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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 hematopoietic growth hormones that stimulate the production, maturation, and function of white blood cells. The best studied are granulocyte-macrophage CSF (GM-CSF) and granulocyte CSF (G-CSF), both of which can be produced by recombinant DNA technology. Clinical indications for these agents include bone marrow failure secondary to administration of chemotherapeutic drugs or radiation, bone marrow transplantation, and a variety of congenital or iatrogenic neutropenias. Toxicity in usual clinical doses is mild, and consists mainly of bone pain and constitutional symptoms such as fever, headache, and myalgias. Interleukin-2 (IL-2) is a lymphokine that stimulates that multiplication of several types of killer cells. These cells can recognize and destroy foreign substances, such as tumors, without destroying normal cells. Major applications of IL-2 include treatment of patients with renal cell carcinoma, in whom the overall objective response rate is 15-30 percent, and malignant melanoma with response rates of about 18 percent. Combination therapy with other biologics and conventional cytotoxic drugs may increase IL-2's efficacy against these tumors. Toxicity is generally severe, but reversible. Hemodynamic toxicity, consisting of hypotension, edema, weight gain, and decreased renal function, is most characteristic. Suggestions are given for pharmacologic management of these and other IL-2 toxicities.
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PMID:Clinical use of biologic response modifiers in cancer treatment: an overview. Part II. Colony-stimulating factors and interleukin-2. 171 21

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.
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PMID:Ras oncogenes amplify lymphokine (interleukin 3, granulocyte-macrophage colony-stimulating factor) induction by calcium ionophore. 172 72

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was added to a culture of human peripheral blood mononuclear cells in the presence of interleukin 2 (IL-2) in vitro to elucidate its effect on the induction of lymphokine-activated killer (LAK) cells. Viable cell counts of cultured cells and their cytotoxic effects against natural killer (NK) cell-resistant Daudi cells and NK cell-sensitive K562 cells were measured using the trypan blue dye exclusion test and a 51Cr release assay from the tumor cells, respectively. Although GM-CSF alone did not influence either the cytotoxicities or the surface phenotypes of the cultured cells, the viable cell counts were significantly increased by the addition of GM-CSF in the presence of IL-2 (P less than 0.01). These findings indicate that the addition of GM-CSF in the presence of IL-2 during the induction of LAK cells is useful for obtaining a larger number of effector cells which possess substantial cytotoxic activity.
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PMID:The effects of recombinant human granulocyte-macrophage colony-stimulating factor on the induction of lymphokine-activated killer cells in vitro. 178 73

Antileishmanial defense has been ascribed to the antimicrobial effects induced by soluble macrophage-activating lymphokines (MAFs), such as interferon-gamma and granulocyte-macrophage colony-stimulating factor. Recently, we identified an additional mechanism of T cell-mediated macrophage activation of defense against Leishmania that is apparently lymphokine independent, requires cell-cell contact, and is not cytotoxic to host cells. By employing antigen-specific murine T cell hybridoma lines, we observed that this property was associated with CD4+ subpopulations possessing the characteristics of the Th1 subset. In the present study, we address the question of whether contact-mediated macrophage activation can also be induced by Th2 lymphocytes. We employed as T effector cells in antileishmanial defense assays the Th2 cell line D10.G1.4 (D10) which is specific for conalbumin. We observed that D10 cells were able to induce activation of Leishmania-infected macrophages only when the macrophages were also primed with conalbumin, and that this activation apparently occurred by a mechanism without the secretion of MAF. Moreover, when mice infected with L. major were injected into footpad lesions with conalbumin and D10 cells, in situ parasite replication was partially inhibited. The expression of this antimicrobial mechanism by Th1 as well as Th2 clones suggests that the property of contact-mediated (lymphokine-independent) activation may be shared by certain lymphocytes in both Th1 and Th2 subpopulations. We hypothesize that this activation mechanism may involve the interaction of a lymphocyte membrane-associated MAF (such as tumor necrosis factor) and its receptor on the infected macrophage, resulting in the induction of antimicrobial effects but not cytotoxicity to the host cell.
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PMID:Th2 lymphocyte clone can activate macrophage antileishmanial defense by a lymphokine-independent mechanism in vitro and can augment parasite attrition in vivo. 182 32

