141 87

Preincubation of human neutrophils with the human hormone granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibits the specific binding of leukotriene B4 ([3H]LTB4) but not the nonmetabolizable bioactive platelet-activating factor ([3H]C-PAF) to intact cells. This inhibition requires that the GM-CSF interacts with intact cells. The action of GM-CSF is not prevented by pertussis toxin. Moreover, the rise in calcium produced by LTB4 but not by PAF is also inhibited in human neutrophils pretreated with GM-CSF. Interestingly, neither the inhibitory action of GM-CSF on [3H]LTB4 binding or LTB4-induced calcium rise nor the potentiation of superoxide production by GM-CSF is reduced by inhibitors of arachidonic acid metabolism by the lipoxygenase pathway. In contrast, preincubation of human neutrophils with either the chemotactic factor formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe) or the active phorbol ester, phorbol 12-myristate 13-acetate (PMA), inhibits the binding of both [3H]LTB4 and [3H]C-PAF to intact cells. The inhibitory actions of GM-CSF, PMA, and fMet-Leu-Phe require that they interact with the intact cells; their actions cannot be reproduced in plasma membrane preparations. The effects of both GM-CSF and fMet-Leu-Phe cannot be prevented by the protein kinase C inhibitor staurosporine. The mechanisms of fMet-Leu-Phe and GM-CSF actions are probably not mediated through the release of LTB4 by the cells. Interestingly, this new action, unlike other reported effects of GM-CSF, is not mediated through a pertussis toxin-sensitive G protein (Gi alpha 2). This indicates that not all GM-CSF receptors are coupled to Gi alpha 2.
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PMID:Modulation of leukotriene B4 and platelet-activating factor binding to neutrophils. 165 24

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) was studied for its ability to stimulate the synthesis and release of the inflammatory mediator platelet-activating factor (PAF) from human neutrophils as measured by bioassay and incorporation of [3H]acetate into PAF. GM-CSF stimulated the synthesis but not the release of PAF from neutrophils. PAF synthesis took place in a time- and concentration-dependent manner, was dependent on a pertussis toxin-sensitive G protein and could be inhibited by antibodies to GM-CSF. On the other hand, pre-incubation of neutrophils with GM-CSF followed by stimulation with the bacterial tripeptide formylmethionylleucylphenylalanine caused PAF synthesis and release. The effect of GM-CSF was qualitative and not simply the result of larger amounts of PAF being synthesized since similar amounts were generated in response to the calcium ionophore A23187 but no released PAF could be detected. In functional studies GM-CSF stimulated superoxide anion generation from neutrophils with a time and dose relationship that paralleled PAF synthesis. In addition, the serine protease inhibitor L-1-tosylamide-2-phenylethyl chloromethyl ketone, which inhibits PAF synthesis, reduced PAF accumulation as well as superoxide generation, raising the possibility of a causal relationship between cell-associated PAF and cell activation. These results identify PAF as a direct product of GM-CSF stimulation in neutrophils where it may play a role in signal transduction and demonstrate that PAF is released only after subsequent neutrophil stimulation. The selective release of PAF may play a role in regulating and amplifying the inflammatory response.
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PMID:Granulocyte-macrophage colony-stimulating factor is a stimulant of platelet-activating factor and superoxide anion generation by human neutrophils. 184 28

The effects of monosodium urate and calcium pyrophosphate dihydrate crystals on the levels of cytoplasmic free calcium and on the oxidative burst in normal human blood neutrophils were examined. The pattern of sensitivity to granulocyte-macrophage colony-stimulating factor, colchicine, cytochalasin B, pertussis toxin, diglyceride kinase, and protein kinase C inhibitors differentiated the mechanism(s) of neutrophil activation by the crystals from that involved in the responses to soluble chemotactic factors and indicated that individual crystals can use several activation pathways.
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PMID:Crystal-induced neutrophil activation. I. Initiation and modulation of calcium mobilization and superoxide production by microcrystals. 184 32

The EGR-1 gene is an immediate early response gene encoding a zinc finger DNA-binding protein. The present studies have examined the regulation of EGR-1 gene expression in human U-937 monocytic leukemia cells treated with granulocyte-macrophage colony-stimulating factor (GM-CSF). The results demonstrate that GM-CSF rapidly and transiently increases EGR-1 gene expression in U-937 cells. Similar findings were obtained in GM-CSF-treated human monocytes. We also show that the regulation of EGR-1 expression by GM-CSF is a pertussis toxin-sensitive event. The results of nuclear run-on assays further demonstrate that the EGR-1 gene is constitutively transcribed in untreated U-937 cells and that GM-CSF has little effect on this rate of transcription. Inhibition of protein synthesis with cycloheximide also had no detectable effect on EGR-1 gene transcription but was associated with superinduction of EGR-1 mRNA levels in GM-CSF-treated cells. Moreover, the half-life of GM-CSF-induced EGR-1 transcripts was prolonged from 33 to 70 min following inhibition of protein synthesis. Taken together, the results indicate that GM-CSF activates signaling pathways which regulate EGR-1 gene expression through a pertussis toxin-sensitive G protein and that these events increase EGR-1 mRNA levels by a posttranscriptional mechanism. This GM-CSF-dependent regulation of EGR-1 expression may provide a mechanism for transducing signals to the nucleus that are involved in the control of gene transcription.
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PMID:Posttranscriptional regulation of the zinc finger-encoding EGR-1 gene by granulocyte-macrophage colony-stimulating factor in human U-937 monocytic leukemia cells: involvement of a pertussis toxin-sensitive G protein. 206 96

