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)

An elucidation of the interaction between the bone marrow microenvironment and hematopoietic stem cells is critical to the understanding of the molecular basis of stem cell self renewal and differentiation. This interaction is dependent, at least in part, on direct cell to cell contact or cellular adhesion to extracellular matrix proteins. Long-term bone marrow cultures (LTMC) provide an appropriate microenvironment for maintenance of primitive hematopoietic stem cells and a means of analyzing this stem cell-stromal cell interaction in vitro. Although LTMC have been successfully generated from murine and human bone marrow, only limited success has been reported in a primate system. In addition, few permanent stromal cell lines are available from nonmurine bone marrow. Because the primate has become a useful model for large animal bone marrow transplant studies and, more specifically, retroviral-mediated gene transfer analysis, we have generated immortalized bone marrow stromal cell lines from primate bone marrow using gene transfer of the Simian virus large T (SV40 LT) antigen. At least one stromal cell line has demonstrated the capacity to maintain early hematopoietic cells in long-term cultures for up to 4 weeks as measured by in vitro progenitor assays. Studies were undertaken to characterize the products of extracellular matrix biosynthesis and growth factor synthesis of this cell line, designated PU-34. In contrast to most murine bone marrow-derived stromal cell lines capable of supporting hematopoiesis in vitro that have been examined, the extracellular matrix produced by this primate cell line includes collagen types I, laminin. Growth factor production analyzed through RNA blot analysis, bone marrow cell culture data, and factor-dependent cell line proliferation assays includes interleukin-6 (IL-6), IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, leukemia inhibitory factor, and a novel cytokine designated IL-11. This immortalized primate bone marrow stromal cell line may be useful in maintaining early progenitor cells for experimental manipulation without the loss of reconstituting capacity and as a potential source of novel hematopoietic growth factors.
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PMID:Stromal cell-associated hematopoiesis: immortalization and characterization of a primate bone marrow-derived stromal cell line. 201 98

A large number of cytokines are found within foci of inflammation. Two of these cytokines, namely interleukin-1 (IL-1) and tumor necrosis factor (TNF), play a key role in orchestrating the mechanisms responsible for inflammation. These two cytokines induce production by many cells of lipid mediators, proteases, and free radicals, all of which play a direct role in development of the deleterious effects of inflammation. IL-1 and/or TNF exert cytotoxic effects on the vascular endothelium, cartilage, bone, muscle, or pancreatic beta-cell islets. Cytokines, including interferon gamma (IFN), IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), amplify the inflammatory response by increasing production of IL-1 and TNF by macrophages. Macrophages also produce other cytokines, such as IL-8 and macrophage chemoattractant protein-1 (MCP-1), with chemoattractant properties that contribute to draw leucocytes to the site of inflammation. IL-6, produced in large amounts during inflammatory processes, induces the production of acute phase proteins by hepatocytes. IL-1, TNF, IL-11, leukemia inhibitory factor (LIF), and transforming growth factor beta (TGF beta) share this effect. TGF beta also has a number of anti-inflammatory effects. TGF beta, IL-4, and IL-10 inhibit production of IL-1 and TNF. Glucocorticoids also have this effect. Glucocorticoids can be produced as a result of a chain of events initiated by IL-1, TNF, and IL-6 and involving the neuro-endocrine axis. Other substances, such as IL-1 receptor antagonist (IL-1 ra) or soluble forms of the TNF receptors, can specifically inhibit the effects of IL-1 and TNF. Cascade production of cytokines, inhibition, negative feed-back, and synergistic mechanisms are parameters that illustrate the concept of "cytokine network" and aptly characterize the role of these mediators in the mechanisms of inflammation.
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PMID:[Contribution of cytokines to inflammatory mechanisms]. 750 93

Studies were undertaken to delineate the actions of stem cell factor (SCF) on human fetal hematopoietic progenitors in vitro. Mononuclear cells from umbilical cord blood of term fetuses were "panned" immunologically, and the resulting hematopoietic progenitors were grown in methylcellulose culture containing various concentrations of SCF alone or in combination with other recombinant hematopoietic growth factors. Neutralizing antibodies to IL-3 and granulocyte-macrophage colony-stimulating factor were added to all plates to which recombinant IL-3 or granulocyte-macrophage colony-stimulating factor were not included to decrease any confounding effect resulting from production of small quantities of these factors within the culture plates. SCF, as a single agent, supported clonogenic maturation of fetal granulocyte-macrophage progenitors (granulocyte-macrophage colony-forming unit, p < 0.05), multipotent progenitors (CFU-MIX, p < 0.05), and erythroid progenitors (erythroid burst-forming unit, p < 0.05). When combined with subplateau concentrations (0.1 microgram/L) of IL-3 or granulocyte-macrophage colony-stimulating factor, SCF had an additive or synergistic effect on clonogenic maturation of granulocyte-macrophage colony-forming unit and CFU-MIX. When combined with higher concentrations (5.0 micrograms/L) of IL-3 or granulocyte-macrophage colony-stimulating factor, SCF generally did not enhance colony formation but did increase the number of cells per colony. Like other pleiotropic cytokines such as IL-6, IL-9, and IL-11, SCF had a broad spectrum of action of fetal hematopoietic progenitors.
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PMID:Effect of recombinant stem cell factor on clonogenic maturation and cycle status of human fetal hematopoietic progenitors. 751 81

