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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)

Cells of the macrophage lineage are a major source of various cytokines and hematopoietic growth factors. With regard to the growth factors acting on cells of their own lineage, macrophage colony-stimulating factor (M-CSF) has been proven to be secreted by monocytes (MO) and macrophages (MAC), whereas the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by human MO/MAC is under debate. Here we report that in elutriation-purified MO, as well as in MAC derived from cultured MO, GM-CSF m-RNA was regularly induced by LPS. In MO the GM-CSF message was still detectable 18 h after stimulation under serum-free conditions, but in contrast was already lost at this time point in MAC. Secreted GM-CSF protein was detected in the culture medium using a sandwich ELISA. Furthermore, a factor-dependent cell line (M-07) was used for a biological assay. Here, a neutralizing anti GM-CSF antibody specifically blocked the proliferation-inducing activity of MO/MAC supernatants. Whereas only small amounts of GM-CSF were detected in MO, its secretion increased severalfold upon MO-to-MAC differentiation in vitro. A similar increase upon in vitro maturation of MO was observed for the production of granulocyte colony-stimulating factor. The highest amounts of GM-CSF (up to 2.8 ng/10(6) cells) were produced by MAC that had been derived from MO cultured under serum-free conditions in the presence of 0.5 mg/ml albumin as the only medium supplement.
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PMID:Developmental regulation of granulocyte-macrophage colony-stimulating factor production during human monocyte-to-macrophage maturation. 137 50

Infections during granulocytopenia are major complications of autologous bone marrow transplantation (ABMT). Since recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) has proved to accelerate bone marrow recovery after cytostatic chemotherapy, we studied its effects on hematopoietic regeneration and on infectious complications after total body irradiation (TBI) and high-dose chemotherapy followed by ABMT. Eighty-one patients with acute lymphoblastic leukemia (ALL) in complete remission (CR) or with non-Hodgkin's lymphoma (NHL) in CR or partial remission were randomized in a double-blind, placebo-controlled trial. They received either rhuGM-CSF 250 micrograms/m2 (Escherichia coli-derived) daily by continuous infusion after ABMT, or placebo. Treatment was continued until the neutrophil counts reached greater than 500/microL for 1 week. The maximum treatment duration was 30 days. Thirty-nine patients in the rhuGM-CSF group and 40 patients in the placebo group were evaluable. The median time needed to reach a neutrophil count of 500/microL was 15 days with rhuGM-CSF and 28 days with placebo (P = .0001). Bacterial infections occurred in 14 (35.9%) of the patients with rhuGM-CSF and in 25 (62.5%) of the patients given the placebo (P = .024). Nine of the 14 bacterial infections in the rhuGM-CSF group and 20 of the 25 infections in the placebo group were diagnosed within the first 10 days after ABMT. Capillary leakage and a reversible fluid retention were seen in five of the rhuGM-CSF-treated patients. Patients treated with rhuGM-CSF had lower serum protein and albumin levels than patients in the placebo group. There was no statistically relevant difference in overall survival between the two groups (P = .47). Relapse occurred in 14 (34%) patients with rhuGM-CSF and in 18 (45%) patients with placebo. We conclude that continuous infusion of rhuGM-CSF after ABMT accelerates the regeneration of granulocytes and reduces the number of bacterial infections.
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PMID:A controlled trial of recombinant human granulocyte-macrophage colony-stimulating factor after total body irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for acute lymphoblastic leukemia or malignant lymphoma. 142 90

