UNIPROT:P04141 - FACTA Search

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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)

Human polymorphonuclear leukocytes (PMN) preincubated overnight with 100 U/mL gamma-interferon (IFN-gamma) had an increased metabolic response, as measured by iodination and/or superoxide production, to stimulation by tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), formylmethionyl-leucyl-phenylalanine (FMLP), opsonized zymosan, and lipopolysaccharide (LPS), as compared with cells comparably preincubated in the absence of IFN-gamma. The decline in the staphylocidal activity of the stored PMN was also prevented in part by IFN-gamma, as was the depressed adherence of PMN stimulated with phorbol myristate acetate (PMA), FMLP, TNF, GM-CSF, and LPS. This protective effect of IFN-gamma on PMN function was associated with the prolonged surface expression of the complement receptor three (CR3) alpha-chain (CD11b), CR3 beta-chain (CD18), FcRII (CD32), and FcRIII (CD16), and the appearance of surface FcRI (CD64). The polymerase chain reaction (PCR) was used to amplify neutrophil RNA-derived cDNA recognized by synthetic oliogonucleotides designed from published nucleotide sequences for specific proteins. Using this procedure, mRNA for gp91-phox, p67-phox, p47-phox, CD64, two forms of CD32, CD16, CD11b, CD18, and actin were found to be depressed after overnight storage of neutrophils, and this decrease in steady-state mRNA levels was in part or totally prevented by IFN-gamma. CD64 and gp91-phox mRNA were generally increased by IFN-gamma to a level greater than that of freshly isolated neutrophils. Northern analysis of CD64 and p47 phox mRNAs confirmed the findings with the PCR method. These findings suggest that storage of PMN in a functionally active state is favored by the presence of IFN-gamma.
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PMID:Effects of gamma-interferon on human neutrophils: protection from deterioration on storage. 131 36

Mobilization of a distinct subset of specific granules provides a physiologically important mechanism to recruit Mac-1 (CD11b/CD18) from an intracellular pool to the external surface of the neutrophil plasma membrane, where the functionally active heterodimer mediates several adherence-dependent processes that are crucial for adequate host defense and cellular inflammatory responses. We observed similar characteristics for translocation of Mac-1 and neutrophil formyl peptide receptors (FPR) and hypothesize that the readily accessible pools of both Mac-1 and FPR are colocalized within this specific granule subset. Plasma membrane levels of both FPR (assessed with 3H-FMLP) and Mac-1 (assessed by fluorescence-activated cell sorter analysis of fluorescein isothiocyanate [FITC]-Mo-1-labeled cells) were markedly downregulated in cells prepared at low temperature from blood cooled to 4 degrees C immediately after removal from the circulation. Levels of both FPR and Mac-1 remained low on cells held at 4 degrees C. Upon warming, spontaneous upregulation of Mac-1 and FPR occurred with similar kinetics and temperature dependency. Translocation of both Mac-1 and FPR was markedly potentiated by exposure of cells to either fluoride ion (which has been shown by others to specifically elicit exocytosis of gelatinase-rich and vitamin B-12 binding protein-poor granules) or granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that markedly potentiates the neutrophils' host defense capabilities. Levels of both FPR and Mac-1 on F-- or GM-CSF-treated neutrophils exceeded those present on cells incubated at 37 degrees C for extended time intervals, indicating that stimulated translocation may involve mobilization of an additional granule subset. Scatchard analysis showed that only low-affinity FPR were translocated during spontaneous and stimulus-dependent upregulation. To directly compare FPR levels on the surface of cells displaying varying levels of Mac-1 within a single cell suspension, cells were labeled with FITC-Mo-1 and sorted into subpopulations based on fluorescence intensity. After sorting, the individual populations were held at 4 degrees C to prevent further spontaneous upregulation, concentrated by centrifugation, and assayed for FPR levels. Under a variety of conditions, FPR levels correlated with Mac-1 (CD11b) expression on cell populations selected on the basis of CD11b fluorescence intensity. Analysis of subcellular fractions obtained from disrupted neutrophils before and after upregulation provided additional support for the hypothesis that Mac-1 and FPR are colocalized within a readily accessible subset of neutrophil granules.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Simultaneous mobilization of Mac-1 (CD11b/CD18) and formyl peptide chemoattractant receptors in human neutrophils. 132 4

