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)

Polycythemia vera (PV) is a clonal disease of the hematopoietic stem cell characterized by a hyperplasia of marrow erythropoiesis, granulocytopoiesis, and megakaryocytopoiesis. We previously reported that highly purified PV blood burst-forming units-erythroid (BFU-E) are hypersensitive to recombinant human interleukin-3 (rIL-3). Because these cells may be only a subset, and not representative of marrow progenitors, we have now studied partially purified marrow hematopoietic progenitor cells. Dose-response experiments with PV marrow BFU-E showed a 38-fold increase in sensitivity to rIL-3 and a 4.3-fold increase in sensitivity to recombinant human erythropoietin (rEpo) compared with normal marrow BFU-E. In addition, PV marrow colony-forming units-granulocyte-macrophage (CFU-GM) and CFU-megakaryocyte (CFU-MK) also showed a marked hypersensitivity to rIL-3 and to human recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). Dose-response curves with rGM-CSF and blood BFU-E showed a 48-fold increase in sensitivity. No effect of rIL-4, rIL-6, human recombinant granulocyte-CSF (rG-CSF), or macrophage-CSF (rM-CSF) was evident, nor was there any effect of PV cell-conditioned medium on normal BFU-E, when compared with normal cell-conditioned medium. Autoradiography with 125I-rEpo showed an increase in Epo receptors after maturation of PV BFU-E to CFU-E similar to that shown with normal BFU-E, but no increase of specific binding of 125I-rIL-3 by PV CD34+ cells was seen compared with normal CD34+ cells. These studies show that PV marrow hematopoietic progenitor cells are hypersensitive to rIL-3 and rGM-CSF, similar to PV blood BFU-E. While the mechanism does not appear to be due to enhanced binding of rIL-3, the hypersensitivity of PV progenitor cells to IL-3 and GM-CSF may be a key factor in the pathogenesis of PV.
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PMID:Polycythemia vera. II. Hypersensitivity of bone marrow erythroid, granulocyte-macrophage, and megakaryocyte progenitor cells to interleukin-3 and granulocyte-macrophage colony-stimulating factor. 149 32

Effects of cytokines on murine megakaryocyte (MK) colony formation from either unfractionated marrow cells or purified early haematopoietic cells were studied. Recombinant interleukin-3 (IL3), interleukin-6 (IL6), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (Epo) and acidic and basic fibroblast growth factor (aFGF and bFGF) each was able to stimulate MK colony growth although they varied somewhat in their potential. IL6 and FGFs, in addition to their effect on MK colony growth, increased the size of individual MK. The combination of IL3 with IL6 or FGF resulted in an additive action. Monoclonal anti-IL6 antibody completely neutralized the activity of mouse IL6 and FGFs but had no effect on human IL6, mouse IL3 and GM-CSF. When using purified lineage negative marrow cells, only IL3 and IL6 promoted MK colony formation. Transforming growth factor beta 1 (TGF-beta 1) at 10-200 pg/ml selectively inhibited IL3-induced MK colony formation, and at 0.2-0.5 ng/ml it still had no obvious effect on the activity of IL6 or GM-CSF but caused an inhibition of FGF-induced MK colony formation. These data suggest that differential mechanisms are involved in the regulation of megakaryocytopoiesis by IL3, IL6, FGFs and GM-CSF, and that TGF-beta 1 negatively regulates MK development mainly by interfering with the action of IL3.
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PMID:New insights into the regulation of megakaryocytopoiesis by haematopoietic and fibroblastic growth factors and transforming growth factor beta 1. 152 Jun 6

