Gene/Protein Disease Symptom Drug Enzyme Compound
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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)

Mature circulating polymorphonuclear cells (PMN) have the shortest half-life among leukocytes and undergo rapid programmed cell death in vitro. In this study, we have examined the possibility that inflammatory signals (cytokines and bacterial products) can regulate PMN survival. PMN in culture were found to rapidly die, with percentages of survival at 24, 48, 72, and 96 hours of 97.3% +/- 1.9%, 36.8% +/- 5.3%, 14.5% +/- 3.1%, and 4.2% +/- 2.9%, respectively (mean +/- SE of 20 different donors). PMN incubated with interleukin-1 beta (IL-1 beta), tumor necrosis factor, granulocyte-macrophage colony-stimulating factor (CSF), granulocyte-CSF, and interferon-gamma (IFN-gamma), but not with prototypic chemoattractants (fMLP, recombinant C5a, and IL-8), showed a marked increase in survival, with values ranging at 72 hours of incubation from 89.5% +/- 5.8% for IL-1 beta to 47.6% +/- 6.4% for IFN-gamma. The calculated half-life was 35 hours for untreated and 115 hours for IL-1-treated PMN. PMN activated with lipopolysaccharide (LPS) or inactivated streptococci also showed a longer survival compared with untreated cells (94.4% +/- 3.2% and 95.5% +/- 2.4%, respectively, at 72 hours). PMN surviving in response to LPS or IL-1 beta retained the capacity to produce superoxide anion when treated with phorbol esters or fMLP. All inducers of PMN survival protect these cells from programmed cell death because they reduced cells with morphologic features of apoptosis and the fragmentation of DNA in multiples of 180 bp. Thus, certain cytokines and bacterial products can prolong PMN survival by interfering with the physiologic process of apoptosis. Prolongation of survival may be important for the regulation of host resistance and inflammation, and may represent a crucial permissive step for certain cytokines and microbial products that activate gene expression and function in PMN.
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PMID:Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. 138 15

Using a methylcellulose culture system, we studied the effects of recombinant human interleukin-3 (IL-3), recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), and recombinant human granulocyte colony-stimulating factor (G-CSF) on the growth of myeloid progenitor cells (CFU-C) from an adult patient with congenital neutropenia. The moderate clinical course and the maturation arrest at blast-promyelocyte stage in the marrow differentiated this patient from those described as having Kostmann-type congenital neutropenia. CFU-C growth in bone marrow cells from the patient responded to IL-3 normally in a dose-dependent manner. GM-CSF stimulated only macrophage colony formation in a dose-dependent manner comparable to that in normal subjects. Neither GM-CSF nor G-CSF stimulated any significant granulocyte colony formation. This evidence suggests that the hematopoietic progenitor cells in this patient had the potential for developing CFU-C with IL-3, and that the neutropenia in this patient could be a result of an intrinsic defect in myelopoiesis along a granulocytic pathway responsive to GM-CSF or G-CSF.
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PMID:Differential effects of IL-3, GM-CSF and G-CSF in an adult with congenital neutropenia. 138 74

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-macrophage colony-stimulating factor (GM-CSF) is a glycoprotein required for the proliferation and differentiation of granulocyte and macrophage precursors. Previous investigations have identified regions in human and murine GM-CSF that are required for bioactivity. In the present study, alanine substitution mutagenesis was undertaken to define more precisely specific amino-terminal residues in murine GM-CSF that are involved in bioactivity and receptor binding. Five double alanine mutants were identified that showed at least 10-fold reductions in bioactivity (K14AK20A, K14AE21A, H15AK20A, H15AE21A, K20AE21A). Each of these mutants maintained a normal N-linked glycosylation pattern when expressed in COS-1 cells, suggesting that native polypeptide backbone conformation was preserved. The purified prokaryotic expression products of two mutants (K14AE21A and H15AE21A) had a 100-fold decrease in bioactivity and a decrease in receptor binding, indicating that the side chains of K14, H15, and E21 are required for optimal receptor binding and maximal bioactivity.
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PMID:Requirement of hydrophilic amino-terminal residues for granulocyte-macrophage colony-stimulating factor bioactivity and receptor binding. 138 12