We have previously reported that cultured human monocytes are lysed by autologous lymphokine-activated killer (LAK) cells in vitro and that treatment of monocytes with interferon-gamma (IFN-gamma) decreased their sensitivity to lysis. Conversely, incubation of monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly enhanced their susceptibility to LAK-mediated cytotoxicity. To determine if certain antigens were differentially modulated on macrophages by IFN-gamma and GM-CSF, cytokine-treated and untreated monocytes were analyzed for the expression of a variety of cell surface markers by flow cytometry. Cytotoxicity assays were performed to assess the ability of antibodies to each of these markers to block LAK lysis of macrophage target cells. While several of the surface structures were differentially modulated by cytokine treatment, it was found that only monoclonal antibodies to the adhesion proteins CD11a and CD18 were capable of blocking lysis of either cytokine-treated or untreated target macrophages.
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PMID:Differential modulation of surface antigens on human macrophages by IFN-gamma and GM-CSF: effect on susceptibility to LAK lysis. 190 35

Interleukin 2 (IL-2)-activated lymphocytes (lymphokine-activated killer [LAK] cells) have been shown to inhibit the formation of autologous human granulocyte-macrophage hemopoietic progenitors (granulocyte-macrophage colony-forming units, CFU-GM) in vitro. Effects of LAK cells on these progenitors may include a number of different mechanisms. LAK cells are potent cytotoxic lymphocytes capable of lysing certain normal autologous cells. They also produce cytokines known to inhibit hemopoiesis (interferon gamma [IFN-gamma] and tumor necrosis factor alpha [TNF-alpha]) or enhance it (granulocyte-macrophage colony-stimulating factor, GM-CSF). In our current study we analyzed the mechanism of suppression of autologous CFU-GM by LAK cells. Our results suggest that LAK cells are not directly cytotoxic to normal CFU-GM. We show that it is possible to abolish the hemopoiesis-inhibiting activity of LAK cells without abrogating their cytotoxicity against tumor cell lines using inhibitors of DNA synthesis, namely hydroxyurea or irradiation.
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PMID:Mechanism of suppression of normal hemopoietic activity by lymphokine-activated killer cells and their products. 190 68

The region extending from -40 to -54 of the 5'-flanking region of the mouse granulocyte-macrophage colony-stimulating factor (GM-CSF) gene shows homology to sequences found in the 5'-flanking regions of other cytokine genes, those encoding interleukin-4 (IL-4), IL-5, and granulocyte colony-stimulating factor (G-CSF). This sequence element is referred to as conserved lymphokine element 0 (CLE0). Saturation mutagenesis of the CLE0 element indicates that in addition to the previously mapped region between -73 and -91 (CLE2+ GC box), the CLE0 element is necessary for induction of the mouse GM-CSF gene by phorbol myristate acetate/Ca ionophore (A23187) stimulation in T cells. The presence of the CLE0 element is necessary to observe stimulation of the transcription activity of the mouse GM-CSF promoter in vitro. Mobility shift assays revealed that this region forms an inducible DNA-protein complex, NF-CLE0, which consists of two complexes of similar mobility, NF-CLE0a and NF-CLE0b. NF-CLE0a and NF-CLE0b recognize the 3' half and 5' half of the CLE0 element, respectively, with an overlapping region recognized by both proteins. The recognition sequence of NF-CLE0a corresponds to the region required for induction by phorbol myristate acetate/A23187, while the recognition sequence of NF-CLE0b contains bases that have inhibitory activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the mouse granulocyte-macrophage colony-stimulating factor (GM-CSF) gene promoter: nuclear factors that interact with an element shared by three lymphokine genes--those for GM-CSF, interleukin-4 (IL-4), and IL-5. 194 68

Various abnormalities of lymphokine production have been described in patients with aplastic anemia. To determine if abnormal production of hematopoietic growth factors could contribute to the process of aplastic anemia we studied the in vitro production of human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) by phytohemagglutinin (PHA)- and antithymocyte globulin (ATG)-stimulated peripheral blood lymphocytes from 29 patients with aplastic anemia and 15 normal controls. GM-CSF production in response to 1% PHA was seen in nearly all samples (43 of 44) and similar amounts of GM-CSF were produced by patients with aplastic anemia and normal controls. Production of GM-CSF by ATG-stimulated lymphocytes was seen in 7 of 23 patients with aplastic anemia (30%); two of these patients also demonstrated low-level spontaneous production of GM-CSF. Production of GM-CSF in response to ATG was also seen in 2 of 11 normal controls (18%) and barely detectable spontaneous production of GM-CSF was seen in both. Biologically active IL-3 could also be detected in PHA- or ATG-stimulated peripheral blood mononuclear cells in several patients and normal controls. Our results indicate that lymphocytes from patients with aplastic anemia can be stimulated in vitro to produce normal quantities of GM-CSF, suggesting that impaired potential for production of T-cell derived hematopoietic growth factors is unlikely to account for the marrow hypoplasia seen. In several patients overproduction of GM-CSF was observed, consistent with the notion that some patients with aplastic anemia may have circulating activated T cells. We also demonstrate that ATG can stimulate the production of growth factors such as IL-3 and GM-CSF, supporting the role for ATG in stimulating hematopoiesis.
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PMID:In vitro production of granulocyte-macrophage colony-stimulating factor in aplastic anemia: possible mechanisms of action of antithymocyte globulin. 207 50

