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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)

We have examined the signal transduction pathways of a number of cytokines that interact with receptors that are members of the hematopoietin receptor superfamily. A 97-kDa protein was phosphorylated on tyrosine in response to stimulation of appropriate target cells with interleukin (IL)-2, IL-3, granulocyte-macrophage colony-stimulating factor (CSF), granulocyte-CSF, or erythropoietin. These data suggest that a 97-kDa phosphotyrosylprotein represents a point of convergence for signal transduction by a number of growth factor receptors that do not have homology with any known protein tyrosine kinase. To address the possibility that p97 may represent a tyrosine kinase involved in multiple signal transduction pathways, we tested the capacity of this protein to bind a tyrosine kinase substrate or ATP. Indeed, a 97-kDa phosphotyrosylprotein purified from IL-2-stimulated lymphoid cells as well as granulocyte-macrophage-CSF-stimulated myeloid cells bound to a polymer of glutamic acid and tyrosine which is a tyrosine kinase substrate. Further, a 97-kDa phosphotyrosylprotein present in both lineages also bound 8-azido-ATP. These data indicate that a 97-kDa phosphotyrosylprotein with properties consistent with those of a protein tyrosine kinase is involved in the signal transduction pathways of certain members of the newly identified hematopoietin receptor superfamily and may represent an early point of convergence in the stimulus-response coupling of multiple cytokine receptors.
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PMID:Characterization of a 97-kDa phosphotyrosylprotein regulated by multiple cytokines. 138 30

Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma-interferon (gamma-IFN), or tumor necrosis factor-alpha (TNF-alpha) triggered the rapid, stable phosphorylation of a 75-Kd protein (p75) when incubated with permeabilized HL60 human myeloid leukemia cells in the presence of [gamma-32P] ATP. Among several chemical inducers of HL60 cell differentiation, dimethyl sulfoxide also triggered p75 labeling, but retinoic acid or 12-O-tetradecanoylphorbol-13-acetate did not elicit this response. Pretreatment of cells with G-CSF or GM-CSF for more than 30 seconds before permeabilization rendered the p75 labeling undetectable, suggesting that ligand-stimulated labeling was rapidly completed within this time in intact cells. Phosphorylation of p75 occurred on serine and tyrosine residues. This conclusion was confirmed by direct phosphoamino acid analysis. Immunoblot analysis of lysates of intact HL60 cells that had been incubated with G-CSF, GM-CSF, IFN, or TNF confirmed that tyrosine phosphorylation of a p75 also occurred in response to these cytokines in intact cells. Pretreatment of intact HL60 cells with one biologic agent or dimethyl sulfoxide abolished p75 labeling in response to incubation of permeabilized cells with a second agent, strongly suggesting that the same protein was phosphorylated in response to these treatments. p75 labeling was strictly dependent on expression of the appropriate ligand receptor. Data suggest that activation of a tyrosine kinase system is an early response to the binding of G-CSF, GM-CSF, TNF, or IFN to their respective cell surface receptors, or to the addition of dimethyl sulfoxide, and that the resulting phosphorylation event(s) may play a role in securing common elements in the biologic responses to these agents.
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PMID:Binding of G-CSF, GM-CSF, tumor necrosis factor-alpha, and gamma-interferon to cell surface receptors on human myeloid leukemia cells triggers rapid tyrosine and serine phosphorylation of a 75-Kd protein. 168 3

Human recombinant colony-stimulating factors may be used to treat or prevent neutropenia caused by marrow toxic chemotherapeutic agents administered to patients with cancer. Despite their common clinical use, little is known about the potential adverse effects that these cytokines may have on the growth of malignant cells. Indeed, several in vitro reports have indicated that colony-stimulating factors may act as stimulating growth factors in some human malignancies. To evaluate these effects in ovarian cancer, we investigated the possible growth effects of granulocyte colony-stimulating factor (G-CSF/Filgrastim) and granulocyte-macrophage colony-stimulating factors (GM-CSF/Sargramostim) on four established ovarian cancer cell lines, as well as five primary ovarian cancer cultures over a wide range of pharmacologic doses. Cell viability was measured by an ATP bioluminescence assay and expressed as a percentage of untreated control cultures. G-CSF showed no growth-stimulating effects in any of the four established cell lines tested. In the OVCAR-3 cell line, a decrease in growth (> 10%) was seen at 10, 100, and 1000 ng/ml after 5 days of continuous treatment. In the same cell line, GM-CSF caused an increase (> 10%) in growth at the same doses. However, these changes did not demonstrate statistical significance in a dose-dependent fashion. In the five primary cultures treated with G-CSF, only one demonstrated statistically significant increases in growth in a dose-dependent manner. GM-CSF treatment had no significant growth alterations in these same five primary cultures. These results would suggest that colony-stimulating factors may act as growth factors in some but not all ovarian cancer cells. Further investigations into the receptor status of ovarian cancer cells for these cytokines are underway to clarify this issue.
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PMID:In vitro growth effects of colony-stimulating factors in ovarian cancer. 751 21

