Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Highly purified progenitors (including erythroid [BFU-E], granulo-monocytic [CFU-GM], multipotent [CFU-GEMM] progenitors, as well as multipotent progenitors with self-renewal capacity [CFU-B]) express high-affinity growth factor receptors (GFRs), with prevalent interleukin-3 receptors (IL-3Rs) (2,700/cell), a > or = 10-fold lower number of IL-6Rs (145/cell) and granulocyte-macrophage colony-stimulating factor receptors (GM-CSFRs) (300/cell), and a barely detectable level of erythropoietin (Ep) receptors (75/cell). Hematopoietic growth factor (HGF) dosages inducing peak clonogenetic effects are associated with partial/subtotal occupancy of the homologous HGF receptor (HGFR). Cross-reactivity between GFRs and heterologous GFs (including IL-6, IL-3, GM-CSF, Ep, and the kit ligand [KL]) was explored by competition experiments on purified progenitors with radiolabeled and excess cold HGFs at +4 degrees C. No cross-reaction was observed between IL-6R, IL-3R, EpR, and the heterologous GFs, whereas the GM-CSFR showed cross-reactivity with IL-3 and, to a lesser extent, KL. Modulation of GFRs was examined after 18 or 40 hours of incubation with GF(s) at 37 degrees C, followed by ligand-binding assay at 20 degrees C. IL-6, IL-3, GM-CSF, and Ep induce a marked down-modulation of their own receptors. Interestingly, each GF induces the transactivation of the R(s) for the "distal" GF(s): (1) IL-6 induces transactivation of IL-3R, but not of GM-CSFR/EpR; (2) IL-3 causes a rapid upmodulation of GM-CSFR/EpR ("pure" progenitors treated with IL-3 show upmodulation of GM-CSFR alpha-chain mRNA by reverse transcriptase-polymerase chain reaction); whereas (3) GM-CSF induces the transactivation of the EpR. This chain upmodulation of HGFRs may underlie the synergistic interactions between the HGFs in clonogenetic culture. It is emphasized that KL does not induce upmodulation of the other GFRs. Finally, Ep, GM-CSF, and IL-3 do not modulate the expression of the "proximal" HGFRs (ie, GM-CSFR/IL-3R/IL-6R, IL-3R/IL-6R, and IL-6R, respectively). These results allow insight into the cellular basis of hematopoiesis, ie, the complex and coordinate interactions between HGFs and their receptors. They are compatible with a model of cascade transactivation via upmodulation of GFRs in the initial key steps of hematopoietic differentiation, whereby the action of each GF enhances the effect of the distal GF(s) by a multistep chain-potentiation mechanism.
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PMID:Cascade transactivation of growth factor receptors in early human hematopoiesis. 845 93

Cytokines transduce their signals through specific receptors. Receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, and IL-5 share the common signal transducing subunit (beta c), whereas the alpha subunits function as specific ligand binding components. In this study we prepared specific mouse monoclonal antibodies against human GM-CSF receptor-alpha subunit (hGMR alpha) by immunizing mice with Ba/F3 cells transfected with hGMR alpha complementary DNA. Using these anti-hGMR alpha antibodies in combination with antibodies against IL-3 receptor-alpha (IL-3R alpha), beta c subunits, and c-kit, we examined expression patterns and modulation of these receptor subunits on several human hematopoietic cells, including CD34+ cells and leukemic cell lines. GMR alpha and IL-3R alpha were expressed on GM-CSF- and IL-3-responsive cell lines, such as TF-1 and UT-7, whereas the expression levels were much lower on UT-7E, a GM-CSF- and IL-3-unresponsive subline of UT-7. The GMR alpha subunit was expressed only on mature granulocytes and monocytes, and IL-3R alpha was expressed on monocytes but not on mature granulocytes, and none of these subunits were expressed on lymphocytes. For CD34+ cells, GMR alpha was expressed more abundantly on CD34+ CD33high cells than on CD34+ CD33low cells, whereas IL-3R alpha was expressed more abundantly on CD34+ CD33low cells than on CD34+ CD33high and CD34+ CD33neg cells. Slight but significant expression of the beta c subunit was detected on CD34+ cells. Expression of not only GMR alpha and IL-3R alpha subunits but also c-kit was specifically downregulated by 48-hour incubation with their respective ligands. Receptor transmodulation between GM-CSF, IL-3, and stem cell factor (or kit ligand) was not detected on CD34+ cells in 48-hour cultures. We also detected upregulation of these alpha subunits by IL-1 alpha and interferon-gamma on leukemic cell lines. Our study showed expression levels for each receptor subunit--including GMR, IL-3R, and c-kit on human bone marrow and peripheral blood cells and leukemic cell lines--and revealed differential regulation of the expression of the receptor subunits.
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PMID:Differential expression of granulocyte-macrophage colony-stimulating factor and IL-3 receptor subunits on human CD34+ cells and leukemic cell lines. 854 66