We have previously shown that 3F8, a murine IgG3, monoclonal antibody (MoAb) specific for the ganglioside GD2, mediates tumor cell kill in vitro and in vivo. We now describe receptor requirements of polymorphonuclear leukocytes (PMN) in 3F8-mediated cytotoxicity (ADCC) of human GD2 (+) melanoma and neuroblastoma cell lines. PMN from a child with leukocyte adhesion deficiency (LAD) were devoid of CD11/CD18 adhesion molecules and mounted no detectable ADCC. MoAb to CD11b, CD11c, and CD18 each efficiently blocked ADCC by normal PMN. In contrast, a panel of different MoAbs to CD11a had no significant inhibitory effect on ADCC, a finding consistent with the low-to-absent expression of the CD11a ligand, intercellular adhesion molecule-1, on the target cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly increased the expression of CD11b, CD11c, and CD18 on normal PMN, decreased the expression of Fc receptors (FcR), and enhanced ADCC by normal but not by LAD PMN. MoAbs to FcRII and FcRIII each efficiently blocked ADCC; anti-FcRI MoAb had no effect. Flow cytometry using anti-FcRII MoAb versus anti-FcRIII MoAb did not show cross competition, suggesting that inhibition of ADCC was not a steric effect resulting from FcRII proximity to FcRIII. PMN deficient in FcRIII (obtained from patients with paroxysmal nocturnal hemoglobinuria) and PMN depleted of FcRIII by treatment with elastase or phosphatidylinositol (PI)-specific phospholipase C produced low ADCC, supporting a role for the PI-liked FcRIII. Thus, optimal ADCC using human PMN, human solid tumor cells, and a clinically active MoAb (conditions that contrast with the heterologous antibodies and nonhuman or nonneoplastic targets used in most models of PMN ADCC) required CD11b, CD11c, FcRII, and the PI-linked FcRIII. Furthermore, in this clinically relevant system, GM-CSF enhancement of antitumor PMN ADCC correlated with increased expression of CD11/CD18 molecules.
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PMID:Absolute requirement of CD11/CD18 adhesion molecules, FcRII and the phosphatidylinositol-linked FcRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity. 134 7

Granulocyte-macrophage colony-stimulating factor (GM-CSF) causes upregulation of neutrophil surface CD11b/CD18 expression, and enhances the adhesion of neutrophils to cultured human endothelial cells in vitro. Systemic administration of GM-CSF results in a rapid, transient decrease in circulating phagocyte numbers. Using a nonhuman primate model (Cynomolgus), we provide histologic evidence that this transient leukopenia is associated with the margination of neutrophils in the pulmonary microcirculation. In four animals receiving 2 to 15 micrograms/kg recombinant human GM-CSF (rhGM-CSF), light microscopic sections of lung contained 36 +/- 8, 17 +/- 7, 21 +/- 6, and 15 +/- 8 (mean +/- SD, n = 20) neutrophils within a graticule grid, as compared with two control animals receiving saline injections whose lung sections contained 2.1 +/- 1.6 and 3.1 +/- 2.1 (mean +/- SD, n = 20) neutrophils within the same grid. Scanning electron microscopy shows activated leukocytes adherent to pulmonary vascular endothelium, but no morphologic evidence of endothelial damage, and no migration of cells into the extravascular space. Margination is associated with an increase in surface expression of CD11b/CD18 on circulating phagocytes, which could contribute to the adhesion to capillary endothelial cells, but CD11b/CD18 levels remain elevated even when demargination is complete. In vitro, monoclonal antibodies (MoAbs) to CD18 and CD11b were able to inhibit neutrophil aggregation and adhesion to endothelium. FMLP-induced neutrophil aggregation was inhibited by 39.8% +/- 11.5% and 44.8% +/- 12.3%, respectively, by MoAbs to CD18 and CD11b (P less than .0005, n = 4 for both); a similar effect was demonstrated on TPA-induced aggregation. MoAb CD18 reduced the adhesion of unstimulated neutrophils to endothelium by 44% (P less than .01, n = 7), and inhibited the amount of GM-CSF-stimulated adhesion by 74% (P less than .001, n = 7), while MoAb to CD11b produced a reduction of unstimulated neutrophil adhesion by 30%, and of GM-CSF-stimulated adhesion by 40% (P less than .01, n = 5, for both). However, when administered in vivo, MoAb CD18 produced only a small, albeit significant, amelioration of GM-CSF-induced margination in vivo, while MoAb CD11b was without effect. These results show that GM-CSF-induced transient leukopenia is associated with enhanced neutrophil adherence to pulmonary vascular endothelium, but suggest that the beta 2 leukocyte integrins CD11/CD18 play only a minor role in this process.
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PMID:Granulocyte-macrophage colony-stimulating factor induces neutrophil adhesion to pulmonary vascular endothelium in vivo: role of beta 2 integrins. 135 72

