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)

Tumor necrosis factor alpha (TNF-alpha) has been previously shown to modulate the expression of hematopoietic growth factor genes in monocytes and other mesenchymal cells. As acute myeloblastic leukemia (AML) blasts can express and produce hematopoietic growth factors, the influence of TNF-alpha on the accumulation of mRNAs for c-myc, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, IL-6 and IL-1 beta was evaluated in fresh blasts from 13 patients with AML. Total cellular RNA was extracted from blast cells cultured for 24 hours with or without TNF-alpha (500 U/ml). The c-myc transcript level was decreased by TNF-alpha treatment in 9/13 cases, and increased in only one case. Among the growth factor genes, the GM-CSF gene was more often and consistently influenced by TNF-alpha, increased levels of its transcript being observed in 6/13 cases following treatment with the cytokine; in no case was there a reduction of GM-CSF mRNA. G-CSF and IL-6 transcripts were more heterogeneously influenced, whereas the IL-3 transcript was never detected in our AML samples. The IL-1 beta message was present in 8/13 untreated and in 13/13 TNF-alpha treated samples. Moreover, in untreated cells, GM-CSF, G-CSF and IL-6 expression was always associated with IL-beta expression. These findings indicate that TNF-alpha can modulate the levels of growth factor transcripts in AML blasts, and raise questions about the effects of TNF-alpha on leukemic hematopoiesis, considering that TNF-alpha, IL-1 and GM-CSF can synergistically stimulate the growth of AML clonogenic cells.
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PMID:Tumor necrosis factor alpha modulates the messenger RNA expression of hematopoietic growth factor genes in fresh blast cells from patients with acute myeloblastic leukemia. 196 Oct 22

Administration of GLA-60, a synthetic lipid A-subunit analogue, significantly increased the numbers of macrophages, lymphocytes and polymorphonuclear leukocytes (PMN) in the peritoneal cavity of cyclophosphamide (CY)-treated immunosuppressed mice. Colony-stimulating factors (CSFs) were induced by GLA-60 in sera of both normal and CY-treated mice in a dose-dependent manner. The CSFs induced in mouse sera stimulated growth of bone marrow stem cells (BMC) which derived from either CY-treated or untreated mice in CSF assay. Three different colonies were formed in CSF assay consisting of granulocytes (G), macrophages (M) and mixed population. Addition of serum CSFs as well as exogenous addition of interleukin 3 (IL-3) or G-CSF to BMC taken from mice 1 day after CY-treatment induced high activity to stimulate the proliferation of those cells. Production of interleukin 1 (IL-1) was also stimulated in sera of CY-treated and untreated mice by administration of GLA-60. These results indicate that restoration of hematopoietic activity by GLA-60 in CY-immunosuppressed mice is due to induction of CSFs and IL-1, which synergistically act on proliferation and differentiation of pluripotential stem cells in bone marrow.
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PMID:Restoration of hematopoietic activity by lipid A analogue GLA-60 in cyclophosphamide-treated immunosuppressed mice. 196 37