Platelets and megakaryocytes express Fc receptors for IgG which are encoded by the Fc gamma RIIA gene. In an effort to establish a cellular model for induction of Fc gamma RIIA expression during megakaryocyte development by hematopoietic growth factors, steady-state Fc gamma RIIA mRNA levels were monitored in c-kit receptor-positive megakaryocytic cells (M07e, HEL, and Dami) in response to c-kit ligand (KL; also known as stem cell factor, mast cell growth factor, or Steel factor). Northern blot analysis showed that exposure of cells to KL led to significant increases in Fc gamma RIIA levels in M07e (15 x at 24 hours), with smaller increases in HEL (1.9 x at 2 hours) and Dami (1.6 x at 24 hours) cells. K562 cells, which lack c-kit receptor, showed no effect of KL on modulating Fc gamma RIIA mRNA levels. The effects of KL were specific for Fc gamma RIIA, as there were no effects on platelet factor 4 (PF4), gamma-globin, or GATA-1 mRNA levels. Effects of KL, alone and in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) and gamma-interferon (IFN-gamma), on surface Fc gamma RIIA expression were assessed by flow cytometry using anti-Fc gamma RII monoclonal antibody IV.3. In M07e cells, KL alone and in combination led to significant increases in the percentage of cells positive for surface Fc gamma RIIA and the mean cell fluorescence intensity. Transient transfection studies of an Fc gamma RIIA promoter-luciferase reporter gene in the presence or absence of KL showed increased reporter gene expression in KL-treated cells, with the largest increase (3.7-fold) in the M07e cells. In HEL and Dami cells, other cytokines active in megakaryocytopoiesis when used alone (interleukin-3 [IL-3], IL-6, IL-11, GM-CSF) had negligible activity in increasing reporter gene activity. These results suggest that increased levels of Fc gamma RIIA mRNA after KL treatment of M07e cells are a result, in part, of increased Fc gamma RIIA gene transcription. Our results indicate that M07e cells represent a cellular model for KL-induced Fc gamma RIIA expression in early megakaryocyte development.
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PMID:Human c-kit ligand (stem cell factor) induces platelet Fc receptor expression in megakaryoblastic cells. 876 99

The effect of the mast cell growth factor (MGF), also known as stem cell factor, steel factor, and kit ligand, alone or in combination with other GFs on clonogenic blast cell growth in 23 patients with acute myeloblastic leukemia (AML) was investigated. MGF alone enhanced colony formation by about 35%, being clearly stimulatory (> 20% increase in colony numbers) in nine patients. The additive effect of MGF on colony growth was observed in combination with interleukin-3 (IL-3). Preincubation of the cells with MGF in suspension did not sensitize them to the effect of IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, or IL-4 in a clonogenic cell culture assay. Although almost all the blast cell samples expressed the c-kit the receptor for MGF, at the mRNA and/or the protein level, the cells did not necessarily respond to exogenous MGF. On the other hand, blast cells were able to respond to exogenous MGF even when the cells themselves expressed MGF. Neither the expression of MGF nor the response of blast cells to exogenous MGF was related to the capability of the cells to form colonies spontaneously. In conclusion, MGF alone, but especially combined with IL-3, was a potent growth factor for clonogenic blast cells in AML. Autocrine production of MGF by AML blast cells analyzed at the mRNA level was not related to autonomous growth of the cells.
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PMID:Effect of mast cell growth factor on clonogenic blast cell growth in acute myelogenous leukemia. 877 15

The cell-surface expression and the functional status of the CD95/Fas antigen on primitive hematopoietic progenitors (PHPs) freshly isolated from human fetal liver (FL) were studied. PHPs were phenotypically defined as CD34++ CD38 -/+ cells. The most immature subfractions of PHPs, CD34++CD38- and CD34+2CD38+ FL cells, expressed CD95, whereas the more mature CD34++CD38++ and CD34+CD38++2 FL cells displayed low CD95 expression. Combinations of cytokines, such as kit ligand (KL) + interleukin-3 or KL + granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulated the expression of CD95 on PHPs upon in vitro culture. Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) further increased the CD95 expression induced by KL+GM-CSF. The hematopoietic potential of sorted CD34++lineage (lin)- CD95+ versus CD34++ lin-CD95-FL cells was compared by colony-forming unit-culture (CFU-C) assays performed in serum-deprived medium. Lin+ cells were composed of erythrocytes, monocytes, T cells, B cells, and natural killer cells. Our results indicated that both CD95- and CD95+ subsets contained pluripotent progenitors, generating myeloid and erythroid progenitors. The functional status of CD95 and the effects of TNF-alpha and IFN-gamma, cytokines known to induce CD95-mediated apoptosis, were analyzed by incubation of PHPs in the presence of anti-CD95 monoclonal antibodies (MoAbs). The effect of anti-CD95 MoAbs was measured by viable cell counting, flow cytometry, and CFU-C assays. A decrease of CFU-C numbers was observed in the presence of anti-CD95 MoAbs and TNF-alpha and/or IFN-gamma. However, whereas growth factor deprivation induced apoptosis of PHPs, cross-linking of CD95 did not lead to apoptosis of PHPs measured by flow cytometry and viable cell counting. The correlation of increased intracytoplasmic levels of bcl-2 with high levels of cell-surface CD34 and the presence of CD95 on fresh FL cells suggests that bcl-2 may be involved in protecting against CD95-mediated apoptosis of FL PHPs.
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PMID:Expression of Fas/CD95 and Bcl-2 by primitive hematopoietic progenitors freshly isolated from human fetal liver. 882 20