The role of CD11/CD18 leukocyte adhesion molecules and their ligands in mediating non-major histocompatibility complex (MHC) restricted lymphocyte cytotoxicity is controversial. In order to examine the role of target cell intercellular adhesion molecule-1 (ICAM-1; CD54), a ligand of lymphocyte function-associated antigen (LFA-1) (CD11a/CD18), we exposed the human leukemia cell line, HL-60, to a variety of agents implicated in modulating ICAM-1 expression and/or sensitivity to lymphocyte cytolysis. Exposure of HL-60 cells to retinoic acid (RA), interferon (IFN)-alpha, IFN-beta, and IFN-gamma induced protection from lymphokine-activated killer (LAK) cytolysis. Only RA and IFN-gamma induced ICAM-1 expression. Tumor necrosis factor and vitamin D3, which also induced ICAM-1 expression, increased HL-60 sensitivity to LAK lysis. Granulocyte-macrophage colony-stimulating factor also increased sensitivity to LAK lysis; ICAM-1 was not induced. The state of cellular differentiation and expression of class I and II MHC antigens also did not correlate with sensitivity to LAK cytolysis. Exposure of untreated HL-60 cells and HL-60 cells expressing ICAM-1 to monoclonal antibody (mAb) versus ICAM-1 did not modulate LAK sensitivity. Exposure of LAK cells to mAb versus LFA-1 partially inhibited cytolysis; mAb versus CD18 inhibited cytolysis more completely. HL-60 cells were resistant to natural killer lysis; exposure to the various experimental agents did not alter sensitivity. We conclude that leukemic cell sensitivity to LAK cytolysis can be modulated by a variety of agents. Although our results suggest a role for leukocyte CD11/CD18 adhesion molecules in LAK cytolysis, the poor correlation between ICAM-1 expression and sensitivity to LAK lysis suggest that interactions other than LFA-1/ICAM-1 conjugation may be more central to the processes involved.
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PMID:Modulation of leukemic cell sensitivity to lymphokine-activated killer cytolysis: role of intercellular adhesion molecule-1. 136 53

