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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)

Mast cell growth factor (MGF, the ligand for c-kit receptor) can stimulate proliferation of factor dependent myeloid cell line, M07e, and MGF synergizes with granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-3 in this effect. The effect of MGF on protein tyrosine kinase activity in M07e cells was investigated by immunoblotting with anti-phosphotyrosine mAb and this was compared with effects of GM-CSF. MGF stimulation rapidly induced or enhanced at least 12 tyrosine phosphorylated bands. Major bands had molecular weights of 145, 120, 110, 98, 62, 55 and 42 kD. P145, the most prominent phosphorylated protein, was identified as c-kit product using anti-c-kit-mAb (YB5.B8), suggesting ligand-dependent receptor autophosphorylation. Five of six tyrosine phosphorylated bands induced or enhanced by GM-CSF stimulation comigrated with those tyrosine phosphorylated by MGF (138, 120, 76, 55 and 42 kD). P42 was identified, at least in part, as mitogen-activated protein (MAP) kinase. MGF induced tyrosine phosphorylation of a complex of GTPase-activating protein (GAP, 120 kD) and GAP associated proteins (p62/p190) as detected by anti-GAP Ab immunoprecipitation followed by immunoblotting with anti-phosphotyrosine mAb. GM-CSF also stimulated slightly but consistently tyrosine phosphorylation of GAP and p190 but not p62. Both MGF and GM-CSF enhanced Raf-1 phosphorylation and increased Raf-1 associated kinase activity in vitro. Phosphoamino acid analysis revealed Raf-1 phosphorylation by these two growth factors occurred almost exclusively on serine residues. No tyrosine phosphorylation of Raf-1 protein was detected. These data suggest shared and unshared components of signaling pathways of both factors, which may be involved in cell proliferation.
Exp Hematol 1991 Dec
PMID:Comparative analysis of signaling pathways between mast cell growth factor (c-kit ligand) and granulocyte-macrophage colony-stimulating factor in a human factor-dependent myeloid cell line involves phosphorylation of Raf-1, GTPase-activating protein and mitogen-activated protein kinase. 172 91

Interleukin 3 (IL-3) expression in PB-3c mastocytes is transiently induced in vitro by treatment with the drug A23187, a calcium ionophore, or constitutively following ras-dependent transformation in vivo. While the mechanism of oncogenically induced IL-3 expression is not clear, A23187-mediated lymphokine mRNA accumulation is primarily the result of calcium-dependent mRNA stabilization. We investigated whether the expression of various ras alleles influenced IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA induction by A23187. It was found that activated forms of ras potentiated ionophore-mediated lymphokine mRNA accumulation. This enhancement involves a post-transcriptional mechanism, as ionophore-induced lymphokine mRNAs are significantly more stable in ras oncogene-expressing lines than in the control line. We propose that one way by which ras genes exert their oncogenic potential is by extending the half-life of short-lived growth factor mRNAs.
Oncogene 1991 Dec
PMID:Ras oncogenes amplify lymphokine (interleukin 3, granulocyte-macrophage colony-stimulating factor) induction by calcium ionophore. 172 72

Colony-stimulating factors are a family of glycoproteins instrumental in regulation of hematopoiesis and inflammation. Clinical effects of various colony-stimulating factors have been reported in murine and human hosts. This review summarizes findings from some clinical trial evaluations of macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, interleukin-1, interleukin-3, interleukin-4, interleukin-5, interleukin-6, and interleukin-7 administration to other species. These factors stimulate clonal expansion of progenitor cells in the bone marrow, induce differentiation of various cell lineages to a mature phenotype, and, in some cases, enhance the effector activities of immune cells. Each colony-stimulating factor has distinct lineages of bone marrow cells upon which they act, although there is some overlap in lineage activity and synergy between colony-stimulating factors. The close relationship in biological activity among different colony-stimulating factors is also reflected at the genomic level at which genes for some hematopoietic growth factors have been mapped to a region of human chromosome 5. Recently, colony-stimulating factor administration to cattle and its potential application to disease control in bovine preventive medicine programs has been investigated. Data from recent hematological, immunological, and intramammary bacterial (Staphylococcus aureus and Klebsiella pneumoniae) challenge studies in dairy cows are reviewed. These studies, with limited numbers of cows, found that rate of new infections, as well as duration and severity of infection, were reduced by pretreatment of cows with granulocyte-colony stimulating factor. The dose-dependent hematological and immunomodulatory effects of granulocyte colony-stimulating factor administration may explain reduced severity and incidence of mastitis in dairy cows given granulocyte colony-stimulating factor.
J Dairy Sci 1991 Dec
PMID:Immunobiology of hematopoietic colony-stimulating factors: potential application to disease prevention in the bovine. 172 1