Murine T helper type 2 clones were stimulated with immobilized anti-CD3 antibody or with recombinant lymphokines to compare the expression of T-cell activation genes induced by these stimuli. Immobilized anti-CD3 antibody, recombinant interleukin 2 (IL-2), and recombinant interleukin 4 (IL-4) all induced proliferation of the T helper type 2 clones 10-5-17 and D10. Proliferation of these clones induced by anti-CD3 antibody was completely inhibited by cyclosporine A, whereas cyclosporine A had little effect on proliferation induced by recombinant IL-2 or recombinant IL-4. Both immobilized anti-CD3 antibody, and recombinant IL-2 induced the expression of the protooncogenes c-myc and c-myb. Immobilized anti-CD3 antibody also induced expression of the lymphokine genes IL-4, interleukin 5 (IL-5), and granulocyte-macrophage colony-stimulating factor. In contrast, recombinant IL-2 induced IL-5 mRNA expression but did not induce detectable expression of IL-4 or granulocyte-macrophage colony-stimulating factor mRNA. Likewise, recombinant IL-4 induced expression of IL-5 but not IL-4 mRNA. Thus, the IL-4 and IL-5 genes appear to be differentially regulated after stimulation with recombinant lymphokines. Effects of cyclosporine A and the protein synthesis inhibitors cycloheximide and anisomycin on IL-4 and IL-5 gene expression suggest that these genes are activated by different pathways after anti-CD3 stimulation. Cyclosporine A completely inhibited anti-CD3-induced expression of IL-4 mRNA but not of IL-5 mRNA, and protein-synthesis inhibitors completely inhibited induction of IL-5 mRNA but not of IL-4 mRNA. Together, our data show that T-cell receptor-mediated and lymphokine receptor-mediated signals induce different patterns of lymphokine gene expression and provide strong evidence that the IL-4 and IL-5 genes are differently regulated.
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PMID:Differential regulation of interleukin 4 and interleukin 5 gene expression: a comparison of T-cell gene induction by anti-CD3 antibody or by exogenous lymphokines. 214 29

Granulocyte-macrophage colony-stimulating factor (GM-CSF) activates a broad range of myeloid cells through binding to high affinity surface membrane receptors. The effects of this hematopoietin are dependent upon the differentiation status of the myeloid cell and range from proliferation of early myeloid progenitor cells to activation of neutrophil and monocyte function. In addition, many of the biological effects of GM-CSF are shared with interleukin-3 (IL-3), a distantly related lymphokine. In this study, we have characterized the GM-CSF receptor of myeloid cells at various stages of differentiation by comparing the binding characteristics and surface regulation of this receptor in early versus late myeloid cells. Scatchard analysis revealed a single class of high affinity receptors on normal neutrophils, monocytes, and myeloblasts from patients with acute myeloid leukemia. Neutrophils expressed significantly higher numbers of receptors, with an approximately 2-fold lower affinity, when compared with other myeloid cells. Two different patterns of GM-CSF receptor regulation and binding were observed. In the first pattern, the GM-CSF receptor of neutrophils was rapidly down-regulated by GM-CSF itself, by phorbol myristate acetate (PMA), and by the calcium ionophore A23187, and it was not competed for by IL-3 (class I receptor). In contrast to the neutrophil receptor, the GM-CSF receptor of the myeloblast demonstrated resistance to the down-regulatory effects of GM-CSF itself, PMA, and A23187, and it was completely competed for by IL-3 (class II receptor). In some cases of acute myeloid leukemia and monocytes, a mixed pattern of partial PMA responsiveness and partial competition by unlabeled IL-3 was observed, suggesting the coexpression of both class I and II receptors in these cells. In these cells, after down-regulation of the class I receptor by PMA, the remaining receptors were shown to be completely cross-competed for by IL-3, further supporting the hypothesis that these cells have a mixture of class I and II receptors. Chemical cross-linking of radiolabeled GM-CSF to myeloid cells revealed the labeling of three proteins (156, 126, and 82 kDa) which were identical in cells expressing either class I or II binding sites. These data show that there are differentiation-associated differences in the regulation of the GM-CSF receptor which may have important physiological consequences.
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PMID:Differentiation-associated expression of two functionally distinct classes of granulocyte-macrophage colony-stimulating factor receptors by human myeloid cells. 216 70


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