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) has been described as a multi-lineage growth factor that induces in vitro colony formation of bone marrow erythroid burst-forming units (BFU-E), multipotential colony-forming units (CFU-GEMM), granulocyte-macrophage CFU (CFU-GM), granulocyte CFU (CFU-G), macrophage CFU (CFU-M), as well as eosinophil colony-forming units (CFU-Eo). Because of the preeminent role of the liver in fetal hematopoiesis, the effect of human recombinant GM-CSF (hrGM-CSF) on hematopoietic cells isolated from human fetal liver was tested in liquid cultures and in semisolid colony assays. hrGM-CSF induced a significant increase in the number of mature eosinophils in liquid culture and to a lesser extent in semisolid cultures when compared to untreated culture controls. The kinetics of this effect on eosinophils reached its peak on day 21 of culture. When GM-CSF and erythropoietin (Ep) were added simultaneously to the cultures, no significant change in the number of eosinophils compared to hrGM-CSF alone was observed. Ep or granulocyte colony-stimulating factor (G-CSF) did not show any CFU-Eo activity when added separately or simultaneously to both liquid and semisolid cultures. These results indicate that hrGM-CSF alone may be a potent stimulating factor for CFU-Eo obtained from human fetal liver and, in combination with other growth factors, control optimal development of human fetal eosinophils.
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PMID:GM-CSF induces eosinophilic cell growth-promoting activity on human fetal liver cells. 152 2

A proportion of fetal liver hemopoietic blast cells express Fc gamma RII, and addition of the anti-Fc gamma RII monoclonal antibody CIKM5 induces a rise in calcium in these cells in suspension. Although these cells are thus capable of mobilizing intracellular calcium in response to surface receptor mediated events, neither granulocyte-macrophage colony-stimulating factor (GM-CSF) nor erythropoietin produced detectable changes in intracellular calcium ion concentration in these cells.
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PMID:Fc gamma RII, but not erythropoietin or GM-CSF, mediates calcium mobilization in fetal hemopoietic blast cells. 156 43

Thymus humoral factor-gamma 2 (THF gamma 2), an octapeptide important for T-lymphocyte regulation, was assessed for its effect on the in vitro growth of human hematopoietic progenitor cells. This was achieved using a recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF)-stimulated myeloid cell colony formation (granulocyte-macrophage colony-forming cells, GM-CFC) assay as well as a recombinant erythropoietin (rEpo)-stimulated erythroid burst formation (erythroid burst-forming units, BFU-E) assay. Cells were obtained from bone marrow (BM) and peripheral blood (PB) of normal healthy donors and from patients with suppressed bone marrows. The latter group included aplastic anemia, leukemia, and lymphoma patients and patients with solid tumors who responded to intensive chemotherapy with significant pancytopenia. THF gamma 2 significantly enhanced normal BM and PB GM-CFC and PB BFU-E by 2- to 2.5-fold. This effect was totally dependent on the presence of the respective growth factors, that is, rGM-CSF or rEpo, and was specifically reversed by an anti-THF gamma 2 antiserum. Furthermore, although THF gamma 2-induced enhancement of GM-CFC colony formation was not affected by lymphocyte or monocyte depletion, the augmenting effect of the peptide on BFU-E was completely abrogated in the absence of lymphocytes. THF gamma 2-induced augmented growth of progenitor cells derived from severely suppressed marrows was minimal. However, cells from moderately neutropenic patients with leukemia in remission or with lymphoma under chemotherapy responded to the peptide similarly to cells from normal donors. These results suggest a stimulatory role for THF gamma 2 on human myeloid and erythroid hematopoietic progenitor cells. They also suggest the lymphocyte dependence of BFU-E enhancement and lymphocyte independence of GM-CFC stimulation by THF gamma 2. In the former case the thymus-derived peptide may act through the induction of certain erythroid-enhancing lymphokines.
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PMID:Thymic humoral factor-gamma 2, an immunoregulatory peptide, enhances human hematopoietic progenitor cell growth. 154 85