To evaluate the effect of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) on patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) who were intolerant to zidovudine because of neutropenia, we performed a randomized, open-label study in which patients were assigned to one of two groups. Zidovudine was discontinued in group A patients before instituting GM-CSF treatment and was restarted in a graduated fashion over 4 weeks. Group B patients continued on full-dose (1,200 mg/d) zidovudine therapy while beginning GM-CSF therapy. A total of 17 patients were entered, eight in group A and nine in group B. Five of eight patients in group A and seven of nine in group B had a history of Pneumocystis carinii pneumonia (PCP). All were homosexual males, except one female in group A who was the sex partner of a bisexual male with AIDS. All patients had neutropenia (absolute neutrophil count [ANC] less than 1,000/microL) while taking full-dose zidovudine. The mean CD4 (+/- SD) lymphocyte level was 37 (+/- 29)/microL and 39 (+/- 44)/microL in groups A and B, respectively. After randomization, patients were begun on subcutaneous GM-CSF at a dose of 1.0 microgram/kg/d. Patients in group A received 2 weeks of daily GM-CSF, at which time zidovudine was restarted if the ANC was greater than 1,000/microL; if the ANC was less than 1,000/microL, the dose of GM-CSF was increased to 3.0 micrograms/kg, and at 2-week intervals either zidovudine was restarted or the dose of GM-CSF was increased to 5 micrograms/kg and then 10 micrograms/kg, to maintain the ANC greater than 1,000/microL. Group B patients received full-dose zidovudine concurrently with GM-CSF administration. The dose of GM-CSF was increased every 2 weeks if necessary to keep the ANC greater than 1,000/microL while maintaining full-dose zidovudine therapy. Patients in each group showed an increase in total white blood cell (WBC) count. Neutrophils and eosinophils were responsible for the majority of this increase. Patients in group A had a more rapid increase in WBC than those in group B; however, by week 8, the WBC in each group was essentially equal. Viral replication as measured by human immunodeficiency virus (HIV) p24 antigen (Ag) was decreased in four patients in each group, increased in one patient in each group, and remained unchanged in the remainder. The ability to culture virus from peripheral blood mononuclear cells was not changed by the regimen. The major toxicities of the regimen were fever and malaise.(ABSTRACT TRUNCATED AT 400 WORDS)
Blood 1991 Dec 15
PMID:Recombinant human granulocyte-macrophage colony-stimulating factor ameliorates zidovudine-induced neutropenia in patients with acquired immunodeficiency syndrome (AIDS)/AIDS-related complex. 174 82

We studied the effect of the combination of rapid culture medium exchange with the addition of the human hematopoietic growth factors interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin (Epo) on the proliferation and differentiation of human long-term bone marrow cultures (LTBMCs). Individually and in combinations, IL-3, GM-CSF, and Epo were added to the culture medium of LTBMCs that were maintained with 50% medium volume exchange per day. The combination of IL-3 + GM-CSF + Epo generated the most prolific cultures with an order of magnitude increase in nonadherent cell production from weeks 2 through 8 in culture as compared with unsupplemented controls. Under these conditions, the cultures produced as many cells as were inoculated every 2 weeks and led to a greater than 2.5-fold expansion in terms of the number of nonadherent cells produced over a 6- to 8-week period. Furthermore, the LTBMCs produced nonadherent colony-forming unit-GM (CFU-GM) for more than 20 weeks. The rapid medium exchange combined with the addition of human hematopoietic CSFs significantly enhances the proliferation and differentiation of LTBMCs. These results indicate that addition of combinations of hematopoietic CSFs, together with a rapid medium exchange rate, can provide culture conditions that are suitable for the expansion of the progenitor cell pool and perhaps for the increased survival of hematopoietic stem cells in culture. Although these culture conditions still fall short of full reconstitution of functional human bone marrow, they provide an improved approach to hematopoietic cell culture that may permit the expansion and manipulation of progenitor cells in vitro.
Blood 1991 Dec 15
PMID:In vitro myelopoiesis stimulated by rapid medium exchange and supplementation with hematopoietic growth factors. 174 83

