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)

The human monoblastlike cell line U937 can be induced to differentiate by a variety of agents including gamma-interferon, phorbol esters, retinoic acid, and 1,25-dihydroxyvitamin D3 (VD3). Incubation of U937 with 1 to 1,000 units of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) did not induce macrophage differentiation. A synergistic effect on macrophage differentiation was observed, however, when U937 was cocultured with 10(-8) mol/L VD3 plus 50 U/mL GM-CSF. GM-CSF-plus VD3-treated cells demonstrated significant increases in OKM1 antigen expression, increased chemokinesis and chemotaxis, and increased Fc receptor-mediated erythrophagocytosis. Human peripheral blood monocyte cultures also demonstrated increased OKM1 antigen expression and chemotaxis when incubated with 50 to 500 U/mL of GM-CSF for 48 to 72 hours. VD3, however, was not necessary for the increases in effector function observed for GM-CSF-stimulated monocyte cultures. In distinction to the synergistic effect of GM-CSF on VD3-induced differentiation of U937, recombinant human granulocyte colony-stimulating factor (G-CSF) at comparable concentrations had no augmenting effect over that observed for VD3 alone. These results suggest that GM-CSF, in the presence of other physiological stimuli, can induce significant phenotypic changes in GM-CSF-nonresponsive cells of the monocytic lineage and can increase the effector functions of GM-CSF-responsive peripheral blood monocyte cultures.
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PMID:Synergistic effect of granulocyte-macrophage colony-stimulating factor and 1,25-dihydroxyvitamin D3 on the differentiation of the human monocytic cell line U937. 327 48

In this study we have examined the expression and modulation of the human granulocyte colony-stimulating factor (G-CSF) receptor (R) in immature and differentiated myeloid cells using a 125I labelled human G-CSF analogue (TG50). Equilibrium binding data revealed a single affinity class of receptor on all cell types expressing G-CSFR (KD 235-606 pM) with neutrophils expressing 2883 +/- 672 Rs/cell. Rapid internalization of surface receptor-bound ligand at 37 degrees C was detected in both immature cells (U937) and neutrophils with > 70% of specifically bound ligand internalized within 5 min. Concentration-response data showed that the level of occupancy of neutrophil G-CSFRs by ligand at 37 degrees C was approximately 5-fold greater than predicted by equilibrium binding data and correlated closely with concentration-response data for biological activity. Re-expression of G-CSFRs following down-regulation by internalization was not detected. Down-regulation of the neutrophil G-CSFR by several agents including granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor (TNF), lipopolysaccharide (LPS), f-met-leu-phe (fMLP), phorbol ester (TPA) and C5a was observed at 37 degrees C but not at 4 degrees C. In contrast, G-CSFRs on immature myeloid cells were significantly down-regulated by TPA only. Differentiation of myeloid leukaemic cell line HL-60 with DMSO, a frequently used model of granulocytic differentiation, was associated with a significant reduction in G-CSFR expression (11 +/- 5% of control) whereas treatment with retinoic acid led to increased G-CSFR expression (161 +/- 3%).
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PMID:Expression and dynamic modulation of the human granulocyte colony-stimulating factor receptor in immature and differentiated myeloid cells. 750 64

The effect of cytokines on the proliferation and differentiation of leukemia cells from 5 patients with acute promyelocytic leukemia (APL) was examined. Interleukin-1 beta (IL-1), interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) augmented uptake of 3H-thymidine into the DNA of APL cells in a dose-dependent manner in all cases. This stimulatory effect was pronounced in some, but not all, cells treated with all-trans retinoic acid (ATRA). However, nitroblue tetrazolium-reducing activity was induced in a concentration-dependent manner by ATRA in all cases. The cytokines greatly enhanced NBT reduction of APL cells treated with ATRA, and a mixture of cytokines was more effective than a single cytokine. Although GM-CSF, IL-3 and IL-1 significantly modulated the ATRA-induced morphological changes, they did not induce CD14 expression, a typical marker of monocytic differentiation. In the presence of ATRA, GM-CSF potentiated production and secretion of tumor necrosis factor-alpha (TNF) in response to lipopolysaccharide, as well as interferon-gamma which is a potent inducer of monocytic differentiation in APL cells. On the other hand, production of TNF in ATRA-treated cells was not affected by G-CSF which significantly enhanced granulocytic differentiation. The effect of cytokines on APL cell differentiation should be considered in ATRA treatment for APL patients. Potentiation of cytokine production in APL cells associated with myelomonocytic differentiation is noteworthy in the pathogenesis of "retinoic acid syndrome".
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PMID:Effect of cytokines on the proliferation and differentiation of acute promyelocytic leukemia cells: possible relationship to the development of "retinoic acid syndrome". 752 Nov 52

