Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The high affinity receptor of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is a heterodimer composed of two members of the cytokine receptor superfamily. GM-CSF binds to the alpha-subunit (GM-R alpha) with low affinity and to the receptor alpha beta complex (GM-R alpha beta) with high affinity. The GM-CSF.GM-R alpha beta complex is responsible for biological activity. Interactions of the N-terminal helix of mouse GM-CSF with mGM-R alpha beta were examined by introducing single alanine substitutions of hydrophilic residues in this region of mGM-CSF. The consequences of these substitutions were evaluated by receptor binding and biological assays. Although all mutant proteins exhibited near wild-type biological activity, most were defective in high affinity receptor binding. In particular, substitution of Glu-21 with alanine abrogated high affinity binding leaving low affinity binding unaffected. Despite near wild-type biological activity, no detectable binding interaction of this mutant with mGM-R beta in the context of mGM-R alpha beta was observed. Cross-linking studies showed an apparent interaction of this mutant protein with mGM-R alpha beta. The deficient receptor binding characteristics and near wild-type biological activity of this mutant protein demonstrate that mGM-CSF receptor activation can occur independently of high affinity binding, suggesting that conformational changes in the receptor induced by mGM-CSF binding generate an active ligand-receptor complex.
 ...
PMID:High affinity ligand binding is not essential for granulocyte-macrophage colony-stimulating factor receptor activation. 146 41

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) derived from E. coli was administered to 24 previously untreated patients with non-Hodgkin's lymphoma following the first cycle of CHOP chemotherapy. Four dose levels were examined, 1.5, 3.0, 5.5 and 11 micrograms/kg and patients were randomized to receive the drug either once or twice daily subcutaneously (s.c.). During rhGM-CSF treatment, the leucocyte counts increased up to 3-4 fold in 20/24 patients, reaching a peak 24-48 (mean 35) hours after initiation of rhGM-CSF. The leukopenic period in cycle one of the CHOP chemotherapy with rhGM-CSF, was shorter than after the course of chemotherapy without rhGM-CSF and also shorter when compared to cycle one of CHOP in the 127 historical controls (p < 0.05 and p < 0.001 respectively). Similar results were observed for neutrophil counts. No effect was seen on platelet counts at nadir but a significant, although moderate increase occurred in the recovery period on days 15 and 22 when compared to control cycles and historical controls. When dose levels were compared, there was only a trend to higher WBC counts at the higher dose groups (5.5 and 11 micrograms/kg) when compared to the two lower dose groups (1.5 and 3.0 micrograms/kg). In the overall evaluation there was no statistical significant difference in results between patients treated s.c. once daily versus twice daily. However when only the two highest dose levels (5.5 + 11 micrograms/kg) were compared, s.c. administration of rhGM-CSF twice daily led to higher leucocyte counts than once daily in the recovery period on day 15 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:A phase I/II study of dose and administration of non-glycosylated bacterially synthesized G-M CSF in chemotherapy-induced neutropenia in patients with non-Hodgkin's lymphomas. 147 49

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.
 ...
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

Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) produces dose-related therapeutic and toxic effects; however, relationships between its pharmacokinetics and pharmacodynamics have not been extensively evaluated. The following studies were undertaken to investigate patterns in the disposition of rHuGM-CSF administered after high-dose chemotherapy (cyclophosphamide, cisplatin, carmustine) and autologous bone marrow support. Continuous 14 or 21 day intravenous infusions or daily 4-hour infusions were studied at doses of 1.2 to 19.2 micrograms/kg/d. GM-CSF was measured by an enzyme-linked immunosorbent assay from serum and urine samples collected throughout drug administration. Pharmacokinetic parameters were determined by compartmental (4-hour infusions) or noncompartmental methods (continuous infusions). GM-CSF was rapidly eliminated from the serum. Average systemic exposure increased with dose, although wide interpatient variability was evident. Approximately one half of the patients receiving continuous infusions demonstrated increasing GM-CSF clearance that corresponded to the appearance of white blood cells in the periphery. Conversely, clearance decreased in those experiencing renal dysfunction during the infusion. The percentage of a GM-CSF dose found in 24-hour urine collections was substantially reduced in the latter group. A subset of patients who developed renal dysfunction also experienced significant hypotension. Rapidly increasing serum GM-CSF concentrations corresponded to the hypotensive episodes. GM-CSF serum concentration monitoring may be useful for evaluation of therapeutic and toxic effects in patients receiving high-dose chemotherapy with autologous bone marrow support.
 ...
PMID:Disposition of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving high-dose chemotherapy and autologous bone marrow support. 151 35