Immunoassays have recently made it possible to specifically measure the circulating levels of hematopoietic growth factors. This is helping us to understand the in vivo regulation of hematopoiesis under conditions of steady state or stress, providing insights into the physiological roles of hematopoietic growth factors and their importance in the pathogenesis of disease. As mediators of pathological processes, hematopoietic growth factors may be targets for antagonist therapy in some diseases. Exogenous hematopoietic growth factors may also be useful therapeutically to augment physiological responses, so understanding hematopoietic growth factor regulation and serum levels may assist the development of specific therapies. Hematopoietic growth factor levels may also serve as tumor markers and assist prognostication or monitoring during the clinical course of an illness. The growth factors of particular interest include the four classic colony-stimulating factors: granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and multi-colony-stimulating factor, also known as interleukin-3. Other cytokines with hematopoietic growth factor activity include interleukin-1, interleukin-6, interleukin-11, stem cell factor (also known as Steel factor or mast cell growth factor), and leukemia inhibitory factor.
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PMID:Measurement and clinical significance of circulating hematopoietic growth factor levels. 937 Dec 87

The receptors for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 share a common signaling subunit betac. However, in the mouse, there is an additional IL-3 signaling protein, betaIL-3, which is specific for IL-3. We have previously reported that IL-3 abrogates the lymphoid potentials of murine lymphohematopoietic progenitors and the reconstituting ability of hematopoietic stem cells. We used bone marrow cells from betac- and betaIL-3-knock-out mice to examine the relative contributions of the receptor proteins to the negative regulation by IL-3. First, we tested the effects of IL-3 on lymphohematopoietic progenitors by using lineage-negative (Lin-) marrow cells of 5-fluorouracil (5-FU)-treated mice in the two-step methylcellulose culture we reported previously. Addition of IL-3 to the combination of steel factor (SF, c-kit ligand) and IL-11 abrogated the B-lymphoid potential of the marrow cells of both types of knock-out mice as well as wild-type mice. Next, we investigated the effects of IL-3 on in vitro expansion of the hematopoietic stem cells. We cultured Lin-Sca-1-positive, c-kit-positive marrow cells from 5-FU-treated mice in suspension in the presence of SF and IL-11 with or without IL-3 for 7 days and tested the reconstituting ability of the cultured cells by transplanting the cells into lethally irradiated Ly-5 congenic mice together with "compromised" marrow cells. Presence of IL-3 in culture abrogated the reconstituting ability of the cells from both types of knock-out mice and the wild-type mice. In contrast, addition of GM-CSF to the suspension culture abrogated neither B-cell potential nor reconstituting abilities of the cultured cells of wild-type mice. These observations may have implications in the choice of cytokines for use in in vitro expansion of human hematopoietic stem cells and progenitors.
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PMID:Negative regulation by interleukin-3 (IL-3) of mouse early B-cell progenitors and stem cells in culture: transduction of the negative signals by betac and betaIL-3 proteins of IL-3 receptor and absence of negative regulation by granulocyte-macrophage colony-stimulating factor. 968 Mar 58

