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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)

Previous experiments have revealed the expression of tumor necrosis factor alpha (TNF-alpha) transcripts in all murine bone marrow-derived macrophage colonies isolated from days 5 through 9 of differentiation in vitro. These results implicated a role for TNF-alpha gene expression during macrophage differentiation. Antisense oligomers to the initiation region of the TNF-alpha message were used to inhibit its expression, thus allowing the role of TNF-alpha gene expression in controlling the differentiation of macrophages to be determined. Results showed that TNF-alpha regulated the proliferation of macrophages during differentiation. Cells isolated on day 3 were exclusively vulnerable to the effects of blocking TNF-alpha gene expression, displaying a 30% increase in proliferation over control cells or sense oligomer-treated cells. Thus, in the absence of TNF-alpha gene expression, cells maintained proliferation instead of undergoing terminal differentiation. Exogenous TNF-alpha was capable of rescuing day 3 antisense-treated cells, therefore maintaining normal levels of proliferation. In contrast, blocking interleukin 1 beta gene expression by antisense oligonucleotide treatment had no effect on proliferation. Addition of exogenous recombinant murine or human TNF-alpha decreased the total cell number 25-50% regardless of whether cells were grown in medium containing colony-stimulating factor 1 (CSF-1) or granulocyte-macrophage colony-stimulating factor (GM-CSF). These results suggested that exogenous TNF-alpha suppressed proliferation of early hematopoietic progenitors, whereas endogenous TNF-alpha regulated proliferation of macrophage progenitors. The number of differentiated, adherent macrophages on day 5 of differentiation in vitro was increased by TNF-alpha treatment of GM-CSF-induced macrophages but was suppressed in CSF-1-induced macrophages. These findings suggest that distinct TNF receptor expression and/or signaling is induced in differentiating macrophages stimulated with either growth factor.
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PMID:Tumor necrosis factor alpha is an autocrine growth regulator during macrophage differentiation. 850 31

Characteristics of hemopoietic-supportive (MS-1 and MS-5) and non-supportive (MS-K) cell lines were compared. Supportive cells adhered to hemopoietic stem cells and produced granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas non-supportive cells did not adhere to hemopoietic cells and only produced macrophage colony-stimulating factor. Both cell lines produced substantial levels of IL-6 and steel factor (SLF) which is reportedly a stem-cell factor. Northern blot analysis revealed that SLF but neither c-kit nor interleukin 3 (IL-3) mRNA was detectable in these cell lines, although IL-3-like activity was found in the supernatant of MS-5 cell culture. These observations suggest that the hemopoietic-supportive function of stromal cells may reside in adherence of stem cells, and production of GM-CSF probably in combination with SLF. SLF may be transferred from stromal cells directly to stem cells through adhesion of stem cells to supportive stromal cells.
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PMID:Characterization of murine hemopoietic-supportive (MS-1 and MS-5) and non-supportive (MS-K) cell lines. 137 98

The murine myeloproliferative syndrome induced by the myeloproliferative sarcoma virus (MPSV) has numerous similarities to human primary myelofibrosis. We have shown that medium conditioned by spleen cells of MPSV-infected mice has the capacity to support the growth of primitive blast cell colonies. The detection of this activity associated with MPSV infection stimulated us to characterize the hematopoietins responsible for this activity. Northern blot analysis showed a large increase, or induction, of interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage-CSF (CSF-1), and granulocyte-CSF (G-CSF) transcripts in the hematopoietic organs of MPSV-infected mice; however, no IL-3 transcript could be detected in either MPSV-infected or normal mice. Significant levels of IL-1 alpha, IL-6, G-CSF, and CSF-1 bioactivities were found in the serum of MPSV-infected mice, but not in controls. Additionally, analysis of medium conditioned by spleen cells of MPSV-infected mice showed the presence of tumor necrosis factor alpha bioactivity. The increased production of cytokines that are able to stimulate pluripotent hematopoietic stem cells corroborates the hypothesis of a possible involvement of hematopoietic growth factors in the development of some myeloproliferative disorders.
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PMID:Enhanced hematopoietic growth factor production in an experimental myeloproliferative syndrome. 137 44