The effects of hematopoietic growth factors were examined on the cellular action of retinoic acid (RA) using the human factor-dependent cell line, MO7e. Treatment of cells with Steel factor (SLF) plus granulocyte-macrophage colony-stimulating factor (GM-CSF) synergistically stimulated cell proliferation compared to that with each factor alone. This synergism was even greater in the presence of RA than in its absence. Treatment of cells with RA resulted in apoptotic cell death associated with internucleosomal DNA fragmentation in the presence of either SLF or GM-CSF. RA-induced apoptosis and DNA fragmentation were completely blocked by treating cells with SLF plus GM-CSF. Northern analysis showed that the inhibition of RA effects on MO7e cells by SLF plus GM-CSF treatment occurred without modulation of expression of RA receptor-alpha (RAR-alpha) gene. Furthermore, a higher amount of AP-1 complex was detected by electrophoretic mobility shift assays in a nuclear extract prepared from cells treated with SLF plus GM-CSF compared to those treated with each factor alone, while the level of RAR-complex remained similar in cells treated with SLF and/or GM-CSF. These data suggest an interaction in signaling pathways among different types of receptors that might be associated with the AP-1 complex.
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PMID:The combination of Steel factor and GM-CSF blocks apoptosis induced by retinoic acid and upregulates AP-1 in a human growth factor-dependent cell line. 753 Feb 13

Retinoic acids (RAs) exert pleiotropic effects on cellular growth and differentiation. All-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA), a stereoisomer of ATRA, induce differentiation of leukemic cell lines and cells from patients with acute myelogenous leukemia (AML) in vitro. Despite information on the effects of RAs on hematopoietic cells, little is known about how RAs act on the hematopoietic microenvironment, especially on bone marrow stromal cells. Based on recent observations that various cytokines produced mainly by bone marrow stromal cells regulate hematopoiesis, we analyzed the effects of RAs on cytokine production by these cells. ATRA or 9-cis RA treatment of human bone marrow stromal cell line KM101, which produces macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) constitutively, enhanced mRNA levels of both cytokines in a dose-dependent manner. Both RAs also stimulated M-CSF production from primary cultures of human bone marrow stromal cells. Both retinoic acid receptor (RAR)-alpha and retinoid X receptor (RXR)-alpha were expressed constitutively in KM101 cells. ATRA did not affect the expression of either receptor, whereas 9-cis RA increased RXR-alpha mRNA expression in a dose-dependent manner, but did not affect levels of RAR-alpha mRNA. These findings may have important biologic implications for both the role of RAs in hematopoiesis and the therapeutic effects of ATRA on the hematopoietic microenvironment in patients with acute promyelocytic leukemia (APL).
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PMID:Retinoids (all-trans and 9-cis retinoic acid) stimulate production of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor by human bone marrow stromal cells. 799 28