We treated a patient with therapy-related myelodysplastic syndrome (MDS) with human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Epo). The patient achieved a hematological remission which continued for more than 16 months despite discontinuation of the treatment. Before the treatment with GM-CSF and Epo the patient had severe pancytopenia, required frequent red cell transfusions, and experienced episodes of severe infection, but after the therapy he no longer needed transfusion and no longer had the infection. While the patient remained in hematological remission, bone marrow examination revealed trilineage dysplasia, and cytogenetic analysis showed an abnormal karyotype [48, XY, +8, +der(1q5p)] in 100% of the metaphases examined. These findings suggest that the hematological remission of this patient may not result from the recovery of the non-clonal hematopoiesis of a normal clone, but result from the monoclonal hematopoiesis of a neoplastic clone.
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PMID:A hematological remission by clonal hematopoiesis after treatment with recombinant human granulocyte-macrophage colony-stimulating factor and erythropoietin in a patient with therapy-related myelodysplastic syndrome. 154 64

We studied the long-term effect of continued zidovudine exposure in mice on hematopoiesis, as determined by peripheral blood indices, assays of erythroid (colony-forming unit-erythroid [CFU-E] and burst-forming unit-erythroid [BFU-E]), myeloid (CFU-granulocyte-macrophage [GM]), megakaryocyte (CFU-Meg), and plasma titers of erythropoietin, granulocyte-macrophage colony-stimulating factor, megakaryocyte colony-stimulating factor, and tumor necrosis factor-alpha. Dose-escalation of zidovudine (0.1, 1.0, and 2.5 mg/ml) induced a dose-dependent decrease in hematocrit, white blood cells, and platelets. High-dose drug, i.e., greater than 1.0 mg/ml, reduced marrow CFU-E; splenic CFU-E was increased after 1 week, then declined. BFU-E was increased at Weeks 1 and 2, then declined to control levels. Splenic BFU-E rose during the examination period that was dose-dependent. Femoral CFU-GM was cyclic, i.e., low-dose drug, 0.1 mg/ml, was increased gradually, the declined; higher doses of 1.0 and 2.5 mg/ml were lower until Week 5, then were above controls. Splenic CFU-GM was increased initially at Week 2 (1.0 mg/ml), then declined; the higher dose (2.5 mg/ml) increased initially, then declined below controls (Week 6). Femoral CFU-Meg was increased after low-dose drug and inhibited after high dose (2.5 mg/ml). Splenic CFU-Meg was reduced initially, followed by an increase at Week 4. Plasma titer of erythropoietin was elevated, proportional to dose escalation of drug, and inversely proportional to the hematocrit. No difference was observed in plasma levels of granulocyte-macrophage colony-stimulating factor, megakaryocyte colony-stimulating factor, or tumor necrosis factor-alpha. This study demonstrates that zidovudine-induced anemia results from: (i) inadequate numbers of bone marrow-derived, erythropoietin-dependent hematopoietic progenitors, i.e., CFU-E; and (ii) a shift in erythropoietin-responsive progenitors from bone marrow to spleen capable of responding to obligatory growth factors.
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PMID:Suppression of murine hematopoiesis in vivo after chronic administration of zidovudine: evidence that zidovudine-induced anemia is the result of decreased bone marrow-derived, erythropoietin-responsive progenitor cells. 154 25

We have assayed modulation of clonal growth of cell lines from human solid tumors in vitro by recombinant human interleukin-6 (rhIL-6), rhIL-3, rh granulocyte-macrophage colony-stimulating factor (GM-CSF), rhG-CSF, rhM-CSF, and rh erythropoietin. Effects of hematopoietic growth factors were also tested in the tritiated thymidine uptake assay. No reproducible and significant modulation of clonal growth was found with rhIL-6, rhM-CSF, and rhEPO. The other cytokines showed stimulation of colony formation in some cell lines from colorectal adenocarcinomas and bladder and lung cancers with the following order of activity: rhIL-3 greater than or equal to rhGM-CSF greater than rhG-CSF. Growth stimulation was only found in clonal assays; it was abolished by neutralizing antibodies and was highly dependent on culture conditions. Stimulation could be masked by elevation of serum concentration and there was an inverse correlation between spontaneous plating efficacy of the control cells and growth stimulation by the factor with the highest activity of the colony-stimulating factor at suboptimal growth conditions. Growth inhibition by the cytokines was not observed. We could not establish autocrine loops for the growth modulation by the cytokines in the cell lines tested so far. Furthermore, we xenotransplanted some responsive cell lines into athymic mice and observed their in vivo growth under systemic application of rhIL-3 and rhGM-CSF or vehicle. There was no significant alteration of the tumor growth by these cytokines at plasma levels sufficient for in vitro growth stimulation. In conclusion, tumor growth stimulation by rhGM-CSF and rhIL-3 as potential hazards for their clinical application in cancer patients in conjunction with cytotoxic chemotherapy is unlikely.
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PMID:Effects of hematopoietic growth factors on malignant nonhematopoietic cells. 155 74