A novel hematopoietic growth factor, the stem cell factor (SCF), for primitive hematopoietic progenitor cells has recently been purified and its gene has been cloned. In this study we tested the mitogenic activity of recombinant human SCF on myeloid leukemia cells as well as the expression of its receptor. We have investigated the proliferation of 31 myeloid leukemia cell lines as well as fresh myeloid leukemic blasts from 17 patients in a 72-hour 3H-thymidine uptake assay in the presence of various concentrations of recombinant human (rh) SCF alone or in combination with saturating concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, interleukin-3 (IL-3), or erythropoietin (EPO). Only five of 31 lines, but fresh leukemic blasts from 12 of 17 patients with acute myeloid leukemia (AML), significantly responded to SCF. The responding cell lines were of the acute promyelocytic, chronic myeloid, megakaryoblastic, and erythroleukemia origin, the responding blast preparations of all French-American-British subtypes. Synergistic activities of SCF were found with G-CSF, GM-CSF, EPO, and IL-3. To determine the SCF binding sites on leukemic cells, we used 125I-radiolabeled SCF in Scatchard analysis and cross-linking studies. The leukemic cell lines responding to SCF expressed from 2,300 up to 29,000 binding sites per cell. The SCF receptor expression was downregulated in vitro by the presence of its ligand. Cross-linking studies demonstrated a 150-Kd SCF receptor on the surface of all responding myeloid leukemias. This study suggests that SCF may be an important factor for the growth of myeloid leukemia cells, either as a direct stimulus or as a synergistic factor for other cytokines. Furthermore, using polymerase chain reaction analysis of total RNA from the myeloid leukemia lines, we found expression of SCF-mRNA in 17 of 30 lines, suggesting autocrine mechanisms in the growth of a subgroup of leukemic cells by coexpression of SCF and its receptor.
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PMID:Effects of human stem cell factor (c-kit ligand) on proliferation of myeloid leukemia cells: heterogeneity in response and synergy with other hematopoietic growth factors. 138 Dec 38

In this study we have made a detailed analysis of growth factor (granulocyte-macrophage colony-stimulating factor [GM-CSF], granulocyte colony-stimulating factor [G-CSF], and macrophage colony-stimulating factor [M-CSF])-induced proliferation and differentiation of highly purified CD34+ committed human myeloid progenitor cells in suspension cultures. The results were compared with colony formation in semisolid medium. Proliferation in suspension cultures was determined by means of incorporation of [3H]thymidine, differentiation by flow cytometric immunophenotyping using a panel of monoclonal antibodies against monomyeloid antigens, and by morphology. A good correlation was found between the number of granulocyte-macrophage colony-forming units (CFU-GM) in semisolid medium and [3H]thymidine incorporation in suspension (r = 0.82), both assessed at day 11. Moreover, the frequency of proliferating cells as determined in suspension cultures by limiting dilution analysis was similar to the frequencies of CFU-GM as measured in semisolid medium. Studies on GM-CSF- and G-CSF-induced cell-growth kinetics revealed distinct proliferation patterns. Immunophenotypically the subsequent induction of the mature granulocytic antigens CD15 and CD67 was observed to be accompanied by a gradual loss of the HLA-DR antigen, whereas little monocytic differentiation was observed. M-CSF, although inducing no colony formation of CD34+ cells and minimal proliferation in suspension, induced monocytic differentiation, demonstrated by the expression of HLA-DR, CD14, and CD36 in the absence of CD15 and CD67. The observed immunophenotypical profiles were confirmed by the results of cytological characterization. Thus, the combined measurement of growth factor-induced proliferation and differentiation of progenitor cells in suspension cultures can be a useful alternative for the CFU-GM assay. Moreover, because small numbers of cells are required, it allows for detailed studies on cell-growth kinetics and developmental stages within the granulocytic and monocytic lineages.
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PMID:Combined measurement of growth and differentiation in suspension cultures of purified human CD34-positive cells enables a detailed analysis of myelopoiesis. 138 96