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) has been described as a multi-lineage growth factor that induces in vitro colony formation of bone marrow erythroid burst-forming units (BFU-E), multipotential colony-forming units (CFU-GEMM), granulocyte-macrophage CFU (CFU-GM), granulocyte CFU (CFU-G), macrophage CFU (CFU-M), as well as eosinophil colony-forming units (CFU-Eo). Because of the preeminent role of the liver in fetal hematopoiesis, the effect of human recombinant GM-CSF (hrGM-CSF) on hematopoietic cells isolated from human fetal liver was tested in liquid cultures and in semisolid colony assays. hrGM-CSF induced a significant increase in the number of mature eosinophils in liquid culture and to a lesser extent in semisolid cultures when compared to untreated culture controls. The kinetics of this effect on eosinophils reached its peak on day 21 of culture. When GM-CSF and erythropoietin (Ep) were added simultaneously to the cultures, no significant change in the number of eosinophils compared to hrGM-CSF alone was observed. Ep or granulocyte colony-stimulating factor (G-CSF) did not show any CFU-Eo activity when added separately or simultaneously to both liquid and semisolid cultures. These results indicate that hrGM-CSF alone may be a potent stimulating factor for CFU-Eo obtained from human fetal liver and, in combination with other growth factors, control optimal development of human fetal eosinophils.
 ...
PMID:GM-CSF induces eosinophilic cell growth-promoting activity on human fetal liver cells. 152 2

Transforming growth factor-beta (TGF-beta) is a family of polypeptide growth factors with multiple functional activities. Recent studies suggest that TGF-beta is a selective inhibitor of hematopoietic cells. In this report, we study the effect of TGF-beta 1 on the proliferation of murine peritoneal exudate macrophages (PEM) in response to purified murine recombinant granulocyte-macrophage colony-stimulating factor (rMuGM-CSF) and human recombinant M-CSF (rHuM-CSF). In mice, PEM and other types of tissue macrophages display multiple types of receptors for CSFs and respond to them, either alone or in combination, to undergo extensive proliferation in vitro. Recombinant human TGF-beta 1 (rHuTGF-beta 1) (0.1 to 1.0 ng/mL) markedly enhanced the growth of PEM in response to rMuGM-CSF but inhibited their responsiveness to rHuM-CSF. Similar effects of rHuTGF-beta 1 were also detected using murine pulmonary alveolar macrophages (PAM) and bone marrow-derived macrophages (BMDM). Receptor binding assays using iodinated rMuGM-CSF and rHuM-CSF showed that rHuTGF-beta 1 treatment greatly enhanced the expression of GM-CSF receptors in PEM, in a time- and dose-dependent manner, suggesting a possible mechanism for the synergistic effect of TGF-beta 1. On the other hand, the expression of M-CSF receptors was not affected by TGF-beta 1 treatment. Analysis by mRNA PCR showed that the synergistic effect of TGF-beta 1 is not due to autocrine CSFs produced by treated cells. Our results suggest that TGF-beta 1 is an important regulator of macrophage proliferation. Depending on the types of CSFs present, TGF-beta 1 may act either as a growth promoter or inhibitor.
 ...
PMID:Transforming growth factor-beta 1 bifunctionally regulates murine macrophage proliferation. 153 54