Large quantities of human blood-derived monocytes have been cultured in suspension in nonadherent cell culture bags and maintained for up to 3 weeks in a serum-free medium. This serum-free medium contained Iscove's modified Dulbecco's medium (IMDM) supplemented with human albumin, alpha-phosphatidylcholine, transferrin, and insulin. Morphology, cell surface antigens, and functional properties of these in vitro maturing macrophages were studied in comparison with macrophages cultured in a standard medium containing 10% fetal calf serum. In this report we demonstrate that this serum-free medium allows a better yield of cell survival than the standard medium; it also allows the differentiation of blood monocytes into fully functional macrophagic cells that express the different antigens found in mature macrophages. The results indicate that the use of serum-free defined medium offers good conditions in which to culture large numbers of human monocytes and allows an accurate analysis of the effect of supplementation with growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on the differentiation and survival of monocytes and macrophages. Serum-free cultures could also be helpful for the precise analysis of the cell secretion activity and for determining the factors that are responsible for monocyte maturation into macrophages.
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PMID:Human blood-derived macrophages: differentiation in vitro of a large quantity of cells in serum-free medium. 157 91

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) generally are rapidly eliminated from the blood after intermittent intravenous infusion. Subcutaneous administration of these agents results in lower peak concentrations but is associated with prolonged systemic exposure. Elimination of the factors appears to occur by several mechanisms, including white blood cell receptor-mediated endocytosis, metabolism by proteases, and urinary excretion by glomerular filtration with subsequent reabsorption and catabolism. The pattern and route of elimination are affected by type of factor and dosage, degree of glycosylation, renal function, and number of white blood cell receptors for the particular CSF. Granulocyte CSF and GM-CSF are approved for use in patients with nonmyeloid malignancy who are receiving myelosuppressive chemotherapy, and those undergoing high-dose chemotherapy and bone marrow transplantation, respectively. In these indications, treatment generally is initiated no earlier than 24 hours after chemotherapy and continued beyond the expected chemotherapy-associated neutrophil count nadir. Limited information suggests that subcutaneous administration is more effective than intermittent intravenous infusion. The latter may require the addition of albumin to ensure stability. Storage and handling guidelines include preventing exposure to extreme temperatures and avoiding excessive agitation of the solution.
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PMID:Pharmacokinetics and administration of colony-stimulating factors. 159 12

Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates production of neutrophils in bone marrow and may decrease the incidence of infection during neutropenia. We evaluated the protective role of recombinant GM-CSF against Pseudomonas aeruginosa challenge in neutropenic mice. CD-1 mice treated with cyclophosphamide on days 1 and 2 of the experiment were given GM-CSF (1, 2, or 4 micrograms/day) starting at day 4 of the experiment according to the following protocol: 1) 1 microgram of GM-CSF 2 hr and 24 hr after challenge; 2) 1 microgram 24 hr before challenge, 2 hr and 24 hr after challenge; 3) 2 micrograms injected 24 hr before and 2 hr after challenge; 4) 2 micrograms given 24 hr before and 2 micrograms given 2 hr and 24 hr after challenge; 5) 4 micrograms administered 2 hr and 24 hr after challenge; and 6) saline and bovine albumin controls. The number of blood neutrophils by days 4 and 5 was similar for GM-CSF-treated and untreated animals. Survival was significantly greater in animals given 2 micrograms of GM-CSF at 24 hr before and at 2 hr and 24 hr after challenge with Pseudomonas. Neutrophils and splenic macrophages obtained from GM-CSF-treated mice (2 micrograms/animal) produced significantly greater amounts of O2- (204 +/- 36 nmoles/10(5) cells) than controls (21 +/- 10 nmoles/10(5) cells). Additionally, neutrophils and macrophages from GM-CSF-treated mice killed significantly more bacteria (P. aeruginosa) in vitro and had a greater number of C3b and Fc receptors (78 +/- 12% and 89 +/- 8%) than did cells obtained from control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protection against gram-negative bacteremia in neutropenic mice with recombinant granulocyte-macrophage colony-stimulating factor. 196 50