Gamma irradiation of plateau-phase clonal bone marrow stromal cell lines produces factor-independent growth of cocultivated clonal interleukin-3/granulocyte-macrophage colony-stimulating factor-dependent hematopoietic progenitor cell lines. The process is associated with three biologic changes including: (i) adherence of hematopoietic cells to stromal cells forming 'cobblestone islands'; (ii) an intermediate stage [during which the cells show proliferation in suspension in the presence in leukemogenic stromal factor (LSF), a factor similar to macrophage colony-stimulating factor (M-CSF) released by irradiated stromal cells, and transient hematopoietic cell surface expression of MAC-1, and c-fms (M-CSF receptor)]; and (iii) a third stage of factor-independence. A monoclonal antibody to M-CSF receptor inhibited proliferation of intermediate stage but not all factor-independent cell subclones. In the present studies, a subclonal factor-independent malignant subline of FDC-P1JL26 derived by cocultivation with gamma-irradiated stromal cells as well as the parent clone and intermediate stage cells were shown to express significant levels of M-CSF polyA+ mRNA and M-CSF of at least two sizes (23 and 15 kDa) as detected by 35S-methionine labelling and immunoprecipitation with polyclonal anti-M-CSF antiserum. There was no significant difference in intracellular M-CSF protein size between cells at each of the three stages of biologic change. This M-CSF was not detected on the cell surface by fluorescence-activated cell sorting (FACS). In contrast, c-fms expression at the cell surface was detected by FACS analysis and c-fms polyA+ mRNA was only detected during the intermediate stage of induction of factor-independence. FDC-P1JL26 parent cells, the subclone stimulated by LSF, and the factor-independent subclone, showed little or no detectable autophosphorylation of the c-fms receptor at tyrosine. There was no detectable rearrangement of the M-CSF or c-fms genes by Southern analysis between clonal lines during the three stages. While we cannot rule out an autocrine mechanism or mutated c-fms receptor mechanism, the data also suggest that evolution of hemopoietic cell factor-independence during cocultivation with irradiated stromal cells may involve a mechanism distal to the c-fms receptor/M-CSF interaction.
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PMID:Expression of M-CSF and its receptor (C-FMS) during factor-independent cell line evolution from hematopoietic progenitor cells cocultivated with gamma irradiated marrow stromal cell lines. 138 39

Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) can have pleiotropic effects on different cell types. M1 myeloid leukaemic cells respond to IL-6 with activation of a terminal differentiation programme which includes activation of genes for certain haemopoietic regulatory proteins (IL-6, IL-1 alpha, IL-1 beta, granulocyte-macrophage colony-stimulating factor [GM-CSF], M-CSF, tumour necrosis factor and transforming growth factor [TGF] beta 1) and for receptors for some of these proteins, thus establishing a network of positive and negative regulatory cytokines. IL-6 and some other cytokines also induce during differentiation sustained levels of transcription factors that can regulate and maintain gene expression in the differentiation programme. M1 leukaemic cells induced to differentiate with IL-6 undergo programmed cell death (apoptosis) on withdrawal of IL-6, and can be rescued from apoptosis by IL-6, IL-3, M-CSF, G-CSF or IL-1, but not by GM-CSF. These differentiating leukaemic cells can also be rescued from apoptosis by the tumour promoter TPA (12-O-tetradecanoylphorbol-13-acetate) but not by the non-tumour-promoting isomer 4-alpha-TPA, and rescue from apoptosis can be achieved by different pathways. Apoptosis can also be induced in undifferentiated M1 leukaemic cells by expression of the wild-type form of the tumour suppressor p53 protein and IL-6 can rescue the cells from this wild-type p53-mediated apoptosis. There are clones of M1 cells that differentiate with IL-6 but not with LIF and another M1 clone that differentiates with either IL-6 or LIF. Differentiation induced by IL-6 or LIF is inhibited by TGF-beta 1. The pleiotropic effects of LIF, like those of IL-6, are presumably also in a network of interacting regulatory proteins.
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PMID:Regulation of leukaemic cells by interleukin 6 and leukaemia inhibitory factor. 142 20