We studied human megakaryocytes to determine if they both expressed and synthesized Fc gamma and CD4 membrane receptors. The strategy employed relied on demonstration of receptor protein and mRNA in megakaryocytes present in freshly made marrow smears, or in megakaryocytes isolated from aspirated normal bone marrow by counterflow centrifugal elutriation. Protein was detected immunochemically, whereas mRNA was detected either by in situ hybridization, or by reverse transcription, polymerase chain reaction (RT-PCR). Using these methods CD4 and Fc gamma RII protein and mRNA were detected in most megakaryocytes. Fc gamma RI and Fc gamma RIII protein was not detected in these cells. Megakaryocytes were also cultured with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to determine the effect of this growth factor on Fc gamma RII expression. As has been noted in cells of the monocyte-macrophage lineage, exposure to rhGM-CSF resulted in a significant increase in the level of megakaryocyte Fc gamma RII mRNA and protein. These observations are significant because they provide a physiologic basis for known viral trophism displayed by megakaryocytes. They are also of interest because they suggest that alternative portals exist for entry of human immunodeficiency virus (HIV-1) into megakaryocytes and that such infection may play a role in acquired immunodeficiency syndrome (AIDS)-related thrombocytopenia.
 ...
PMID:Expression of Fc gamma RII and CD4 receptors by normal human megakaryocytes. 153 89

The use of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) as therapy in neonatal sepsis has been proposed because of observed defects in polymorphonuclear leukocyte (PMNL) production and function in infected neonates. Newborn rats were infected intraperitoneally (ip) with type III group B streptococcus (III-GBS) and effects of treatment with rhGM-CSF given ip 7-19 h after infection were studied. Overall mortality was 67% in controls and 37% in animals treated with rhGM-CSF (P = .003). No changes in peripheral blood PMNL number or oxidative metabolic function were found in infected or uninfected animals given rhGM-CSF compared with controls. In uninfected animals, there was an increase in the oxidative burst of peritoneal cells at 3.5 h (P = .043) and in the numbers of peritoneal cells at 3 h (P = .001) in animals receiving ip rhGM-CSF compared with controls. Phagocyte priming, cellular influx into the peritoneum, or both appear to contribute to the decreased mortality observed in this model of rhGM-CSF therapy of III-GBS disease in neonates.
 ...
PMID:Therapeutic use of recombinant human granulocyte-macrophage colony-stimulating factor in neonatal rats with type III group B streptococcal sepsis. 153 38

Natural suppressor (NS) cells, which nonspecifically suppress immune responses, are present in the spleen following exposure to radiation, chronic graft-versus-host disease, or cancer and in normal bone marrow. A model system is described which allows the study of cytokines activating and inhibiting NS cells, cytokines mediating NS activity, and NS effects on cytokine synthesis. Recombinant interleukin-3 (rIL-3) and granulocyte-macrophage colony-stimulating factor (rGM-CSF) efficiently activated NS cells present in normal bone marrow and were effective at concentrations as low as 5 U/ml. At high concentrations, GM-CSF, but not IL-3, did not activate NS cells. Recombinant interferon-gamma (rIFN-gamma) blocked the activation of bone marrow NS cells by rIL-3, but did not down-regulate NS cells once activated. The NS cells secreted one or more soluble suppressor factors, which blocked IL-2 synthesis and also inhibited IL-2-dependent T cell proliferation in the presence of excess IL-2.
 ...
PMID:Cytokine regulation of bone marrow natural suppressor cell activity in the suppression of lymphocyte function. 153 70

Murine receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) and Multi-CSF (interleukin-3) can exist in both high- and low-affinity forms and demonstrate trans-modulation by several different ligands. In contrast the recently cloned human GM-CSF receptor and murine interleukin-3 (IL-3) receptor display only low-affinity binding. To begin to understand the molecular basis of the formation of high- and low-affinity receptors and their trans-modulation we have developed methods for the solubilization and assay of GM-CSF and interleukin-3 receptors so that their binding characteristics can be studied in cell-free solution. Both receptors displayed a single class of high-affinity binding on intact FDC-P1 cells and IL-3 receptors had unaltered binding characteristics in cells, membranes and in detergent solution. However, GM-CSF receptors were converted to a single class of low-affinity binding in detergent solution while both high- and low-affinity forms were evident in membranes. The basis of affinity conversion of GM-CSF receptors was exclusively a change in the kinetic dissociation rate of ligand. Cross-linking experiments suggested that high-affinity receptors for GM-CSF and IL-3 might consist of two different protein species and, if this is so, the data suggest that this association is more stable for IL-3 than for GM-CSF receptors.
 ...
PMID:Affinity conversion of receptors for colony stimulating factors: properties of solubilized receptors. 153 15


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>