Colony-stimulating factor 1 (CSF-1) is required for the survival, proliferation and differentiation of monocytes. We previously demonstrated that the CSF-1 receptor is linked to a pertussis toxin-sensitive G protein and that the induction of Na+ influx by CSF-1 is a pertussis toxin-sensitive event. The present studies have examined activation of protein kinase C as a potential intracellular signaling event induced by the activated CSF-1 receptor. The results demonstrate that CSF-1 stimulates translocation of protein kinase C activity from the cytosol to membrane fractions. This activation of protein kinase C was sensitive to pretreatment of the monocytes with pertussis toxin. Lipid distribution studies demonstrated that phosphatidylcholine (PC) is the major phospholipid in human monocytes. Moreover, the results indicate that CSF-1 stimulation is associated with decreases in PC, but not in phosphatidylinositol (PI), levels. The absence of an effect of CSF-1 on PI turnover was confirmed by the lack of changes in inositol phosphate production. In contrast, CSF-1 stimulation was associated with increased hydrolysis of PC to phosphorylcholine and diacylglycerol (DAG) in both intact monocytes and cell-free assays. Furthermore, the increase in PC turnover induced by CSF-1 was sensitive to pertussis toxin. The results also demonstrate that the induction of Na+ influx by CSF-1 is inhibited by the protein kinase C inhibitors staurosporine and the isoquinoline derivative H7, but not by HA1004.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Colony-stimulating factor 1 activates protein kinase C in human monocytes. 219 73

The addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to human neutrophils causes a rapid increase in the basal and fMet-Leu-Phe-stimulated Na+ influx and an increase in intracellular pH. The increase can be seen as early as 5 min after the addition of GM-CSF. Changes produced by GM-CSF are totally inhibited by amiloride and are significantly reduced in pertussis toxin-treated cells. The stimulation of the Na+/H+ exchange mechanism by GM-CSF inhibits further stimulation of this system with either fMet-Leu-Phe or phorbol 12-myristate 13-acetate. In addition, membrane preparations isolated from GM-CSF-treated neutrophils have higher basal and stimulated GTPase activities. The basal and the fMet-Leu-Phe- or platelet-activating factor-stimulated GTPase activities are reduced in pertussis toxin-treated cells. Cells pretreated with GM-CSF accumulate more radioactive phosphate than control cells, and this increase is diminished by pertussis toxin treatment. In addition, GM-CSF causes a rapid increase in the tyrosine phosphorylation levels of five proteins with molecular masses of 118 kDa, 92 kDa, 78 kDa, 54 kDa, and 40 kDa. These results clearly show that GM-CSF, on its own, can initiate several changes and that these changes are mediated in part by the pertussis toxin-sensitive guanine nucleotide regulatory protein.
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PMID:Granulocyte-macrophage colony-stimulating factor and human neutrophils: role of guanine nucleotide regulatory proteins. 247 Nov 89

1. The mechanism by which incubation of human peripheral blood neutrophils with exogenous arachidonic acid leads to 5-lipoxygenase product synthesis was investigated. 2. Incubation of neutrophils with arachidonic acid caused a concentration- and time-dependent synthesis of leukotriene B4, its omega-oxidation products, and 5-hydroxyeicosatetraenoic acid. 3. The threshold concentration of arachidonic acid required for this effect was equal to, or greater than 3.3 microM and the synthesis increased with up to 33 microM arachidonic acid, the highest concentration used. Synthesis induced by arachidonic acid increased with time for up to 15 min and the major products detected were the omega-oxidation products of leukotriene B4. 4. Pre-incubation of neutrophils with pertussis toxin inhibited the synthesis of 5-lipoxygenase products induced by arachidonic acid by 75% or more, but had no effect on either arachidonic acid-induced synthesis of the 15-lipoxygenase product, 15-hydroxyeicosatetraenoic acid, or activation of the 5-lipoxygenase induced by the calcium ionophore A23187. 5. Pre-incubation of neutrophils with granulocyte-macrophage colony-stimulating factor lead to enhanced leukotriene synthesis in response to arachidonic acid. 6. These results imply that exogenous arachidonic acid is not only used as a substrate, but also activates the 5-lipoxygenase. Possible mechanisms of action are discussed.
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PMID:Activation of the human neutrophil 5-lipoxygenase by exogenous arachidonic acid: involvement of pertussis toxin-sensitive guanine nucleotide-binding proteins. 250 84

Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycerol-3-phosphocholine; PAF) enhances the release of newly synthesized PAF as measured by [3H]acetate incorporation into PAF in human neutrophils. The response was dose-dependent, rapid, transient, and inhibitable by the PAF antagonist BN-52021. The non-metabolizable bioactive PAF analogue (C-PAF) but not lyso-PAF enhances the release of newly synthesized PAF. Newly synthesized PAF was also released after stimulation of these cells with fMet-Leu-Phe. The human granulocyte-macrophage colony-stimulating factor potentiates the stimulated release of PAF. The intracellular calcium chelator BAPTA inhibits the rise of [Ca2+]i and the release of PAF but not the Na+/H+ antiport activity. PAF release, but not the rise in the intracellular concentration of free calcium, was inhibited in pertussis toxin-treated neutrophils stimulated with PAF. The release of PAF in pertussis toxin-treated cells was also inhibited in cells stimulated with fMet-Leu-Phe or opsonized zymosan. These results suggest that functional pertussis toxin-sensitive guanine nucleotide regulatory protein and/or one or more of the changes produced by phospholipase C activation are necessary for PAF release produced by physiological stimuli. It appears that PAF release requires a coordinated action of receptor-coupled G-proteins, calcium, and other parameters.
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PMID:Calcium is necessary but not sufficient for the platelet-activating factor release in human neutrophils stimulated by physiological stimuli. Role of G-proteins. 251 17


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