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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)

Colony-stimulating factors (CSFs) are glycoproteins that stimulate the growth of hematopoietic progenitors and enhance the functional activity of mature effector cells. Human granulocyte/macrophage colony-stimulating factor (GM-CSF) is a 22-kDa glycoprotein that stimulates the growth of myeloid and erythroid progenitors in vitro and increases the responsiveness of neutrophils, monocytes, and eosinophils to physiologic stimuli. Elucidation of the cell and tissue sources of CSFs, as well as study of their regulation of expression, is required to understand their role in physiologic and pathophysiologic states. An extensive survey of normal and neoplastic human tissues did not reveal constitutive production of detectable levels of GM-CSF mRNA in any of the 64 samples studied. Antigen- or lectin-activated T lymphocytes have been shown to produce GM-CSF; therefore, to elucidate the genetic sequences required, we constructed recombinant plasmids containing 5' flanking DNA of the GM-CSF gene linked to the marker chloramphenicol acetyltransferase gene. The recombinant constructs were transfected into a human T-cell leukemia virus type I (HTLV)-infected T-lymphoblast cell line that can be stimulated to produce high levels of GM-CSF. We show here that the 5' flanking sequences of the GM-CSF gene can direct increased expression of the chloramphenicol acetyltransferase gene in activated T-lymphoblast cells.
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PMID:Regulation of expression of human granulocyte/macrophage colony-stimulating factor. 349 Jun 69

Clones of complementary DNA encoding the human lymphokine known as granulocyte-macrophage colony-stimulating factor (GM-CSF) were isolated by means of a mammalian cell (monkey COS cell) expression screening system. One of these clones was used to produce recombinant GM-CSF in mammalian cells. The recombinant hematopoietin was similar to the natural product that was purified to apparent homogeneity from medium conditioned by a human T-cell line. The human T-cell GM-CSF was found to be 60 percent homologous with the GM-CSF recently cloned from murine lung messenger RNA.
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PMID:Human GM-CSF: molecular cloning of the complementary DNA and purification of the natural and recombinant proteins. 392 23

A cDNA sequence coding for a human granulocyte-macrophage colony-stimulating factor has been isolated from cDNA libraries prepared from mRNA derived from concanavalin A-activated human T-cell clones. The libraries constructed in the pcD vector system were screened by transfecting COS-7 monkey cells with DNA pools to express the products encoded by full-length cDNA inserts. By assaying the cell supernatants, we identified clones encoding a factor that stimulates the formation of granulocyte and macrophage colonies from human progenitor cells. These results demonstrate that identification of full-length cDNAs for many colony-stimulating factors may be achieved entirely on the basis of detecting the functional polypeptide produced in mammalian cells.
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PMID:Isolation of cDNA for a human granulocyte-macrophage colony-stimulating factor by functional expression in mammalian cells. 392 54

We have previously demonstrated that protein production and mRNA expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and IL-3 are decreased in activated mononuclear cells (MNC) from human umbilical cord compared with adult peripheral blood. Reduced production of these colony-stimulating factors (CSF) during states of increased demand, as occurs during overwhelming bacterial infection, may play a role in the pathogenesis of neutropenia and thrombocytopenia in the newborn. To determine whether the reduced mRNA expression and CSF production from activated cord MNC is secondary to the decreased transcriptional activity of the corresponding genes, we determined the transcriptional rate of GM-CSF, G-CSF, IL-3, and M-CSF by nuclear run-on assays. Cord and adult MNC were isolated by Ficoll-Hypaque density centrifugation. A total of 10(8) MNC from cord and adult blood were stimulated as follows: GM-CSF and G-CSF [32 nmol/L phorbol-12-myristate-6-acetate (20 micrograms/L) + 2 mg/L phytohemagglutinin for 6 h]; IL-3 [32 nmol/L phorbol-12-myristate-6-acetate (20 micrograms/L) + 0.5 mumol/L A 23187 for 6 h]; and macrophage CSF (2 micrograms/L recombinant human GM-CSF for 24 h). The nuclei from unstimulated and stimulated cells were isolated and labeled with 32P-uridine triphosphate. Newly elongated 32P-labeled RNA transcripts were hybridized to slot blots of CSF DNA. To minimize cross hybridization artifacts, short fragments (0.5-1.0 kb) of cDNA were used.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transcriptional rates of granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, interleukin-3, and macrophage colony-stimulating factor genes in activated cord versus adult mononuclear cells: alteration in cytokine expression may be secondary to posttranscriptional instability. 750 24

