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)

AIC2A and AIC2B are closely related genes encoding components of the receptors for murine interleukin-3 (IL-3) (AIC2A) and granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5 (AIC2B). We have studied the parallel regulation of expression of these genes in erythroid and myeloid progenitor cell lines. AIC2A and AIC2B transcription was transiently induced in these cells in response to a variety of hematopoietic growth factors, including erythropoietin (EPO), monocyte-CSF, IL-3, GM-CSF, and stem cell factor (SCF or kit ligand). Run-on assays established that the increase occurred mainly at the transcriptional level. Immunoprecipitation experiments confirmed that the increase in messenger RNA expression resulted in augmented synthesis of both AIC2A and AIC2B proteins, and binding studies further showed these proteins to be functional. We observed a fourfold increase in low-affinity IL-3 sites in an erythroid precursor cell line stimulated with EPO, and a threefold increase in GM-CSF high-affinity sites in a myeloid cell line stimulated with IL-3. In addition, we showed that the increase in the IL-3 receptor chain AIC2A in the erythroid precursor cell line correlated with the ability of IL-3 to exert a cooperative effect with EPO in the induction of beta-globin in these cells.
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PMID:Enhanced expression of interleukin-3 and granulocyte-macrophage colony-stimulating factor receptor subunits in murine hematopoietic cells stimulated with hematopoietic growth factors. 138 62

To provide insights into the pathogenesis of Diamond-Blackfan anemia, we examined the in vitro response of erythroid progenitors to the recently isolated ligand for c-kit (stem cell factor, SCF). For these studies, marrow or blood mononuclear cells from 10 Diamond-Blackfan patients were cultured with erythropoietin (Ep), Ep and interleukin-3, Ep and granulocyte-macrophage colony-stimulating factor, or Ep and lymphocyte conditioned media (LCM). These combinations were tested in the presence or absence of SCF. The mean number of cells per erythroid burst increased 5 to 50-fold in cultures containing SCF. Furthermore, many additional erythroid bursts were seen (mean increment 3.2 x baseline values). Although burst-forming unit-erythroid (BFU-E) from all patients responded, there were differences among individuals in the sensitivity of their BFU-E to SCF. In six patients and all control studies, plateau frequencies of erythroid bursts were achieved with less than or equal to 10 ng/mL SCF, whereas in studies from the other four patients, over 50 ng/mL SCF was required. These data invite speculation that the c-kit receptor/ligand axis is involved in the pathogenesis of Diamond-Blackfan anemia. More importantly and regardless of whether the observed patterns of response reflect the primary defect or an epiphenomenon, our data strongly support a therapeutic trial of SCF in patients with Diamond-Blackfan anemia.
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PMID:Diamond-blackfan anemia: in vitro response of erythroid progenitors to the ligand for c-kit. 171 87

Isoelectric focusing demonstrated that T cell growth factor (TCGF), T cell replacing factor (TRF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) derived from concanavalin A-stimulated T cell hybridomas and spleen cells are heterogeneous with respect to charge. The spleen cell-derived TCGF and TRF activities focused with isoelectric points (pI) between 3.5 and 6.5 whereas the range for GM-CSF activity was broader (pI, 3.5 to 8.0). The T cell hybridoma-derived activities were slightly more acidic. Neuraminidase treatment of both hybridoma 123 and spleen cell-derived material resulted in a major peak of each activity (TRF/TCGF pI, 4.9; GM-CSF pI, 4.7). Neuraminidase treatment of hybridoma T6-derived material resulted in peaks of TRF and TCGF around 6.0 as well as one around 5.0, suggesting that this charge heterogeneity was due to causes other than variations in the level of sialic acid on the relevant molecules. Tunicamycin-treated spleen cells or hybridoma 123 cells released biologically active TCGF, TRF, and GM-CSF. Each of these three activities from tunicamycin-treated spleen cells focused with pI around 5.0. A major fraction of TRF, TCGF, and GM-CSF activities bound to wheat-germ agglutinin. GM-CSF also bound to concanavalin A and lentil lectin. These results suggest that the molecules responsible for TCGF, TRF, and GM-SCF activities are glycosylated and that the observed heterogeneity in charge and lectin-binding characteristics is due in part to variable glycosylation. Glycosylation was not critical for any of the three biologic activities. No conclusive separation of TRF and TCGF activities was observed in these experiments although GM-CSF differed from TRF and TCGF in that it bound to Concanavalin A.
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PMID:Biochemical characterization of regulatory factors derived from T cell hybridomas and spleen cells. II. Evidence for glycosylation of T cell growth factor, T cell replacing factor, and granulocyte-macrophage colony-stimulating factor. 697 70