We have previously shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) gene expression induced by interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in the murine stromal cell line +/+.1-LDA 11 involves activation of phospholipase A2 (PLA2). Furthermore, induction of GM-CSF gene expression due to release of arachidonic acid as a result of PLA2 activation was mediated by the transcriptional factor c-jun. In the present study, we have investigated the potential mechanism involved in the induction of c-jun gene expression by arachidonic acid. Arachidonic acid induced transcription of c-jun mRNA. Downregulation of protein kinase C (PKC) by chronic exposure of stromal cells to the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA; 400 nmol/L) did not effect c-jun expression induced by arachidonate. Moreover, pretreatment of cells with the PKC inhibitor, calphostin C (1 mumol/L), caused a marked decrease of c-jun expression induced by TPA, but had no influence on c-jun expression induced by arachidonate. To explore the hypothesis that a tyrosine kinase signalling pathway, independent of PKC activation, was involved in arachidonate-induced c-jun expression, stromal cells were pretreated with the protein tyrosine kinase inhibitor, genistein, before challenge with arachidonic acid. Arachidonate 50 mumol/L)-induced c-jun expression was inhibited, in a dose- and time-dependent manner, by genistein. Genistein similarly inhibited c-jun expression in stromal cells exposed to IL-1 (500 U/mL) plus TNF-alpha (500 U/mL). The potential role of a tyrosine kinase pathway in arachidonate-mediated c-jun expression was further investigated by assaying the tyrosine kinase activity of cells challenged with arachidonic acid, IL-1, and TNF-alpha. Exposure of stromal cells to arachidonic acid induced a 2.1-fold increase in intracellular tyrosine kinase activity determined by phosphorylation of the synthetic peptide, raytide, in the presence of [gamma-32P]-ATP. Similarly, IL-1 and TNF-alpha induced 1.7- and 2.4-fold increases in tyrosine protein kinase activity, respectively. The effect of arachidonic acid on tyrosine kinase activity was inhibited by genistein and was enhanced by sodium vanadate. The increase of protein tyrosine kinase activity detected in arachidonate-stimulated cells was associated, in a dose- and time-dependent fashion, with tyrosine phosphorylation of 240-, 40-, and 29-kD substrates. These results are consistent with the hypothesis that a tyrosine phosphorylation process is triggered by arachidonate as an early event in the signalling pathway that leads to increased expression of c-jun.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Arachidonic acid induces c-jun gene expression in stromal cells stimulated by interleukin-1 and tumor necrosis factor-alpha: evidence for a tyrosine-kinase-dependent process. 757 89