We studied the effect of leukocidin from Staphylococcus aureus V8 strains (Luk-PV) on the generation of Leukotriene B4 (LTB4) and its metabolites from human polymorphonuclear neutrophils (PMNs). Significant amounts of LTB4 were generated by PMNs after leukocidin exposure in a time- and dose-dependent manner, as shown by reversed-phase high-performance liquid chromatography analysis. In this regard, the S and F components of leukocidin acted synergistically. The calcium ionophore A23187 induced LTB4 generation, and the metabolism of exogenously added LTB4 into biologically less active omega-oxidated compounds was significantly decreased after leukocidin exposure. Priming of PMNs with granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF prior to leukocidin exposure substantially increased toxin- and calcium ionophore A23187-induced LTB4 formation. The inhibitory effects of leukocidin on mediator release were accompanied by membrane damage and DNA fragmentation, which were both restored after pretreatment with GM-CSF. The data suggest that the presence of costimulatory priming factors such as GM-CSF or G-CSF in the microenvironment of an inflammatory focus determines the pathophysiological effects induced by S. aureus leukocidin.
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PMID:Leukotriene B4 generation and DNA fragmentation induced by leukocidin from Staphylococcus aureus: protective role of granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF for human neutrophils. 751 77

The effect of cytokines on the proliferation and differentiation of leukemia cells from 5 patients with acute promyelocytic leukemia (APL) was examined. Interleukin-1 beta (IL-1), interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) augmented uptake of 3H-thymidine into the DNA of APL cells in a dose-dependent manner in all cases. This stimulatory effect was pronounced in some, but not all, cells treated with all-trans retinoic acid (ATRA). However, nitroblue tetrazolium-reducing activity was induced in a concentration-dependent manner by ATRA in all cases. The cytokines greatly enhanced NBT reduction of APL cells treated with ATRA, and a mixture of cytokines was more effective than a single cytokine. Although GM-CSF, IL-3 and IL-1 significantly modulated the ATRA-induced morphological changes, they did not induce CD14 expression, a typical marker of monocytic differentiation. In the presence of ATRA, GM-CSF potentiated production and secretion of tumor necrosis factor-alpha (TNF) in response to lipopolysaccharide, as well as interferon-gamma which is a potent inducer of monocytic differentiation in APL cells. On the other hand, production of TNF in ATRA-treated cells was not affected by G-CSF which significantly enhanced granulocytic differentiation. The effect of cytokines on APL cell differentiation should be considered in ATRA treatment for APL patients. Potentiation of cytokine production in APL cells associated with myelomonocytic differentiation is noteworthy in the pathogenesis of "retinoic acid syndrome".
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PMID:Effect of cytokines on the proliferation and differentiation of acute promyelocytic leukemia cells: possible relationship to the development of "retinoic acid syndrome". 752 Nov 52

Colony-stimulating factors (CSFs) are proteins that play normal roles in human hematopoietic physiology. Many of these factors have been cloned and sequences. This has led to recombinant DNA technology that now allows for production of large quantities of pharmacologically pure compounds. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are two such compounds that have been approved by the US Food and Drug Administration for human use in specific medical circumstances. This article summarizes the experience of one institution in using these two CSFs and adds brief commentary on four other CSFs that are expected to come to general use in the near future--interleukin-1, interleukin-3, interleukin-6, and erythropoietin. Both G-CSF and GM-CSF are effective in protecting patients from the leukotoxic effects of cancer chemotherapy, but GM-CSF appears to have a comparatively narrow "dosing window," wherein the agent is effective and tolerable. Future studies should address combining these agents with platelet protective compounds to improve patient safety.
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PMID:The use of colony-stimulating factors as bone marrow support for systemic anticancer chemotherapy. 752 98