The effect of eosinophil cationic protein (ECP) on immunoglobulin (Ig) production by and proliferation of human plasma cells was studied. ECP inhibited Ig production by and proliferation of the human plasma cell lines, IM-9 and AF-10, in a dose-dependent fashion. As little as 0.05 ng/ml ECP was found to be inhibitory, and the maximal inhibition was achieved at doses of 0.1-0.5 ng/ml ECP. This inhibition was not due to cytotoxicity, since viability was always greater than 98%. Kinetic experiments demonstrated that inhibition was observable after 24 hr of culture with ECP and that the inhibitory effect of ECP was reversible. The inhibitory effect of ECP could be blocked by anti-ECP serum, but not by control serum. Of the various cytokines tested, including interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, interferon (IFN)-alpha, IFN-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Epo), IL-6 reversed the inhibition, while other cytokines failed to do so. ECP also inhibited Ig (IgG1, IgG2, IgG3, IgG4, IgM, and IgA) production by and proliferation of PCA-1+ plasma cells generated in vitro with a similar dose-response pattern. This inhibition also was blocked by anti-ECP serum but not by control serum, and was restored by IL-6. These results suggest that ECP may interact with IL-6 in controlling plasma cell responses.
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PMID:Eosinophil cationic protein inhibits immunoglobulin production and proliferation in vitro in human plasma cells. 157 57

The osteoclast is known to be derived from the hematopoietic stem cell, but its lineage remains controversial. There is evidence that osteoclastic differentiation is induced through a contact-dependent interaction between bone marrow stromal cells and hematopoietic precursors. To analyze osteoclastic lineage, colonies were generated in semisolid medium from mouse spleen cells in the presence of Wehi-conditioned medium, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or macrophage colony-stimulating factor (M-CSF) with or without erythropoietin (epo). After 5-8 days colonies were picked and phenotyped and incubated with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] on bone slices or coverslips with bone marrow-derived cell lines (ts8 or ST2) that induce osteoclastic differentiation. Cells of osteoclastic phenotype [as judged by calcitonin receptor (CTR) expression or bone resorption] were observed only in multilineage colonies. The ability of cells that generate macrophage colonies (CFU-M) to generate osteoclasts was tested by incubating alveolar or peritoneal macrophages on ts8 or ST2 cells. Despite colony formation, no osteoclastic differentiation was detectable. Last, individual cells from blast cell colonies were incubated (1 cell per culture well) on ts8 or ST2 cells in the presence of 1,25-(OH)2D3 and epo (to expose the lineage potential of the plated cell). We found CTR-positive (CTRP) cells in 6 of 66 macrophage colonies, 7 of 12 granulocyte-macrophage (GM) colonies, and 49 of 50 colonies containing multiple lineages other than GM colonies. No single-lineage CTRP colonies were observed. Although most macrophage colonies did not contain CTRP, no CTRP were observed in colonies from which macrophages were absent. These results suggest that osteoclasts are derived from a multilineage precursor rather than from CFU-M.
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PMID:Derivation of osteoclasts from hematopoietic colony-forming cells in culture. 158 38


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