Morphological hallmarks of inflammatory and degenerative diseases of the brain are hypertrophy of astrocytes and accumulation of macrophages recruited from circulating blood monocytes and/or from resident macrophages, the so-called microglial cells. Recently, production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by astrocytes has been suggested to contribute to the macrophage response. Here we report that in addition to GM-CSF, murine astrocytes also produce macrophage (M)-CSF upon stimulation with tumor necrosis factor alpha, interleukin-1 and lipopolysaccharides. The bioactivity detected in supernatant of astrocytes was characterized using the M-CSF-dependent cell line M-NFS-60 and neutralizing anti-M-CSF antibodies. RNase protection analysis showed M-CSF mRNA already in unstimulated astrocytes without striking up-regulation by the stimuli. Thus, in astrocytes the expression of the M-CSF gene is predominantly regulated at the posttranscriptional level.
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PMID:Production of macrophage colony-stimulating factor by astrocytes and brain macrophages. 143 Jan 51

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.
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PMID:Transforming growth factor-beta 1 bifunctionally regulates murine macrophage proliferation. 153 54

Gamma-irradiation of plateau phase cultures of the clonal murine bone marrow stromal cell line D2XRII followed by cocultivation of a clonal interleukin 3 (IL-3) (granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent hematopoietic progenitor cell line FDC-P1JL26 results in a significant increase in "cobblestone islands" of attachment and emergence of subclonal factor-independent malignant sublines. Biochemical purification of conditioned medium from irradiated D2XRII cells yielded a 75,000-dalton glycoprotein termed leukemogenic stromal factor (LSF) that was neutralized by a polyclonal antiserum to murine macrophage colony-stimulating factor (M-CSF). A monoclonal antibody to the murine M-CSF receptor (c-fms) neutralized the biological activity of this molecule in a manner comparable to its effect on recombinant human or murine M-CSF. FDC-P1JL26 parent cells were positive for Ly5, MEL-14, mGR, VLA-4, PGP-1 (CD44), and Thy1.2. After culture in LSF, Thy1.2, MEL-14, and mGR became undetectable; however, significant cell surface MAC-1 antigen and c-fms (M-CSF receptor) were expressed. Neither line was positive for Ly6, Ly22, I-CAM-1, or B220 antigen. LSF-precultured FDC-P1JL26 cells transferred as single cells to microwell culture with 5000-cGy-irradiated D2XRII cells revealed a 60-fold increase in frequency of cobblestone island formation and evolution of factor-independent subclones compared to the parent line. Both parent and LSF-precultured cells became factor independent at a 100-fold lower frequency if kept in suspension in LSF in the absence of stromal cells. Antiserum to M-CSF or monoclonal antibody to the murine M-CSF receptor (c-fms) did not inhibit or displace cobblestone island formation by either clone of FDC-P1 on irradiated stromal cells indicating a mechanism of binding not involving the M-CSF receptor. However, anti-serum to the M-CSF receptor inhibited growth of one factor-independent subclone. In separate studies, a subclone of IL-3-dependent 32Dc13 cells, expressing the transfected murine c-fms protooncogene but not the parent 32Dc13 cell line or another subclone expressing the transfected gene for the human M-CSF receptor, showed adherence and became factor independent when cocultivated with irradiated D2XRII stromal cells. Thus, irradiated stromal cells bind M-CSF receptor-positive hematopoietic progenitor cells and induce c-fms-dependent factor-independent tumorigenic subclones. The cellular interactions in this model may be relevant to gamma-irradiation leukemogenesis in vivo.
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PMID:Humoral and cell surface interactions during gamma-irradiation leukemogenesis in vitro. 153 94


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