By employing a monoclonal antibody against the stem cell factor receptor (SCF-R), c-kit oncogene product, we analysed in flow cytometric technique the density of SCF-R on GM/SO cells which were incubated under various culture conditions. These experiments revealed that there is an inverse correlation between the SCF-R density on the cells and the doses of granulocyte-macrophage colony-stimulating factor (GM-CSF) in culture medium; the lower the dose, the higher the density of SCF-R on the cells. More detailed analyses showed that, in contrast to SCF which rapidly downregulates its own receptor, GM-CSF does not alter the measurable level of SCF-R in an exposition period of 60 minutes, which suggests that the internalization or shedding of the receptor is not the mechanism of action. Since the most striking difference regarding density of SCF-R between GM-CSF-treated and untreated cells was observed on day 2, the modulation of c-kit oncogene protein by GM-CSF likely occur prior to expression of protein onto the cell surface. In order to exclude the possibility that altered cell viability due to insufficient GM-CSF content in culture medium might be responsible for the increased SCF-R densities on GM-CSF-dependent cells, we subsequently generated a GM-CSF-independent subclone which still responded to GM-CSF as well as the dependent did. The experiments carried out with this subclone confirmed the results presented above. Thus our data suggest that GM-CSF is directly involved in the regulation of SCF receptor density on GM/SO cells.
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PMID:Granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the density of stem cell factor receptors (c-kit oncogene product) on a GM-CSF-dependent human myeloid cell line. 750 37

The clinical symptoms of allergy are caused by cellular (IgE-triggered) responses to an allergen. Effector cells of allergy include eosinophil and basophil granulocytes, as well as tissue mast cells. Growth and accumulation, as well as IgE-dependent and independent functions of these cells are regulated by distinct proteohormones and peptides. The hemopoietic cytokines IL-3 (interleukin-3), IL-5 and GM-CSF (granulocyte-macrophage colony-stimulating factor) are involved in the regulation of basophils (and eosinophils), whereas the ligand for c-kit, SCF (stem cell factor) is a mast cell-specific agonist. Basophils and mast cells express high-affinity IgE-binding sites. Allergen binding to IgE on mast cells and basophils, and consecutive cross-linking of IgE receptors is followed by production and/or secretion of inflammatory mediator substances. Specific activation and deactivation of mast cells/basophils in vitro has been demonstrated by use of recombinant cytokines and allergens, and specific haptens or by use of novel drugs, and should lead to epitope-specific diagnosis and better management of allergic diseases in the future.
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PMID:[Effector cells in allergy: biological principles and new pharmacologic concepts]. 750 62