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was established as the constitutive and elicited human umbilical vein endothelial cell-derived eosinophil viability-sustaining factor. Stimulation of endothelium cell monolayers with IL-1 alpha (5 U/ml) increased the 48-h elaboration of GM-CSF from a mean of 3.2 to a mean of 8.2 pM (P less than 0.05). Dexamethasone (100 nM) decreased the constitutive GM-CSF elaboration by 49% (P less than 0.001) but did not diminish production by IL-1 alpha-stimulated endothelium. However, eosinophil viability decreased by 21% in dexamethasone-pretreated IL-1 alpha-stimulated endothelial cell-conditioned medium (P less than 0.05), which suggested viability antagonism by glucocorticoids. After 24 h of culture, eosinophil viability for replicate cells in enriched medium alone or with 1 pM GM-CSF decreased from means of 43 and 75% to means of 21 and 54%, respectively, when dexamethasone was included (P less than 0.05). However, 10 pM GM-CSF, IL-3, or IL-5 protected the cells against dexamethasone and against endonuclease-specific DNA fragmentation. In this model system of eosinophil-tissue interactions, dexamethasone prevents the endothelial cells from inducing a pathobiologic phenotypic change in the eosinophil by suppression of GM-CSF elaboration to concentrations that are not cytoprotective. Cytokine priming by GM-CSF, IL-3, or IL-5 may account for the differential responsiveness of select eosinophilic disorders to glucocorticoids.
J Clin Invest 1991 Dec
PMID:Eosinophil hematopoietins antagonize the programmed cell death of eosinophils. Cytokine and glucocorticoid effects on eosinophils maintained by endothelial cell-conditioned medium. 175 57

In an effort to overcome bone marrow failure in myelodysplastic syndrome (MDS), we have investigated recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) in phase I-II clinical trials. Although these agents partially increased peripheral blood granulocyte counts, their effect on other hematopoietic lineages was generally sporadic. Since in vitro analysis and in vivo studies in primates indicate that GM-CSF and IL-3 synergistically enhance hematopoietic stem cell proliferation, we evaluated their combined effect on marrow progenitors obtained from ten MDS patients. When used singly, each growth factor stimulated replication of granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) colony-forming cells in a dose-dependent fashion. When colony-stimulating activity was compared at concentrations that maximally amplified individual MDS patients' colony numbers, IL-3 was a more potent stimulant in some patients and GM-CSF in others. When used in combination, IL-3 plus GM-CSF was more effective than each growth factor by itself in five of six patients. Our data indicate that the MDS hematopoietic progenitor stimulatory effect of these growth factors varies from patient to patient. However, the combination of GM-CSF and IL-3 appears to be more potent than the individual molecules in the majority of patients.
Ann Hematol 1991 Dec
PMID:Granulocyte-macrophage colony-stimulating factor and interleukin-3 in combination: a potent and consistent myelodysplastic syndrome bone marrow stimulant in vitro. 175 90