IL-5 and granulocyte macrophage-colony-stimulating factor (GM-CSF) are important regulators of eosinophil survival, proliferation, and effector function. To determine whether IL-5 and/or GM-CSF are generated by eosinophils at sites of allergic inflammation, we have used in situ hybridization with 35S-labeled RNA probes to study the expression of IL-5 and GM-CSF mRNA in bronchoalveolar lavage (BAL) eosinophils derived from asthmatics (n = 5) before and after endobronchial allergen challenge. Endobronchial allergen challenge induced a significant airway eosinophilia (pre-allergen challenge 0.6 +/- 0.5% eosinophilia vs post-allergen challenge 48.2 +/- 25.6% eosinophilia). Post-allergen challenge eosinophils expressed IL-5 and GM-CSF mRNA, but did not express IL-1 beta or IL-2 mRNA. To determine whether the IL-5 mRNA-positive cells coexpressed GM-CSF mRNA, double mRNA labeling experiments with a digoxigenin-11-UTP nonradioactive labeled IL-5 RNA probe and a GM-CSF 35S-labeled RNA probe were performed. These studies demonstrated that individual eosinophils expressed one of four cytokine mRNA profiles (IL-5+, GM-CSF+, 34 +/- 13%; IL-5+, GM-CSF-, 34 +/- 5%; IL-5-, GM-CSF+, 11 +/- 9%; IL-5-, GM-CSF-, 21 +/- 25%). The expression of IL-5 and GM-CSF by eosinophils at sites of allergic inflammation in asthmatics may provide an important autocrine pathway, maintaining the viability and effector function of the recruited eosinophils.
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PMID:Eosinophils express interleukin 5 and granulocyte macrophage-colony-stimulating factor mRNA at sites of allergic inflammation in asthmatics. 140 Oct 75

Natural suppressor (NS) cells, which nonspecifically suppress immune responses, are generally found at sites of hemopoietic generation or regeneration. Murine bone marrow NS cells were activated by recombinant interleukin 3 (rIL-3) or recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) and produced a soluble suppressor factor. In the present study, the soluble suppressor factor from bone marrow NS cells was found to be a potent inhibitor of myeloid colony formation at concentrations below those required for immunosuppression. NS cell supernatants inhibited the growth of granulocyte-macrophage colony-forming units (CFU-GM), granulocyte erythrocyte macrophage megakaryocyte colony-forming units (CFU-GEMM), and erythroid colony-forming units (CFU-E) to a similar extent. Neutralizing anti-transforming growth factor beta (TGF-beta) reversed the suppressive effects of the supernatants, suggesting that TGF-beta was involved in the suppression. The NS cell supernatants also inhibited the production of colony-stimulating activity by bone marrow stromal cells and the transcription of GM-CSF mRNA by activated T cells. These data suggest that NS cells are important regulators of hemopoiesis. NS cells, which are non-adherent, radioresistant non-T cells resident in the bone marrow, were shown to be sensitive to treatment with the lysosomotropic agent, L-leucine methyl ester, suggesting that the NS cells may be of large granular lymphocytic or monocytic lineage. Cytotoxicity studies revealed that cells in the NS population had natural cytotoxic (NC), but not natural killer (NK) activity.
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PMID:Bone marrow natural suppressor cells inhibit the growth of myeloid progenitor cells and the synthesis of colony-stimulating factors. 142 97

In this paper, the release of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the lung of patients with HIV-1 infection was evaluated. This cytokine has well recognized effects on granulocyte and macrophage growth and differentiation and plays some role in the mechanisms leading to the accumulation of alveolar macrophages (AM) in patients with interstitial lung disease. Detectable levels of GM-CSF (up to 10 pg/ml) were demonstrated in unconcentrated bronchoalveolar lavage fluid retrieved from HIV-1-seropositive patients, thus suggesting that the GM-CSF is released in vivo in the lung during HIV-1 infection. A statistically significant correlation was demonstrated between the bronchoalveolar lavage concentrations of GM-CSF and the absolute numbers of AM and lung neutrophils. Cell-free supernatants obtained from unstimulated 24-h cultured AM isolated from HIV-1-infected patients contained discrete amounts of GM-CSF, as demonstrated by an immunoenzymatic assay. AM lost the capability of releasing GM-CSF after 72 h of culture, thus suggesting that the production of GM-CSF is not constitutive in AM. After exposition of AM with LPS, the release of GM-CSF and the expression of its mRNA significantly increased with respect to the baseline values; interestingly, the amount of GM-CSF released by LPS-stimulated AM was more than 10-fold higher in HIV-1-infected patients than in healthy subjects. As demonstrated by flow cytometry analysis, more than 70% of freshly isolated AM efficiently bound phycoerythrin-GM-CSF, thus indicating that they express the receptor for GM-CSF. Determination of AM in G1, S, and G2+M by flow cytometry showed that, after 48 h of culture with GM-CSF, 5.5 to 7% of AM entered the proliferative phase of the cell cycle. Taken together, these findings suggest that AM might represent an important source of GM-CSF production in HIV-1 infection. In particular, the hypothesis is formulated that pulmonary opportunists might trigger AM to synthesize GM-CSF in situ. The local overproduction of this cytokine is likely to play a role in the pathogenic events leading to the local proliferation of AM and recruitment of neutrophils in AIDS-associated interstitial lung disease.
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PMID:Release of granulocyte-macrophage colony-stimulating factor by alveolar macrophages in the lung of HIV-1-infected patients. A mechanism accounting for macrophage and neutrophil accumulation. 143 Nov 12