We have studied the effects of recombinant human interleukin-9 (IL-9), alone and combined with stem cell factor (SCF, c-kit ligand), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) on the clonogenic proliferation of highly enriched human hematopoietic CD34+ and CD34+CD33-DR- progenitor cells. Colony assays were performed under serum-containing and serum-free conditions. IL-9, as a single agent, did not support colony formation. The addition of erythropoietin (Epo) to IL-9 induced the growth of erythroid progenitors (BFU-E) derived from both CD34+ and CD34+CD33-DR- cells. The IL-9-dependent growth of BFU-E derived from CD34+ cells was increased in an additive manner by SCF and, to a lesser extent, by IL-3, whereas CD34+CD33-DR- erythroid precursors were also responsive to GM-CSF in combination with IL-9. The addition of SCF to IL-9 did stimulate the development of CD34+ and CD34+CD33-DR- macroscopic, multicentered BFU-E and multilineage colonies (CFU-GEMM). When IL-9 was used in serum-free conditions, the growth of CD34+ and CD34+CD33-DR- BFU-E was observed in the presence of Epo. Moreover, a marked synergy on BFU-E colony formation was evident when IL-9 was combined with SCF, and their activity was enhanced by the addition of IL-3. IL-9 showed a negligible proliferative activity on colony-forming units-granulocyte/macrophage (CFU-GM). However, it increased the number of CD34+CD33-DR- CFU-GM responsive to IL-3 (37% of the colonies generated by phytohemagglutinin-stimulated lymphocyte conditioned medium [PHA-LCM]). The effects of IL-9 on CD34+CD33-DR- cells were also studied in a short-term suspension culture system, which evaluates the proliferation of progenitors earlier than day 14 CFU-C (Delta assay). In this system, IL-9 had a minimal activity on its own. In combination with SCF, however, it induced a nine-fold expansion of CD34+CD33-DR- cells, which generated a greater number of CFU-GM than BFU-E in secondary methylcellulose cultures. These experiments indicate that IL-9 induces the proliferation of very primitive human erythroid cells, and this effect is potentiated by SCF and other cytokines. Furthermore, IL-9 synergizes in vitro with the c-kit ligand in expanding the pool of early pluripotent hematopoietic progenitor cells.
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PMID:Stem cell factor (c-kit ligand) enhances the interleukin-9-dependent proliferation of human CD34+ and CD34+CD33-DR- cells. 752 Mar 94

Primary autologous as well as allogeneic and xenogeneic stroma will support human stem cell proliferation and differentiation for several months. In the present study, we investigated the capacity of porcine microvascular endothelial cells (PMVECs) together with combinations of cytokines (granulocyte-macrophage colony-stimulating factor [GM-CSF] + stem factor [SCF], interleukin-3 [IL-3] + SCF + IL-6, and GM-CSF + IL-3 + SCF + IL-6) to support the expansion and development of purified human CD34+ bone marrow cells. In short-term cultures (7 days), the greatest expansion of nonadherent hematopoietic cells and clonogenic progenitors was seen with CD34+ cells in direct contact with PMVEC monolayers (PMVEC contact), followed by PMVEC noncontact and liquid suspension cultures, respectively. Maximal expansion of nonadherent cells (42-fold) and total CD34+ cells (12.6-fold) occurred in PMVEC contact cultures treated with GM-CSF + IL-3 + SCF + IL-6, with similar increases in the number of granulocyte-macrophage colony-forming units (CFU-GM), CFU-mix, erythroid burst-forming units (BFU-E), CFU-blast and CFU-megakaryocyte (CFU-Mk) progenitor cells. Moreover, the number of CD34+ CD38- and CD34+ CD38+ cells increased 148.1-fold and 8.0-fold, respectively. Replating studies show that cells from day 7 dispersed blast cell colonies generated on cytokine-treated PMVEC monolayers have a high replating potential for multilineage progenitor cells. In long-term PMVEC contact cultures, CD34+ cells seeded onto PMVEC monolayers with GM-CSF + IL-3 + SCF + IL-6 showed a total calculated expansion of over 5,000,000-fold of nonadherent cells over 35 days in culture. Maximal clonogenic cell production was observed at day 28, with 6,353-fold for total CFC and comparable increases for CFU-GM, CFU-mix, CFU-blast, BFU-E, and CFU-Mk. The total number of CD34+ cells increased 2,584-fold at day 28. Furthermore, the extended growth kinetics of these cultures indicates that these phenotypically primitive progenitor cells are also functionally expanded on PMVEC monolayers. These results support the hypothesis that direct contact with a PMVEC monolayer supports the initial expansion of hematopoietic progenitor cells with a high replating potential and, possibly, a more primitive phenotype (CD34+, CD34+/CD38-).
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PMID:Porcine brain microvascular endothelial cells support the in vitro expansion of human primitive hematopoietic bone marrow progenitor cells with a high replating potential: requirement for cell-to-cell interactions and colony-stimulating factors. 753 87