The human myeloid cell line HL-60 expresses approximately 300 high-affinity granulocyte-macrophage colony-stimulating factor receptors (GM-CSFRs), yet treatment of these cells with GM-CSF does not result in enhanced cellular proliferation or increases in protein tyrosine phosphorylation. In contrast, GM-CSF induces rapid increases in protein tyrosine phosphorylation and proliferative responses in HL-60 cells pretreated for 3 days in dimethyl sulfoxide (DMSO). Similarly, HL-60 cells pretreated with retinoic acid or 1,25 dihydroxyvitamin D3 were also capable of responding to GM-CSF. Interestingly, each of these treatments resulted in increased expression of the src-like tyrosine kinase hck. Stimulation with GM-CSF increased hck autophosphorylation in DMSO-treated HL-60 cells, suggesting that hck is a component of the GM-CSF signal transduction pathway. To determine if hck has a role in the DMSO-induced recoupling of the GM-CSFR, we overexpressed hck in HL-60 cells. The resulting cell line (HL-60/hck) expresses hck mRNA and protein at levels comparable with DMSO-treated HL-60 cells. Stimulation of HL-60/hck cells with GM-CSF results in activation of hck, increases in protein tyrosine phosphorylation, and increased proliferation. These results show that cytokine receptors can exist in an uncoupled form and suggest that in HL-60 cells, appropriate levels of the src-like tyrosine kinase hck are critical for functional coupling of the GM-CSFR to biologic responses.
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PMID:Hck expression correlates with granulocyte-macrophage colony-stimulating factor-induced proliferation in HL-60 cells. 801 33

Direct and indirect evidence strongly indicates that the proto-oncogene c-myb plays an important role in the regulation of both the proliferation and differentiation of hematopoietic cells. In addition, recent data suggest that the structurally related B-myb gene is also necessary for the proliferation of these cells. To help understand the relationship between these two related gene products during proliferation and differentiation of myeloid cells, we have studied in parallel the regulated expression of c-myb and B-myb RNAs and proteins in human myeloid cells that were either growth-arrested or induced to differentiate along different pathways. For this purpose, we have produced a polyclonal antibody directed against a fragment of the recombinant B-myb protein. We have thus been able to detect the B-myb protein in human cell lines and have found it to be a 93-kD protein localized in the nucleus. We have chosen two models to study the expression of both c-myb and B-myb mRNAs and proteins during myeloid proliferation and differentiation. One of the models was the HL-60 cell line, which can be induced to differentiate towards the monocytic pathway with either phorbol ester (phorbol myristate acetate) or vitamin D3 and towards the granulocytic pathway with either dimethyl sulfoxide or retinoic acid. In addition, we have studied another recently established human leukemic cell line, called GF-D8, which is strictly dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) for proliferation. The results show that the expression of B-myb RNA and protein closely correlates with proliferation in all experimental setups studied, whereas the c-myb protein levels do not always do so. We observed that the c-myb protein levels decreased well before the decrease of B-myb protein and of proliferation itself during differentiation toward monocytes. Such a difference was not present during granulocytic differentiation, in which c-myb levels decreased, if anything, later than those of B-myb and proliferation. Most striking was the finding that high levels of c-myb RNA and protein, but not of B-myb, were present in the GF-D8 cell line, even after growth arrest by GM-CSF deprivation. These data suggest that B-myb may function solely in the regulation of cellular proliferation, whereas c-myb has additional functions, for example, in the maintenance of an undifferentiated state.
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PMID:Dissociation between p93B-myb and p75c-myb expression during the proliferation and differentiation of human myeloid cell lines. 814 46

In mouse dorsal skin multistage carcinogenesis models, tumor promotion can be mediated by chemical agents, but also by wounding or abrasion of the epidermis, suggesting that endogenous growth factors mediate this process. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one such factor that has been reported to be produced by keratinocytes in vitro, and has been suggested both to stimulate keratinocyte proliferation, and also to be a chemoattractant for neutrophils and macrophages. In this study we examined the expression and function of GM-CSF in mouse skin following the application of tumor-promoting agents. Both single and multiple applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in accumulation of GM-CSF mRNA in the epidermis. Various phorbol and non-phorbol ester tumor promoters were found to induce increases in epidermal GM-CSF mRNA levels commensurate with their relative tumor promoting capabilities. Fluocinolone acetonide (FA) and tosyl phenylalanine chloromethyl ketone (TPCK), inhibitors of tumor promotion, inhibited tumor promoter-mediated GM-CSF accumulation, whereas all-trans-retinoic acid (RA) enhanced the TPA-induced increase. The retinoic acid analogue RO-109359 which, unlike RA, does not have tumor promoting activity per se, inhibited the TPA-induced increase in epidermal GM-CSF mRNA levels. When an antibody specific to GM-CSF was administered prior to TPA, the promoter-induced dermal inflammation and increase in epidermal dark cell number were reduced, yet promoter-induced epidermal hyperplasia was not. These findings implied that elevation of GM-CSF levels plays an important role in chemically-mediated mouse skin tumor promotion and principally via effects on promoter-induced inflammation and increased epidermal dark cell number.
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PMID:Granulocyte-macrophage colony-stimulating factor (GM-CSF) is expressed in mouse skin in response to tumor-promoting agents and modulates dermal inflammation and epidermal dark cell numbers. 814 76

Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AMLs) characterized by the presence of the t(15,17) translocation and the resulting promyelocytic myeloid leukemia/retinoic acid receptor alpha (PML/RAR alpha) fusion proteins. To date APL is the only AML that is sufficiently sensitive to all-trans retinoic acid's (ATRA) differentiating effect. In vivo ATRA alone achieves complete remission in most APL patients. However, failure or partial responses are observed and the molecular basis of the absence of ATRA response in these patients has not been determined. To gain insights in the cell growth and differentiation of APL cells, expression of hematopoietic growth factors (HGF) shown to be produced by leukemic cells (interleukin-1 beta [IL-1 beta], IL-6, tumor necrosis factor alpha (TNF alpha), granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], and IL-3) was studied in 16 APL samples. Twelve APL cases expressed IL-1 beta, IL-6, and TNF alpha, but not G-CSF, GM-CSF, and IL-3. These cases achieved complete remission with ATRA therapy. The four remaining patients (either TNF alpha negative or G-CSF, GM-CSF or IL-3 positive) did not achieve complete remission with ATRA. In all cases, in vivo response to ATRA therapy was correlated to the in vitro differentiation effect of all-trans retinoic acid 10(-6) mol/L. Thus, ATRA differentiation induction was strongly correlated to the HGF expression (P < .0001). These results suggest that the presence or absence of HGF's expression by APL cells may contribute to the therapeutic effect of ATRA in this disease.
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PMID:Hematopoietic growth factor expression and ATRA sensitivity in acute promyelocytic blast cells. 819 61

All-trans retinoic acid (RA) is an important morphogen in vertebrate development, a normal constituent in human adult blood and is also involved in the control of cell growth and differentiation in acute promyelocytic leukemia. We have examined the effects of RA on normal hematopoiesis by using early hematopoietic progenitor cells (HPC) stringently purified from adult peripheral blood. In clonogenetic fetal calf serum-supplemented (FCS+) or -nonsupplemented (FCS-) culture treated with saturating levels of interleukin-3 (IL-3) granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Ep) (combined with c-kit ligand in FCS(-)-culture conditions), RA induces a dramatic dose-dependent shift from erythroid to granulomonocytic colony formation, the latter colonies being essentially represented by granulocytic clones. This shift is apparently not caused by a recruitment phenomenon, because in FCS+ culture, the total number of colonies is not significantly modified by RA addition. In FCS- liquid-suspension culture supplemented with saturating Ep level and low-dose IL-3/GM-CSF, adult HPC undergo unilineage erythropoietic differentiation: Here again, treatment with high-dose RA induces a shift from the erythroid to granulocytic differentiation pathway. Studies on RA time-response or pulse treatment in semisolid or liquid culture show that early RA addition is most effective, thus indicating that early but not late HPC are sensitive to its action. We then analyzed the expression of the master GATA1 gene, which encodes a finger transcription factor required for normal erythroid development; addition of RA to HPC stimulated into unilineage erythropoietic differentiation in liquid culture caused a virtually complete inhibition of GATA1 mRNA induction. These results indicate that RA directly inhibits the erythroid differentiation program at the level of early adult HPC, and may lead to a shift from the erythroid to granulocytic differentiation pathway. This phenomenon is correlated with inhibition of GATA1 induction in the early stages of erythropoietic differentiation.
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PMID:Retinoic acid downmodulates erythroid differentiation and GATA1 expression in purified adult-progenitor culture. 829 27


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