An elucidation of the interaction between the bone marrow microenvironment and hematopoietic stem cells is critical to the understanding of the molecular basis of stem cell self renewal and differentiation. This interaction is dependent, at least in part, on direct cell to cell contact or cellular adhesion to extracellular matrix proteins. Long-term bone marrow cultures (LTMC) provide an appropriate microenvironment for maintenance of primitive hematopoietic stem cells and a means of analyzing this stem cell-stromal cell interaction in vitro. Although LTMC have been successfully generated from murine and human bone marrow, only limited success has been reported in a primate system. In addition, few permanent stromal cell lines are available from nonmurine bone marrow. Because the primate has become a useful model for large animal bone marrow transplant studies and, more specifically, retroviral-mediated gene transfer analysis, we have generated immortalized bone marrow stromal cell lines from primate bone marrow using gene transfer of the Simian virus large T (SV40 LT) antigen. At least one stromal cell line has demonstrated the capacity to maintain early hematopoietic cells in long-term cultures for up to 4 weeks as measured by in vitro progenitor assays. Studies were undertaken to characterize the products of extracellular matrix biosynthesis and growth factor synthesis of this cell line, designated PU-34. In contrast to most murine bone marrow-derived stromal cell lines capable of supporting hematopoiesis in vitro that have been examined, the extracellular matrix produced by this primate cell line includes collagen types I, laminin. Growth factor production analyzed through RNA blot analysis, bone marrow cell culture data, and factor-dependent cell line proliferation assays includes interleukin-6 (IL-6), IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, leukemia inhibitory factor, and a novel cytokine designated IL-11. This immortalized primate bone marrow stromal cell line may be useful in maintaining early progenitor cells for experimental manipulation without the loss of reconstituting capacity and as a potential source of novel hematopoietic growth factors.
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PMID:Stromal cell-associated hematopoiesis: immortalization and characterization of a primate bone marrow-derived stromal cell line. 201 98

Myelosuppression is the main limiting factor in cancer chemotherapy. The development of recombinant hematopoietic growth factors which stimulate myeloid progenitors and mainly neutrophil precursor cells leads to the evaluation of their potential activity in numerous fields of oncology. The available clinical trials have demonstrated the ability of G-CSF (granulocyte colony-stimulating factor) and GM-CSF (granulocyte-macrophage colony-stimulating factor) to accelerate neutrophil recovery following cytotoxic chemotherapy, and therefore to reduce the incidence of neutropenic febrile episodes and thereby improve the quality of life of patients receiving chemotherapy. The main goals of the future studies will be to determine to what extent the increase of dose intensity may lead to higher response rates and survival at least in patients with chemosensitive tumors.
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PMID:[Use of hematopoietic growth factors in oncology]. 203 83

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) exert multiple effects on the proliferation, differentiation, and function of myeloid lineage cells through their interaction with specific cell-surface receptors. There is a considerable degree of overlap in the biological effects of these two growth factors, but little is known about the mechanisms of postreceptor signal transduction. We have investigated the effects of GM-CSF and IL-3 on protein tyrosine-kinase activity in a human cell line, MO7E, which proliferates in response to either factor. Tyrosine-kinase activity was detected using immunoblotting with a monoclonal antibody (MoAb) specific for phosphotyrosine. GM-CSF and IL-3 were found to induce a nearly identical pattern of protein tyrosine phosphorylation using both one- and two-dimensional gel electrophoresis. Tyrosine phosphorylation of two cytosolic proteins in particular was increased more than 10-fold, a 93-Kd protein (pp93) and a 70-Kd protein (pp70). Tyrosine phosphorylation of pp93 and pp70 was observed within 1 minute, reached a maximum at 5 to 15 minutes, and gradually decreased thereafter. Other proteins of 150, 125, 63, 55, 42, and 36 Kd were also phosphorylated on tyrosine in response to both GM-CSF and IL-3, although to a lesser degree. Tyrosine phosphorylation was dependent on the concentration of GM-CSF over the range of 0.1 to 10 ng/mL and on IL-3 over the range of 1 to 30 ng/mL. Stimulation of MO7E cells with 12-0-tetradecanoyl-phorbol-13-acetate (TPA) or cytokines such as G-CSF, M-CSF, interleukin-1 (IL-1), interleukin-4 (IL-4), interleukin-6 (IL-6), interferon gamma, tumor necrosis factor (TNF), or transforming growth factor-beta (TGF-beta) did not induce tyrosine phosphorylation of pp93 or pp70, suggesting that these two phosphoproteins are specific for GM-CSF-or IL-3-induced activation. The extent and duration of phosphorylation of all the substrates were increased by pretreatment of cells with vanadate, an inhibitor of protein-tyrosine phosphatases. Importantly, culture of MO7E cells with vanadate (up to 10 mumol/L) resulted in a dose-dependent increase in GM-CSF-or IL-3-induced proliferation of up to 1.8-fold. These results suggest that tyrosine phosphorylation may be important for GM-CSF and IL-3 receptor-mediated signal transduction and that cell proliferation may be, at least partially, regulated by a balance between CSF-induced protein-tyrosine kinase activity and protein-tyrosine phosphatase activity.
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PMID:Signal transduction of the human granulocyte-macrophage colony-stimulating factor and interleukin-3 receptors involves tyrosine phosphorylation of a common set of cytoplasmic proteins. 216 6