We have previously reported that serum stem factor (SCF) levels are significantly lower in patients with myelodysplastic syndrome (MDS) than normal controls. We have now studied the effects of adding SCF to cultures of blood mononuclear cells from patients with MDS and normal subjects. Three of 17 patients with MDS showed marked increases in erythroid colony numbers with SCF + erythropoietin compared to interleukin-3 + erythropoietin. In two cases (1RA and 1ISA) the erythroid colony numbers became normal. The same RA patient also showed a marked increase in myeloid colony numbers, which were undetectable with granulocyte-macrophage colony-stimulating factor alone, but within the normal range when SCF was added. A fourth patient (ISA) showed a 4.7-fold increase in myeloid colonies with SCF, but no erythroid response. The normal subjects showed a trend towards increased numbers of myeloid colonies with SCF; erythroid colonies did not increase. A correlation was found between the MDS patients' haemoglobin levels and erythroid colony numbers with and without SCF, but there was no correlation between erythroid or myeloid colonies in the presence of SCF and their serum SCF level.
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PMID:Responsiveness to stem cell factor (SCF) of peripheral blood colony-forming cells from patients with myelodysplastic syndromes (MDS). 754 50

We have further characterized the biological activities, mechanism of action, and target cell populations of recombinant human and murine thrombopoietin (rhTPO and rmTPO) in in vitro human and murine model systems. Alone, hTPO or mTPO stimulated the maturation of immature murine megakaryoblasts as measured in a single cell assay. The combination of hTPO or mTPO and interleukin-6 (IL-6) resulted in a further increase in megakaryocyte differentiation in this system. Murine TPO stimulated mouse megakaryocyte progenitor development. Human megakaryocyte progenitor development was potentiated by hTPO alone and further augmented in the presence of the early-acting cytokines (IL-3) or kit ligand/stem cell factor (KL/SCF). To further define the mechanism of action of TPO, neutralization studies were performed with antisera to IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1 beta, and IL-11. No diminution in TPO activity was observed in the presence of these antisera. Moreover, because adhesive interactions are known to modulate hematopoiesis, we studied whether hTPO might alter such interactions between human bone marrow (BM) megakaryocytes and human BM stromal fibroblasts. No changes were observed in either megakaryocyte expression of the surface molecules lymphocyte function-associated antigen-1, very late activation antigen-4, or intercellular adhesion molecule-1 or the adhesion of megakaryocytes to stromal fibroblasts after treatment with the growth factor. Furthermore, no induction of secretion of the cytokines IL-1 alpha, IL-1 beta, GM-CSF, IL-6, granulocyte-CSF, tumor necrosis factor-alpha, transforming growth factor-beta 1, or transforming growth factor-beta 2 by primary human BM megakaryocytes was noted after treatment of the cells with hTPO. To address whether TPO affects very primitive hematopoietic progenitors, we studied the residual cells from the BMs of mice treated with high doses of 5-fluorouracil. Although no effect of mTPO alone was noted on the viability or replication of such primitive murine progenitor populations, the triple combination of IL-3 + KL/SCF + TPO stimulated growth of megakaryocyte progenitors. These results indicate that TPO is a highly lineage-specific growth factor whose primary biological effects are likely to be direct modulation of the growth and maturation of committed megakaryocyte precursors and immature megakaryoblasts.
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PMID:Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand. 763 39

The M07e megakaryoblastic leukemia cell line is strictly dependent on either interleukin 3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF) for continuous growth. This study shows that recombinant human stem-cell factor (rhSCF) can completely replace these lymphokines in supporting the continued propagation of M07e cells mostly by eliciting GM-CSF secretion in this target. In fact, in short-term proliferation assays the stimulatory activity of SCF is blocked about 75% by a GM-CSF-specific serum. In addition, we could detect GM-CSF expression by SCF-stimulated M07e cells, both at the protein and mRNA levels. In contrast, SCF does not induce transcripts for any other cytokine to which M07e cells are responsive, including IL-2, IL-3, IL-4, and IL-6. Overall, these data show that the ability of SCF to support the growth of this megakaryocytic cell line is mediated mostly by the induction of an autocrine loop of activation involving GM-CSF production. The finding that SCF can stimulate GM-CSF secretion also in an IL-2-dependent T-lymphoblastic leukemia cell line indicates that SCF can act on cells of both myeloid and lymphoid lineages, and that the ability to induce cytokines in target cells represents an important aspect of its mechanism of action.
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PMID:Human stem cell factor (c-kit ligand) induces an autocrine loop of growth in a GM-CSF-dependent megakaryocytic leukemia cell line. 767 80


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