The application of ex vivo expansion to cell products pharmacologically purged in vitro may provide sufficient numbers of cells for rapid engraftment in a product with reduced tumor burden. To pursue this possibility we evaluated the effect of 4-hydroperoxycyclophosphamide (4-HC) treatment on granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (G-PBSC) and their subsequent expansion potential. A small number of G-PBSC CD34+ cells are resistant to 4-HC and are phenotypically and functionally immature. 4-HC-resistant G-PBSC cells are CD34+ bright, CD38+/-, DR(lo), CD13(lo), CD33-, CD71-, and rhodamine dull. In six experiments, treating G-PBSC with 60 microg/mL of 4-HC at 37 degrees C for 30 minutes reduced the number of colony-forming units (CFUs) per 5000 CD34+ cells by 96.3% (from 1333 +/- 137 to 46.5 +/- 11). This purging also reduced the frequency of 5-week long-term culture initiating cells (LTC-ICs) from 1/39 (range 1/27 to 1/62) to <1/1680 (range 1/1180 to 1/2420). Ex vivo expansion cultures were used to compare the proliferative potential of treated and untreated CD34+ cells. These cells were cultured with either the HS-5 stromal cell line serum-deprived conditioned media supplemented with 10 ng/mL kit ligand (HS-5CM/KL) or a recombinant growth factor mix (GFmix) containing 10 ng/mL each of interleukin (IL)-1, IL-3, IL-6, KL, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and 3 U/mL of erythropoietin. Culturing untreated CD34+ G-PBSC with 10% HS-5CM/KL increased total nucleated cells by 460-fold after 15 days. Progenitors, which were measured as CFUs, also increased by 47-fold over the same period. More significantly, culturing the 4-HC-treated CD34+ cells with HS-5/KL increased CFUs 98-fold and the nucleated cells increased 4573-fold. The absolute number of CFUs present after expansion of the 4-HC-resistant cells with HS-5CM/KL was threefold higher than that detected before purging and significantly higher than that obtained with GFmix. These data indicate that G-PBSC contain a very immature pool of cells not detectable using the 5-week LTC-IC assay, but have extremely high proliferative potential. Additionally, pharmacological purging of G-PBSC greatly reduces mature cells while retaining an immature population. Also significant is the finding that supernatant from the HS-5 bone marrow stromal cell line plus KL can fully regenerate progenitors from the 4-HC-resistant CD34+ G-PBSC.
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PMID:Ex vivo expansion of immature 4-hydroperoxycyclophosphamide-resistant progenitor cells from G-CSF-mobilized peripheral blood. 976 8

We show a dramatic downregulation of the stem cell factor (SCF) receptor in different hematopoietic cell lines by murine stroma. Growth of the human erythroid/macrophage progenitor cell line TF-1 is dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3). However, TF-1 cells clone and proliferate equally well on stroma. Independent stroma-dependent TF-1 clones (TF-1S) were generated on MS-5 stroma. Growth of TF-1S and TF-1 cells on stroma still requires interaction between c-kit (SCF receptor) and its ligand SCF, because antibodies against c-kit inhibit growth to less than 2%. Surprisingly, c-kit receptor expression (RNA and protein) was downregulated by 2 to 3 orders of magnitude in TF-1S and TF-1 cells grown on stroma. This stroma-dependent regulation of the kit receptor in TF-1 was also observed on exposure to kit ligand-negative stroma, thus indicating the need for heterologous receptor ligand interaction. Removal of stroma induced upregulation by 2 to 4 orders of magnitude. Downregulation and upregulation of c-kit expression could also be shown for the megakaryocytic progenitor cell line M-07e and was comparable to that of TF-1, indicating that stroma-dependent regulation of c-kit is a general mechanism. Downregulation may be an economic way to compensate for the increased sensitivity of the c-kit/ligand interaction on stroma. The stroma-dependent c-kit regulation most likely occurs at the transcriptional level, because mechanisms, such as splicing, attenuation, differential promoter usage, or mRNA stability, could be excluded.
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PMID:Downregulation of c-kit (stem cell factor receptor) in transformed hematopoietic precursor cells by stroma cells. 988 16

Hematopoietic growth factors (HGFs) stimulate growth, differentiation, and prevent apoptosis of progenitor cells. Each growth factor has a specific cell surface receptor, which activates both unique and shared signal transduction pathways. We found that several HGFs, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), steel factor (SF), and thrombopoietin (TPO) induce a rapid increase in reactive oxygen species (ROS) in quiescent cells. In an effort to understand the potential biochemical and biological consequences of increased ROS in these cells, we exposed growth factor-deprived cells to hydrogen peroxide (H2O2) at concentrations that increased intracellular ROS. H2O2 induced a dose-dependent increase in tyrosine phosphorylation, including increased tyrosine phosphorylation of the GM-CSF receptor beta chain (betac), STAT5, and other signaling proteins. H2O2 also induced expression of the early response gene c-FOS, and G1- to S-phase transition, but not S- to G2/M-phase transition of MO7e cells. The cell permeable antioxidant pyrrolidine dithiocarbamate (PDTC) decreased the intracellular levels of ROS and inhibited tyrosine phosphorylation induced by GM-CSF in MO7e cells, suggesting that ROS generation plays an important role in GM-CSF signaling. Consistent with this notion, PDTC and two other antioxidants, N-acetyl cysteine and 2-mercaptoethanol, reduced growth and viability of MO7e cells. These results suggest that generation of ROS in response to HGFs may contribute to downstream signaling events, especially those involving tyrosine phosphorylation.
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PMID:Hematopoietic growth factors signal through the formation of reactive oxygen species. 1178 38


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