The presence of a novel 38 kDa protein that is tyrosine phosphorylated in human neutrophils, a terminally differentiated cell, upon stimulation of these cells with low concentrations of lipopolysaccharide (LPS) in combination with serum has been demonstrated. This 38 kDa protein was identified as the mammalian homologue of HOG1 in yeast, the p38 mitogen-activated protein (MAP) kinase. This conclusion is based on the experimental findings that anti-phosphotyrosine (anti-PY) antibody immunoprecipitates a 38 kDa protein that is recognized by anti-p38 MAP kinase antibody, and conversely, anti-p38 MAP kinase antibody immunoprecipitates a 38 kDa protein that can be recognized by anti-PY antibody. Moreover, this tyrosine phosphorylated protein is found associated entirely with the cytosol. It was also found that this p38 MAP kinase is activated following stimulation of these cells with low concentrations of LPS in combination with serum. This conclusion is based on three experimental findings. First, soluble fractions isolated from LPS-stimulated cells phosphorylate heat shock protein 27 (hsp27) in an in vitro assay, and this effect is not inhibited by protein kinase C and protein kinase A inhibitor peptides. This effect is similar to the effect produced by the commercially available phosphorylated and activated MAPKAP kinase-2 (MAP kinase activated protein kinase-2). Secondly, a 27 kDa protein that aligns with a protein recognized by anti-hsp27 antibody is phosphorylated upon LPS stimulation of intact human neutrophils prelabelled with radioactive phosphate. Lastly, immune complex protein kinase assays, using [gamma-32P]ATP and activating transcription factor 2 (ATF2) as substrates, showed increased p38 MAP kinase activity from LPS-stimulated human neutrophils. The phosphorylation and activation of this p38 MAP kinase can be affected by both G-protein-coupled receptors such as platelet-activating factor (PAF) and non-G-protein-coupled receptors such as the cytokine-coupled receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor alpha (TNF-alpha). The effect of low concentrations of PAF is greatly increased in cells pretreated with LPS. The tyrosine phosphorylation of the p38 MAP kinase is not restricted to stimuli that mediate their actions through membrane-associated receptors, but it can be affected by agents that bypass membrane-associated receptors such as the protein translation blocker anisomycin. While anisomycin is known to increase the tyrosine phosphorylation of the 54 kDa SAPK (stress-activated protein kinase), this is the first report that shows that anisomycin also tyrosine phosphorylates the p38 MAP kinase. Cytokine receptors that increase the tyrosine phosphorylation and activation of the erk1 and erk2 MAP kinases have less effect on this p38 MAP kinase than those that do not affect the erk1 and erk2 MAP kinases. The possible role of the p38 MAP kinase in the phosphorylation of cytosolic phospholipase A2 is discussed.
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PMID:Tyrosine phosphorylation and activation of a new mitogen-activated protein (MAP)-kinase cascade in human neutrophils stimulated with various agonists. 876 79

In addition to ATP, platelets and other cell types can secrete high quantities of diadenosine polyphosphates Ap3A, Ap4A, Ap5A and Ap6A. There is increasing evidence to show that these molecules can function as novel modulators of cell function. For this report we have measured the effects of the diadenosine polyphosphates Ap5A and Ap6A on neutrophil apoptosis. These molecules can themselves delay neutrophil apoptosis (as assessed by morphology, function. CD16 expression and chromatin integrity), and are as effective on a molar basis as ATP, Ap3A and Ap4A. Moreover, these dinucleotides act synergistically with granulocyte-macrophage colony-stimulating factor (GM-CSF) to delay neutrophil apoptosis. Thus, diadenosine polyphosphates may act, in concert with cytokines, as novel modulators of neutrophil function and survival in certain types of inflammatory conditions.
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PMID:Neutrophil apoptosis is delayed by the diadenosine polyphosphates, Ap5A and Ap6A: synergism with granulocyte-macrophage colony-stimulating factor. 898 38

In a recent study, we showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) and supernatants from partially stimulated platelets undergoing selective alpha-granule release synergistically enhanced polymorphonuclear leukocyte (PMN) response to N-formyl-methionyl-leucyl-phenylalanine (fMLP). The active factor released from platelet alpha-granules was identified as platelet factor four (PF4). In this study we investigate the joint effect on PMN reactivity of GM-CSF and supernatants from platelets maximally stimulated to release both alpha- and dense granule contents. These platelet supernatants enhanced PMN chemiluminescence (CL; a measure of the oxidative burst) during short incubations, whereas longer incubations led to the loss of this enhancement and the prevention of PMN priming by GM-CSF. The platelet-derived inhibitory factor was of low molecular weight, originated from the dense granule precursor(s), and its generation required the presence of PMN. When ATP/ADP were incubated with PMN at concentrations found in platelet-dense granules, they produced a similar biphasic effect on PMN reactivity (a potentiation followed by inhibition) as seen with the platelet supernatants. The inhibitory effect of these nucleotides coincided with their conversion to AMP. AMP per se had an immediate inhibitory effect on PMN response to fMLP and prevented PMN priming by GM-CSF. This study confirms that partially stimulated platelets enhance PMN reactivity. However, during maximal stimulation, nucleotides released from the platelet-dense granules are converted to AMP, which in turn can counteract the PMN priming effects of factors such as PF4 and GM-CSF.
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PMID:Sequential potentiation and inhibition of PMN reactivity by maximally stimulated platelets. 906 Apr 55