Polycythemia vera (PV) is a clonal disease of the hematopoietic stem cell characterized by a hyperplasia of marrow erythropoiesis, granulocytopoiesis, and megakaryocytopoiesis. We previously reported that highly purified PV blood burst-forming units-erythroid (BFU-E) are hypersensitive to recombinant human interleukin-3 (rIL-3). Because these cells may be only a subset, and not representative of marrow progenitors, we have now studied partially purified marrow hematopoietic progenitor cells. Dose-response experiments with PV marrow BFU-E showed a 38-fold increase in sensitivity to rIL-3 and a 4.3-fold increase in sensitivity to recombinant human erythropoietin (rEpo) compared with normal marrow BFU-E. In addition, PV marrow colony-forming units-granulocyte-macrophage (CFU-GM) and CFU-megakaryocyte (CFU-MK) also showed a marked hypersensitivity to rIL-3 and to human recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). Dose-response curves with rGM-CSF and blood BFU-E showed a 48-fold increase in sensitivity. No effect of rIL-4, rIL-6, human recombinant granulocyte-CSF (rG-CSF), or macrophage-CSF (rM-CSF) was evident, nor was there any effect of PV cell-conditioned medium on normal BFU-E, when compared with normal cell-conditioned medium. Autoradiography with 125I-rEpo showed an increase in Epo receptors after maturation of PV BFU-E to CFU-E similar to that shown with normal BFU-E, but no increase of specific binding of 125I-rIL-3 by PV CD34+ cells was seen compared with normal CD34+ cells. These studies show that PV marrow hematopoietic progenitor cells are hypersensitive to rIL-3 and rGM-CSF, similar to PV blood BFU-E. While the mechanism does not appear to be due to enhanced binding of rIL-3, the hypersensitivity of PV progenitor cells to IL-3 and GM-CSF may be a key factor in the pathogenesis of PV.
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PMID:Polycythemia vera. II. Hypersensitivity of bone marrow erythroid, granulocyte-macrophage, and megakaryocyte progenitor cells to interleukin-3 and granulocyte-macrophage colony-stimulating factor. 149 32

Plasma lactoferrin content was measured before and after therapy with recombinant granulocyte-macrophage colony-stimulating factor in five patients with aplastic anaemia, six with myelodysplasia, and three with prolonged, severe, chemotherapy-induced neutropenia. Before therapy plasma lactoferrin content was uniformly low. However, patients with aplastic anemia and those with chemotherapy-induced neutropenia had a normal lactoferrin:neutrophil ratio. The low levels of plasma lactoferrin thus reflected the low granulocyte mass. On the other hand, patients with myelodysplasia also had reduced lactoferrin:neutrophil ratios, suggesting qualitative/quantitative abnormalities of neutrophil lactoferrin production. After treatment with granulocyte-macrophage colony-stimulating factor, plasma lactoferrin levels increased in patients with aplastic anemia and in those with chemotherapy-induced neutropenia who showed a neutrophil response to treatment. In these patients, the lactoferrin:neutrophil ratio became elevated, suggesting increased synthesis/release of lactoferrin from neutrophils. However, patients with myelodysplasia continued to show depressed lactoferrin:neutrophil ratios, even when there had been an increase in granulocyte count, suggesting persistent abnormalities of neutrophil lactoferrin production/release. The implications of these findings for treatment of neutropenic patients with granulocyte-macrophage colony-stimulating factors are discussed.
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PMID:Plasma lactoferrin content in neutropenic patients: effects of treatment with recombinant granulocyte-macrophage colony-stimulating factor. 151 94

We report a case of Felty's syndrome in which infectious complications due to severe neutropenia could be overcome by short-term treatment with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, 7 micrograms/kg/day s.c.). Leukocyte counts rose from 1,050/mm3 at presentation to 4,470/mm3 after 15 days of treatment. A flare-up of arthritis was not noted. Defects in granulocyte function and clinical improvement prior to leukocyte rise suggest that the beneficial effect of GM-CSF is mainly due to an improvement of granulocyte function.
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PMID:Felty's syndrome: favorable response to granulocyte-macrophage colony-stimulating factor in the acute phase. 151 33


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