In a placebo-controlled double-blind dose-finding trial, 15 patients with ovarian cancer stage III or IV received daily s.c. 1.5, 3, or 6 micrograms/kg recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). At each dose step three patients received recombinant human GM-CSF, and two received placebo. Chemotherapy comprised 6 cycles of carboplatin, 300 mg/m2, and cyclophosphamide, 750 mg/m2, by i.v. bolus on day 1 every 4 weeks. GM-CSF, given on days 6-12 on an outpatient basis, raised the mean leukocyte count on days 7, 10, and 15 and the mean neutrophil count on days 7 and 10 at all dose levels as compared with the control group. Neutrophil counts of less than 0.5 x 10(9)/liter occurred in 20 of 22 cycles in the control group and in 5 of 17 cycles at the 6-micrograms/kg/day GM-CSF dose level (P less than 0.0005). In comparison with the control group, the mean eosinophil count was higher on days 10 and 15 at all GM-CSF doses, as was the mean monocyte count on day 15. The mean platelet count was raised at the 3- and 6-micrograms GM-CSF doses on days 15 and 22. Chemotherapy dose reduction or postponement due to myelotoxicity occurred in 9 of 28 cycles in the placebo groups versus 5 of 44 cycles in the GM-CSF group (not significant). Local skin infiltrates at the GM-CSF injection sites occurred in 8/9 patients, leading to premature removal of two patients from the study. Capillary leakage of 131I-albumin was increased in all patients 5 days after the first chemotherapy course but was not significantly affected by 4 days of GM-CSF treatment. Tumor necrosis factor alpha and C-reactive protein serum levels increased during GM-CSF administration at the 6-micrograms dose level, but interleukin 6 serum levels were not affected. We conclude that a dose of 3 and 6 micrograms/kg/day GM-CSF reduces the severity of neutropenia and thrombocytopenia after carboplatin-cyclophosphamide. This GM-CSF dose does not induce additional capillary leakage.
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PMID:A double-blind placebo-controlled study with granulocyte-macrophage colony-stimulating factor during chemotherapy for ovarian carcinoma. 198 77

Colony-stimulating factor-1 (CSF-1 or M-CSF) supports the proliferation and survival of mononuclear phagocytes by binding to a receptor (CSF-1R) encoded by the c-fms proto-oncogene. Whereas the CSF-1R kinase is normally regulated by ligand, receptors bearing 'activating mutations' act constitutively as enzymes and can transform fibroblasts and haemopoietic cells of different lineages. Introduction of human CSF-1R enables mouse NIH-3T3 cells to form colonies in agar in response to human CSF-1 and to proliferate in serum-free medium supplemented with CSF-1, albumin, transferrin and insulin. Similarly, expression of human CSF-1R in interleukin 3-dependent mouse FDC-P1 myeloid cells enables them to grow in CSF-1. High levels of CSF-1R expression in FDC-P1 cells can induce factor-independent growth which is abrogated by a 'neutralizing' monoclonal antibody to the receptor. Therefore, critical mutations in the c-fms gene or overexpression of CSF-1R in immature myeloid precursors might each contribute to leukaemia.
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PMID:Signal-response coupling mediated by the transduced colony-stimulating factor-1 receptor and its oncogenic fms variants in naive cells. 215 60

A Phase I study of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was undertaken in 21 patients with advanced malignancy or neutropenia. rhGM-CSF was administered once daily by i.v. bolus injection (0.3 to 3 micrograms/kg/day) or 2-h i.v. infusion (3 to 20 micrograms/kg day) for 10 days. rhGM-CSF at all i.v. doses caused an immediate transient decrease in circulating neutrophils, eosinophils, and monocytes. By 6 h after rhGM-CSF, circulating leukocyte levels were restored. Daily i.v. bolus dosing (0.3 to 3 micrograms/kg/day) did not elevate leukocyte levels except in one neutropenic patient. Daily 2-h i.v. infusions (10 to 20 micrograms/kg/day) caused a dose-dependent leukocytosis with increased levels of neutrophils (up to 4.3-fold), eosinophils (up to 18-fold), and monocytes (up to 3.5-fold). Marrow aspirates showed increased proportions of promyelocytes and myelocytes during rhGM-CSF administration. Retreatment after 10 days without rhGM-CSF resulted in a more marked leukocytosis at doses greater than or equal to 10 micrograms/kg/day. Platelet levels decreased for the first 3 days and then increased during the first course of rhGM-CSF administration. Two patients with chronic lymphocytic leukemia had a transient reduction in lymphocytosis. Serum cholesterol and albumin levels decreased, and vitamin B12 levels increased during rhGM-CSF treatment. At doses of up to 15 micrograms/kg/day, rhGM-CSF was relatively well tolerated by the patients, but adverse effects included bone pain, lethargy, fever, rash, and weight gain. A first dose reaction characterized by hypoxia and hypotension was identified at dose levels greater than or equal to 1 microgram/kg. Dosing i.v. was less potent at inducing a leukocytosis than previously observed for equivalent s.c. doses and was associated with a higher incidence of generalized rash and first dose reactions. The maximal tolerated dose of i.v. rhGM-CSF was 15 micrograms/kg/day. Phase II studies in which the derived effect is to raise leukocyte levels should be undertaken at rhGM-CSF doses of 3 to 15 micrograms/kg/day.
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PMID:Phase I study of intravenously administered bacterially synthesized granulocyte-macrophage colony-stimulating factor and comparison with subcutaneous administration. 240 73