Activated polymorphonuclear neutrophilic granulocytes (PMN) play an important role in propagation of inflammatory reactions and are capable of mediating tissue damage particularly by release of reactive oxygen species and lysosomal contents. Cytokines produced by monocytes as well as epidermal cells were recently shown to modulate PMN function. Therefore, the effect of immunomodulating cytokines on the oxidative metabolism of isolated human PMN was tested by functional as well as ultrastructural criteria. The following recombinant human cytokines were tested: tumor necrosis factor (TNF alpha), lymphotoxin (TNF beta), granulocyte-macrophage colony-stimulating factor (GM-CSF), M-CSF, G-CSF, PDGF, TGF-beta, interleukin-1 (IL-1) alpha and beta, IL-2, IL-3, IL-4, IL-5, IL-6, MONAP/MOC/NAF (IL-8), interferon-alpha and -gamma. Only TNF alpha, TNF beta and GM-CSF were found to be direct stimuli of the oxidative burst in human PMN whereas IL-3, IL-5, and IL-8 were active only at extremely high concentrations. None of the other cytokines tested induced any significant effect on isolated human PMN at physiological concentrations. The results clearly demonstrate that only selected cytokines are capable of inducing a long lasting activation of PMN oxidative metabolism. Release of these mediators represents a specific signal for PMN activation in inflammatory disease states.
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PMID:Activation of the oxidative metabolism in human polymorphonuclear neutrophilic granulocytes: the role of immuno-modulating cytokines. 225 41

NFS-60 cells were previously obtained from leukemia cells that were infected with the Cas-Br-M murine leukemia virus in vivo. We examined the proliferation and differentiation capacity of NFS-60 cells in the presence of native and recombinant (r) interleukin 3 (IL-3), recombinant granulocyte colony-stimulating factor (rG-CSF), recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), and r-erythropoietin (Ep) using methylcellulose culture methods. This cell line was able to form colonies in response to each hemopoietic factor, but colony formation was rarely seen in their absence. Some populations of NFS-60 cells could differentiate into neutrophils and macrophages in the presence of IL-3 and GM-CSF. Moreover, in the presence of Ep, this cell line formed well-hemoglobinized colonies as well as nonerythroid colonies. In the presence of G-CSF, NFS-60 cells remained in the promyelocytic state. Electron microscopic studies confirmed these morphologies. A single-cell transfer experiment demonstrated that neutrophils, macrophages, and erythroblasts were derived from a single cell. It is concluded that the NFS-60 cell line is a factor-dependent, bipotential hemopoietic cell line.
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PMID:Bipotential murine hemopoietic cell line (NFS-60) that is responsive to IL-3, GM-CSF, G-CSF, and erythropoietin. 245 92

We have previously demonstrated that cultured rat chloroleukemia cells, MIA C51, will terminally differentiate to macrophages when treated with rat lung-conditioned medium in vitro and in vivo. In the present study we fractionated rat monocyte-conditioned medium by ultrafiltration according to molecular size. The fraction with molecular weight (mol wt) 30 to 50 Kd containing partially purified granulocyte-macrophage colony-stimulating factor (GM-CSF) activity caused the differentiation of C51 cells to macrophages in vitro and in diffusion chambers in vivo. Treatment of young rats with this fraction aborted the development of chloroleukemia from transplanted C51 cells. In contrast, the fraction with mol wt 10 to 30 Kd containing virtually all the G-CSF activity exhibited no differentiation activity either in vitro or in vivo. It is concluded that in this rat myelogenous leukemia model partially purified GM-CSF but not G-CSF contains the effector molecule(s) causing terminal differentiation of C51 cells and tumor cell rejection.
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PMID:Treatment with monocyte-derived partially purified GM-CSF but not G-CSF aborts the development of transplanted chloroleukemia in rats. 245 47