Cholesterol efflux is a fundamental process that serves to mitigate cholesterol accumulation and macrophage foam cell formation. Recently, we reported that cholesterol efflux to high density lipoprotein subfraction 3 was reduced by interferon-gamma (IFN-gamma) and that this decrease was associated with an increase in acyl coenzyme A:cholesterol acyltransferase (ACAT) expression. In the present study, although treatment of murine peritoneal macrophages with IFN-gamma resulted in a 2-fold decrease in HDL-mediated cholesterol efflux, efflux to lipid-free apolipoprotein A-I was reduced >4-fold and approached basal levels. This decrease was associated with a 3- to 4-fold reduction in ATP-binding-cassette transporter 1 (ABC1) mRNA content, the gene responsible for the defect in Tangier disease. Consistent with the reduction in cholesterol and phospholipid efflux in Tangier fibroblasts, downregulation of ABC1 expression by IFN-gamma also resulted in reduced phosphatidylcholine and sphingomyelin efflux to apolipoprotein A-I. Whereas foam cells had a 3-fold increase in ABC1 mRNA, the decrease in ABC1 message levels by IFN-gamma was observed in foam cells and control macrophages. This effect of IFN-gamma was independent of general macrophage activation (inasmuch as similar changes were not detected with granulocyte-macrophage colony-stimulating factor) and was not observed with other ABC transporters (inasmuch as the expression of the transporter in antigen processing was upregulated 4-fold in these same cells). Therefore, by decreasing cholesterol efflux through pathways that include the upregulation of ACAT and the downregulation of ABC1, IFN-gamma can shift the equilibrium between macrophages and foam cells and thus impact the progression of an atherosclerotic lesion.
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PMID:Interferon-gamma induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells. 1084 53

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a powerful arteriogenic factor in the hypoperfused rat brain. To test the pathophysiological relevance of this response, the influence of GM-CSF on brain energy state was investigated in a model of hemodynamic stroke. Sprague-Dawley rats were submitted to three-vessel (bilateral vertebral and unilateral common carotid artery) occlusion (3-VO) to induce unilaterally accentuated brain hypoperfusion. One week later, hemodynamic stroke was induced by additional lowering of arterial blood pressure. Experiments were terminated by in situ freezing of the brain. ATP was measured in cryostat sections by using a bioluminescence method. The use of 3-VO, in combination with 15 min of hypotension of 50, 40, or 30 mmHg, did not produce disturbances of energy metabolism, however, focal areas of ATP depletion were unilaterally detected after 3-VO, in combination with 15 min of hypotension of 20 mmHg. Treating such animals with GM-CSF (40 microg.kg(-1).d(-1)) during the 1-week interval between 3-VO and induced hypotension significantly reduced the hemispheric volume of energy depletion from 48.8 +/- 44.2% (untreated group, n = 10) to 15.8 +/- 17.4% (treated group, n = 8, P = 0.033). GM-CSF-induced arteriogenesis is another approach to protect the brain against ischemic injury.
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PMID:Granulocyte-macrophage colony-stimulating factor-induced arteriogenesis reduces energy failure in hemodynamic stroke. 1530 85

Regulation of P2X7 receptor expression is of interest because activation of this receptor by extracellular ATP triggers a wide variety of cell functions in leukocytes. However, its expression and modulation in human peripheral blood mononuclear cells (PBMC) and monocytes remain unclear. RT-PCR was used to detect the constitutive level of P2X7 receptor and the levels upon stimulation with bacteria, bacterial product, mitogen and various cytokines in human PBMC and monocytes. P2X7 receptor mRNA was detected in PBMC and monocytes. P2X7 receptor expression in PBMC was up-regulated by interleukin-2, -4, -6 (IL-2, IL-4, IL-6) tumour necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS) and heat-inactivated Staphylococcus aureus Cowan strain I (SAC). However, interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and phytohemagglutinin-M (PHA-M) had little effect on the expression of P2X7 receptor. Furthermore, LPS and M-CSF could up-regulate P2X7 receptor expression in monocytes, while IFN-gamma, TNF-alpha and GM-CSF had weak effects, but pretreatment with these inducers could not further enhance LPS-stimulated P2X7 receptor expression in monocytes. The results obtained demonstrate that inflammatory stimuli drive P2X7 expression, thus supporting the hypothesis that P2X7 receptor may play a role in the inflammatory responses against bacteria infection, which need further verification.
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PMID:Effects of various inducers on the expression of P2X7 receptor in human peripheral blood mononuclear cells. 1583 Jan 4


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