Stimulation of clonogenic acute myeloid leukemia (AML) cells by hematopoietic growth factors (HGF) is capable of enhancing cytosine-arabinoside (Ara-C) cytotoxicity in vitro. Until now it has not been known to what extent in vitro Ara-C cytotoxicity can be restored by HGF stimulation in samples from previously treated AML patients. Therefore, we studied the individual effects of the hematopoietic growth factors (HGF) granulocyte colony-stimulating factor (G-CSF), interleukin-3 (IL-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation on the Ara-C sensitivity of clonogenic leukemic cells from six patients with newly diagnosed AML. These results were directly compared with the outcome using AML samples from the same patients at relapse or primary refractory AML. In one patient, a sample of the second relapse was also studied. The results were expressed as IC50 values, and were used to calculate sensitivity ratios, defined as the ratio of the IC50 value with drug exposure alone and with HGF plus Ara-C. In AML samples treated with Ara-C alone and no HGF, IC50 values of Ara-C in relapsed/refractory AML were greater than IC50 values of AML cells at diagnosis. Addition of either HGF enhanced the Ara-C cytotoxicity for the relapsed samples significantly (for G-CSF p = 0.036, IL-3 p = 0.036, and for GM-CSF p = 0.036). The values of Ara-C sensitization of AML samples due to HGF at relapse did not significantly differ from those at diagnosis. However, enhancement of Ara-C cytotoxicity to AML progenitors by IL-3 or GM-CSF stimulation was significantly less in the cell specimens from AML recurrence patients as compared with the original diagnosis samples. In three AML samples at diagnosis and at their relapse, Ara-C incorporation into the DNA was determined. IL-3 stimulation enhanced Ara-C incorporation in all samples tested. Nevertheless, Ara-C incorporation in the relapsed samples was significantly less than that in the diagnosis samples of the same patients. A good correlation between Ara-C incorporation and bromodeoxyuridine (BrdU) incorporation was found. The results indicate that HGF stimulation in relapsed/refractory AML enhances Ara-C cytotoxicity, but not to the level that was observed with AML samples at diagnosis.
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PMID:Hematopoietic growth factor stimulation and cytarabine cytotoxicity in vitro: effects in untreated and relapsed or primary refractory acute myeloid leukemia cells. 752 89

The application of hematopoietic growth factors in the treatment on acute myeloid leukemia (AML) may principally aim at shortening the period of treatment associated neutropenia and reducing the rate of infectious complications by their post-therapeutic administration but may also be used to increase the sensitivity of leukemic blasts to antileukemic therapy by pretherapeutic growth stimulation. Both aspects were addressed in subsequent clinical phase II studies and preclinical investigations. In a first clinical trial, 36 patients with high-risk AML received granulocyte-macrophage colony-stimulating factor (GM-CSF) after successful cytoreductive chemotherapy and experienced a shortening of the period of post-therapeutic neutropenia by 6 to 9 days, leading to a significant reduction of treatment-associated deaths from 39% to 14%. In preclinical studies an enhancement of the cytotoxicity of cytosine arabinoside (AraC) on leukemic blasts could be shown by pretreatment with GM-CSF or IL-3. Investigations on the impact of hematopoietic growth factors on the intracellular metabolism of AraC indicated that this effect was primarily mediated by an increase in the activity of DNA-polymerase-alpha. The evaluation of different doses of AraC showed the most marked increase after the combination of GM-CSF with conventional rather than high doses of AraC. Based on these preclinical experiments, a prospective randomized trial was subsequently initiated investigating the effect of GM-CSF before and during induction, consolidation, and the first two cycles of maintenance chemotherapy in newly diagnosed AML. This ongoing trial has enrolled 67 patients at the current time. An early interim analysis showed no differences in remission rates but a tendency toward a longer remission duration in patients receiving GM-CSF. These data indicate that hematopoietic growth factors like GM-CSF in particular may provide a new perspective in the treatment of acute myeloid leukemia with the possibility of reducing treatment associated mortality and perhaps of increasing the efficacy of antileukemic treatment.
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PMID:New perspectives in the treatment of acute myeloid leukemia by hematopoietic growth factors. 752 49

The effects of hematopoietic growth factors were examined on the cellular action of retinoic acid (RA) using the human factor-dependent cell line, MO7e. Treatment of cells with Steel factor (SLF) plus granulocyte-macrophage colony-stimulating factor (GM-CSF) synergistically stimulated cell proliferation compared to that with each factor alone. This synergism was even greater in the presence of RA than in its absence. Treatment of cells with RA resulted in apoptotic cell death associated with internucleosomal DNA fragmentation in the presence of either SLF or GM-CSF. RA-induced apoptosis and DNA fragmentation were completely blocked by treating cells with SLF plus GM-CSF. Northern analysis showed that the inhibition of RA effects on MO7e cells by SLF plus GM-CSF treatment occurred without modulation of expression of RA receptor-alpha (RAR-alpha) gene. Furthermore, a higher amount of AP-1 complex was detected by electrophoretic mobility shift assays in a nuclear extract prepared from cells treated with SLF plus GM-CSF compared to those treated with each factor alone, while the level of RAR-complex remained similar in cells treated with SLF and/or GM-CSF. These data suggest an interaction in signaling pathways among different types of receptors that might be associated with the AP-1 complex.
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PMID:The combination of Steel factor and GM-CSF blocks apoptosis induced by retinoic acid and upregulates AP-1 in a human growth factor-dependent cell line. 753 Feb 13


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