Eosinophils are known to adhere to cytokine-activated endothelium. Whereas transendothelial migration for neutrophils is an inevitable consequence of this endothelial-dependent adherence, this has not yet been shown for eosinophils. By means of human umbilical vein endothelial cells (HUVE) grown to confluence on microporous filters as an in vitro model of leukocytic migration across postcapillary venules, we have characterized the conditions leading to endothelium-driven transmigration of blood eosinophils from normals and from patients with allergic asthma. Freshly isolated eosinophils from nonallergic donors adhered to interleukin-1 (IL-1) and tumor necrosis factor-activated HUVE, but did not penetrate these monolayers. In contrast, eosinophils from allergic asthma patients showed an increased adherence and transmigration capacity. This increased functional competence was not caused by a difference in density phenotype, because the eosinophils from both groups showed a comparable density distribution over discontinuous Percoll gradients. Moreover, no difference existed within one group among eosinophils harvested from the Percoll density bands 1.080, 1.085, and 1.090 g/mL in terms of transendothelial migration. In vitro cultivation of freshly isolated eosinophils from nonallergic individuals in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3 induced a stepwise decrease of the density distribution over such gradients. In contrast, eosinophils from patients with allergic asthma directly shifted to a final density of 1.075 g/mL within 24 hours of culture. Notwithstanding the kinetics of density changes, eosinophils from nonallergic donors already expressed the capacity to transmigrate IL-1-activated HUVE monolayers 20 hours after cultivation with different combinations of GM-CSF, IL-3, and IL-5. Inhibition studies with monoclonal antibodies showed that endothelium-driven transmigration of eosinophils predominantly implicates CD11/CD18 structures on the eosinophil surface, whereas no significant inhibition was found with the anti-VLA-4 monoclonal antibody HP2/1. From cytofluorometric studies, we conclude that spontaneous transmigration of eosinophils from allergic asthma patients is not accompanied by quantitative upregulation of these antigens. Taken together, these results allow the conclusion that blood eosinophils from allergic asthma patients have undergone in vivo priming, mimicked in vitro by cytokines such as GM-CSF, IL-3, and IL-5, leading to induction of the capacity to migrate across cytokine-activated HUVE monolayers.
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PMID:Migration of primed human eosinophils across cytokine-activated endothelial cell monolayers. 158 39

We have previously reported that cultured human monocytes are lysed by autologous lymphokine-activated killer (LAK) cells in vitro and that treatment of monocytes with interferon-gamma (IFN-gamma) decreased their sensitivity to lysis. Conversely, incubation of monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly enhanced their susceptibility to LAK-mediated cytotoxicity. To determine if certain antigens were differentially modulated on macrophages by IFN-gamma and GM-CSF, cytokine-treated and untreated monocytes were analyzed for the expression of a variety of cell surface markers by flow cytometry. Cytotoxicity assays were performed to assess the ability of antibodies to each of these markers to block LAK lysis of macrophage target cells. While several of the surface structures were differentially modulated by cytokine treatment, it was found that only monoclonal antibodies to the adhesion proteins CD11a and CD18 were capable of blocking lysis of either cytokine-treated or untreated target macrophages.
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PMID:Differential modulation of surface antigens on human macrophages by IFN-gamma and GM-CSF: effect on susceptibility to LAK lysis. 190 35

Polymorphonuclear leukocytes (PMN) constitutively synthesize various plasma membrane proteins including CR1(3) (CD35), CR3 (or Mac-1) alpha-chain (CD11b) and MHC class I. PMN are also able to up-regulate rapidly the expression of CR1 and CR3 to the plasma membrane in response to agonists such as FMLP. To determine whether constitutive PMN translation was static or up-regulatable, PMN were cultured in the presence or absence of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) for 8 h. CR1, CR3 and class I proteins immunoprecipitated from lysates of 35S-methionine pulse-labeled PMN were resolved by SDS-PAGE, fluorographed and quantified by densitometry. GM-CSF-treated PMN synthesized 4.5-fold more class I protein, 3.7-fold more CR1, 2.4-fold more CD11b and 3.4-fold more CR3 beta-chain (CD18), compared with untreated control cells. Actinomycin D treatment of replicate samples of PMN decreased the amount of these proteins synthesized by each group of PMN from 30 to 90%, implying that continued translation was required for the increases in protein synthesis. Nascent CR and class I proteins were inserted into the plasma membrane of PMN, thereby supplementing the molecules already expressed on the cell surface. In addition to these longer term effects of GM-CSF, we observed its acute up-regulatory effects on PMN. GM-CSF induced a five- to 12-fold increase in the expression of CR1 and CR3 on the PMN cell surface within 30 min. These increases were both dose- and time-dependent with maximum up-regulation occurring at 25 pM and at 30 min. In contrast to the long term biosynthetic events, this rapid up-regulation was not dependent on protein synthesis but was due instead to mobilization of CR from intracellular compartments similar to those up-regulated by FMLP. These results demonstrate that PMN can respond to microenvironmental stimuli such as GM-CSF both by rapidly up-regulating and increasing translation and expression of functionally important plasma membrane proteins.
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PMID:Granulocyte-macrophage colony-stimulating factor increases synthesis and expression of CR1 and CR3 by human peripheral blood neutrophils. 197 99