Human interleukin (IL)-5 receptors were characterized by means of binding studies using bioactive 125I-labeled IL-5. Of purified primary myeloid cells, eosinophils and basophils but not neutrophils or monocytes expressed surface receptors for IL-5. Binding studies showed that eosinophils expressed a single class of high affinity receptors (Ka = 1.2 x 10(10) M-1) with the number of receptors being small (less than 1000 receptors/cell) and varying between individuals. Among several cell lines examined only HL-60 cells showed detectable IL-5 receptors which were small in numbers (200 receptors/cell) and also bound 125I-IL-5 with high affinity. The binding of IL-5 was rapid at 37 degrees C while requiring several hours to reach equilibrium at 4 degrees C. Specificity studies revealed that the two other human eosinophilopoietic cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibited the binding of 125I-IL-5 to eosinophils. No competition was observed by other eosinophil activating or nonactivating cytokines. The inhibition of 125I-IL-5 binding by IL-3 and GM-CSF was partial up to a concentration of competitor of 10(-7) M with GM-CSF consistently being the stronger competitor. Converse experiments using IL-5 as a competitor revealed that this cytokine inhibited the binding of 125I-IL-3 and of 125I-GM-CSF in some but not all the individuals tested, perhaps reflecting eosinophil heterogeneity in vivo. Cross-linking experiments on HL-60 cells demonstrated two IL-5-containing complexes of Mr 150,000 and Mr 80,000 both of which were inhibited by GM-CSF. The competition between IL-5, IL-3, and GM-CSF on the surface of mature eosinophils may represent a unifying mechanism that may help explain the common biological effects of these three eosinophilopoietic cytokines on eosinophil function. This unique pattern of competition may also be beneficial to the host by preventing excessive eosinophil stimulation.
J Biol Chem 1991 Dec 25
PMID:Interleukin-5, interleukin-3, and granulocyte-macrophage colony-stimulating factor cross-compete for binding to cell surface receptors on human eosinophils. 176 68

Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) may reduce myelosuppression and, thus, allow dose escalation of certain chemotherapeutic agents. We conducted two sequential phase I trials of escalating doses of carboplatin and a fixed dose and schedule of rHuGM-CSF in ovarian cancer patients who had not previously had chemotherapy, i.e., chemotherapy-naive patients. In the first trial, patients were assigned to regimens of increasing dose levels of carboplatin (starting at 400 mg/m2) and fixed doses and schedules of cyclophosphamide (600 mg/m2) and rHuGM-CSF (10 micrograms/kg given subcutaneously once daily on days 2-11). Chemotherapy was given every 3 weeks (regimen A). In the subsequent trial, the design was the same except that cyclophosphamide was omitted (regimen B). Fifteen patients received regimen A, and seven patients received regimen B. In regimen A, all three patients treated at the first dose level tolerated five cycles at full doses. Hematologic toxicity was dose limiting at the 600-mg/m2 dose level. When 500 mg/m2 carboplatin was given, six of eight patients tolerated three or four cycles at full doses before requiring dose reductions or treatment delays. In regimen B, doses could not be escalated above the first dose level (600 mg/m2) because of severe hematological toxicity. Nonhematological toxicity was tolerable and managed with acetaminophen, antihistamines, and/or nonsteroidal, anti-inflammatory medication. Compliance was excellent. We conclude that (a) rHuGM-CSF can be given safely and reliably to chemotherapy-naive ovarian cancer patients receiving these treatment regimens, (b) early and severe thrombocytopenia was a major problem with or without cyclophosphamide with doses of carboplatin at or above 600 mg/m2, and (c) 500 mg/m2 carboplatin administered every 3 weeks is the highest dose in regimen A that can be given safely in the outpatient setting.
J Natl Cancer Inst 1991 Dec 04
PMID:Two phase I studies of carboplatin dose escalation in chemotherapy-naive ovarian cancer patients supported with granulocyte-macrophage colony-stimulating factor. 177 May 54

Five primary hematopoietic growth factors have been extensively evaluated in trials in patients with inadequate blood cell formation. Results have convincingly demonstrated that various chronic anemias can be corrected with erythropoietin. Similarly, there is no doubt that granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) increase the number of leukocytes and improve the function of cells in patients with congenital and acquired leukopenias. Recent studies indicate that interleukin-3 (IL-3) and macrophage colony-stimulating factor (M-CSF) can also stimulate blood cell production in patients. As a result, morbidity and perhaps mortality associated with severe cytopenias can be reduced substantially.
Ann Med 1991 Dec
PMID:Hematopoietic growth factors in clinical hematology. 177 17


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