The effects of transforming growth factor beta 1 or beta 2 (TGF-beta 1 or -beta 2) on the in vitro proliferation and differentiation of normal and malignant human hematopoietic cells were studied. Both forms of TGF-beta suppressed both the normal cellular proliferation and colony formation induced by recombinant human interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the presence of GM-CSF or IL-3, optimal concentrations of TGF-beta (400 pmol/L) inhibited colony formation by erythroid (BFU-E), multipotential (CFU-GEMM), and granulocyte-macrophage (CFU-GM) progenitor cells by 90% to 100%, whereas granulocyte or monocyte cluster formation was not inhibited. In contrast, neither form of TGF-beta had any effect on G-CSF-induced hematopoiesis. The suppressive action appeared to be mediated directly by TGF-beta since antiproliferative responses were also observed in accessory cell-depleted bone marrow cells. In contrast to normal bone marrow cells, both GM- and G-CSF-induced proliferation of cells from patients with chronic myelogenous leukemia were suppressed in a dose-dependent manner by TGF-beta. Differential effects of TGF-beta on the proliferation of established leukemic lines were also observed since most cell lines of myelomonocytic nature studied were strongly inhibited where erythroid cell lines were either insensitive or poorly inhibited by TGF-beta. These results suggest that TGF-beta is an important modulator of human hematopoiesis that selectively regulates the growth of less mature hematopoietic cell populations with a high proliferative capacity as opposed to more differentiated cells, which are not affected by TGF-beta.
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PMID:Transforming growth factor beta selectively inhibits normal and leukemic human bone marrow cell growth in vitro. 246 Jan 53

[3H]thymidine uptake by NFS-60 cells in microcultures was found to increase in a linear fashion with the increasing doses of purified recombinant human granulocyte colony-stimulating factor (rhG-CSF). Such increases were found neither with rhG-CSF samples pretreated with rabbit anti-rhG-CSF serum nor with other human colony-stimulating factors such as granulocyte-macrophage colony-stimulating factor (hGM-CSF) or macrophage colony-stimulating factor (hM-CSF). Based on these findings, sera from normal persons and patients with severe infections or various hematological disorders were tested after dialysis using this system in order to determine whether G-CSF levels in sera can be estimated or not. In ten normal persons, five patients with acute myelogenous leukemia (AML M1, M2, and M3), five with myelodysplastic syndrome, and four with chronic myelogenous leukemia, no increases in [3H]thymidine uptake were found within the dose range of 0.4 microliters to 50 microliters. In contrast, linear dose responses parallel to a G-CSF standard curve were observed in one patient with a severe bacterial infection, four with aplastic anemia, two with acute myelomonocytic leukemia (AMMoL) (M4), and two with idiopathic neutropenia tested. From the standard curve, the probable levels of G-CSF were calculated as follows: approximately 200 pg/ml with infection, 130-220 pg/ml with aplastic anemia, 150 and 200 pg/ml with AMMoL, and 1120 and 1200 pg/ml with idiopathic neutropenia. The activities of sera were reduced by the anti-rhG-CSF serum pretreatment in the same way as documented in the case of rhG-CSF. Furthermore, the level in a patient with a severe infection became undetectable soon after elimination of the infection and blood neutrophil counts had returned to normal. These findings indicate that the microbioassay system will be useful for measuring circulating G-CSF levels which would fluctuate in accord with requirements for stimulating neutrophil production or with abnormal production of hG-CSF.
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PMID:A new bioassay for human granulocyte colony-stimulating factor (hG-CSF) using murine myeloblastic NFS-60 cells as targets and estimation of its levels in sera from normal healthy persons and patients with infectious and hematological disorders. 246 30


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