Incubation of human bloodstream neutrophils with 50 u/ml recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) "primed" the respiratory burst (as assessed by fMet-Leu-Phe stimulated luminol-dependent chemiluminescence) and resulted in a rapid (within 15 min) up-regulation of expression of CD11b and CD18 (as measured by FACS analysis). This rapid "priming" and modulation of receptor expression was not inhibited by cycloheximide and hence appeared to be independent of de novo protein biosynthesis. When neutrophils were incubated for up to 5 h in culture, the fluorescence distributions of CD11b and CD18 declined indicating the loss of expression of these receptors as the neutrophils aged, but in rGM-CSF treated suspensions receptor expression was maintained. When neutrophils were incubated in the presence of cycloheximide, they progressively lost their ability to generate reactive oxidants in response to fMet-Leu-Phe so that by 5 h incubation with this inhibitor they could only generate about 25% of the oxidative response stimulated in untreated cells, and the expression of CD16 and CD18 was grossly impaired. Similar effects were observed in rGM-CSF treated suspensions except that cycloheximide required longer incubation times (typically 4-5 h) before impairment of function or receptor expression occurred. These data show that de novo protein biosynthesis is required for both the maintenance of neutrophil function and also for the continued expression of some plasma membrane receptors.
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PMID:Receptor expression and oxidase activity in human neutrophils: regulation by granulocyte-macrophage colony-stimulating factor and dependence upon protein biosynthesis. 197 13

Adhesion is known to prime neutrophils for physiological activation in response to cytokines and other stimuli. We have employed the technique of receptor cross-linking to study the potential role of CD18, the common beta-subunit of the beta 2-integrin family of adhesion molecules, in the regulation of the respiratory burst, as measured by luminol-enhanced chemiluminescence and iodination, in human neutrophils. CD18 cross-linking primed neutrophils to activate the respiratory burst after stimulation with tumor necrosis factor alpha (TNF-alpha) (100 units/mL), formylmethionyl-leucyl-phenylalanine (fMLP) (1 microM), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (1 micrograms/mL), but not granulocyte colony-stimulating factor (G-CSF) (1 micrograms/mL), interferon-gamma (IFN-gamma) (100 U/mL), or phorbol myristate acetate (100 nM). The maximal rate of chemiluminescence induced by fMLP, TNF-alpha, and GM-CSF was enhanced 8-, 6-, and 1.5-fold, respectively, following CD18 cross-linking. Priming of the respiratory burst by direct engagement of CD18 was confirmed in neutrophil-mediated iodination experiments, where iodination induced by TNF-alpha, fMLP, and GM-CSF was increased 15-, 20-, and 7-fold, respectively, by CD18 cross-linking. Immunoblot experiments demonstrated that TNF-alpha-induced tyrosine phosphorylation was both accelerated and more intense in neutrophils after cross-linking of CD18. Major tyrosine phosphoprotein products include proteins with approximate molecular masses of 40, 70, and 110 kDa. Genistein (50 microM), a selective tyrosine kinase inhibitor, reduced the TNF-alpha-stimulated respiratory burst by > 80% whether or not CD18 was cross-linked. These results affirm the importance of CD18 in adhesion-dependent priming of neutrophil functions and demonstrate that CD18 engagement per se is sufficient to prime neutrophils for cytokine-induced signal transduction mediated by tyrosine phosphorylation.
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PMID:Cross-linking of CD18 primes human neutrophils for activation of the respiratory burst in response to specific stimuli: implications for adhesion-dependent physiological responses in neutrophils. 749 67

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