The purpose of this study was to examine the effect of lithium chloride (LiCl) on human monocytes. Patients undergoing lithium therapy have elevated white blood cell counts. Since both tumor necrosis factor alpha (TNF alpha) and interleukin 1 (IL-1), which are secreted by monocytes, can stimulate endothelial cells to produce granulocyte-macrophage colony-stimulating factor (GM-CSF), we determined whether lithium-stimulated monocytes produced TNF alpha and/or IL-1. Normal human monocytes were incubated for 24 h with medium (negative control), lipopolysaccharide (positive control), or LiCl (0.05-50 mM). The supernatants were removed and assayed for IL-1 and TNF alpha secretion using the D10.G4.01 and L929 assays, respectively. Lithium did not stimulate IL-1 secretion but did stimulate TNF alpha secretion (5-10 U/ml of TNF alpha per 2 x 10(5) monocytes). The increased secretion of TNF alpha was associated with a fourfold increase in TNF alpha mRNA. TNF alpha activity in the supernatants was neutralized by a monoclonal antibody against human TNF alpha but not by antibody against human albumin. Other alkali metals such as rubidium and cesium did not stimulate monocytes to secrete TNF alpha. These data indicate that one mechanism by which Li may cause granulocytosis is through a transcriptional enhancement of TNF production and subsequent secretion by monocytes.
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PMID:Lithium chloride stimulates human monocytes to secrete tumor necrosis factor/cachectin. 255 37

Inflammation can be demonstrated in the airway mucosa of asthmatics, even in the absence of overt symptoms, but the pathogenesis of this chronic inflammation is incompletely defined. It has been suggested that inflammatory cytokines produced by epithelium may play important roles in this process. Therefore, we measured the cytokines interleukin-8 (IL-8), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in nasal lavage fluids from school-age children who were (1) "normal" (nonallergic/nonasthmatic), (2) allergic to house-dust mite antigen but nonasthmatic (no history of wheezing), or (3) allergic and asthmatic (history of > or = 10 wheezing episodes). Children underwent a single nasal lavage procedure while asymptomatic and on no anti-inflammatory medications or anti-histamines. In addition to cytokine concentrations, cell counts, differentials, albumin, histamine, and eosinophil cationic protein (ECP) concentrations were determined in nasal lavage fluids. Significant increases in IL-8 and ECP were observed in asthmatics compared with both normals and allergic nonasthmatics. Overall, IL-8 in nasal lavage fluids correlated significantly with ECP. Allergic nonasthmatics did not have significant increases in cytokines or other mediators compared with normal subjects. Concentrations of IL-6 did not differ significantly among the three groups, and GM-CSF was undetectable in all samples tested. We conclude that increased IL-8 production and eosinophil activation are characteristic of the airways of asthmatic children when asymptomatic, and we speculate that IL-8 plays a role in the maintenance of airway inflammation in asthma.
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PMID:Nasal lavage cytokines in normal, allergic, and asthmatic school-age children. 755 84


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