ELF-153 is a cell line that has been established from a patient with a poorly differentiated acute myeloid leukemia associated with an acute myelofibrosis. A majority of cells had a blast morphology with the phenotype of a myeloid hematopoietic progenitor, ie, CD34+, CD33+, CD13+, HLA-DR+, but CD38-, and the remaining cells (5% to 10%) expressed platelet restricted proteins such as CD41, CD42, CD36, CD61, and von Willebrand factor; some of them were polyploid (up to 32N) and exhibited demarcation membranes and alpha granules. No erythroid or other lineage-specific markers were detected. Proliferation of ELF-153 cells was highly stimulated by interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor and to a lesser extent by stem cell factor and IL-6. In contrast, the cell line did not respond to erythropoietin, leukemia inhibitory factor, IL-7, IL-11, granulocyte colony-stimulating factor, and basic fibroblast growth factor. ELF-153 cells could be separated by flow cytometry into three discrete cell populations (CD34+/CD61-, CD34+/CD61+, and CD34-/CD61+) with different proliferative and endomitotic properties corresponding to distinct stages of the mega karyocyte (MK) differentiation. This MK differentiation, which involved a minority of ELF-153, could be increased in the presence of 5-azacytidine and phorbol ester, but could not be significantly modified by growth factors. By contrast, cytochalasin B dramatically induced polyploidization without differentiation. It is noteworthy that association of 5-azacytidine to cytochalasin B dramatically induced the production of polyploid MK cells. To understand the molecular mechanisms underlying this MK differentiation, the expression of GATA-1 and GATA-2 was investigated in subpopulations of ELF-153. A high level of GATA-1 and GATA-2 mRNA was only present in the CD61+ cells. Therefore, these two transactivating factors may play an important role in the MK differentiation of ELF-153. We conclude that ELF-153 might be an important tool to investigate the mechanisms by which transcription factors control differentiation of MK progenitors.
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PMID:Growth and differentiation of the human megakaryoblastic cell line (ELF-153): a model for early stages of megakaryocytopoiesis. 751 73

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

Interactions between different cytokines, extracellular matrix components, and various cell types inside the bone marrow microenvironment are believed to play important roles in the regulation of hematopoiesis. We observed that both interleukin-1 (IL-1) and 12-O-tetradecanoylphorbol-13-acetate (TPA) can stimulate the expression of IL-11 and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes in a primate bone marrow stromal fibroblast cell line, PU-34. We also found that IL-1 or TPA-stimulated IL-11 and GM-CSF expression in PU-34 cells can be abolished by heparin, a class of molecules related to extracellular matrix components, glycosaminoglycans. Because the growth inhibitory signals provided by extracellular factors were less understood, the mechanisms of heparin inhibition of IL-11 and GM-CSF gene expression were further investigated. Our data demonstrate for the first time that heparin did not alter the transcription of endogenous IL-11 and GM-CSF genes or an exogenous IL-11 promoter construct containing an AP-1 sequence. Instead, heparin facilitated the degradation of the corresponding mRNAs. Through RNA gel shift assays, heparin-mediated mRNA destabilization was tentatively linked to its competition for mRNA binding proteins both in the cell-free system and in intact cells. Collectively, our findings suggest that varying degrees of heparin inhibition may provide a novel mechanism for the regulation of cytokine expression during the growth and differentiation of different lineages of hematopoietic cells.
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PMID:Heparin inhibits the expression of interleukin-11 and granulocyte-macrophage colony-stimulating factor in primate bone marrow stromal fibroblasts through mRNA destabilization. 767 97

The replating capability of human umbilical cord blood (CB) multipotential (CFU-GEMM) progenitors was assessed in vitro as an estimate of self-renewal using erythropoietin (Epo), steel factor (SLF), and either fetal bovine serum (FBS) or CB plasma. This study found a much higher replating efficiency for CB CFU-GEMM than previously reported, in terms of the percentage of colonies that could be replated, the number of secondary colonies per replated primary colony, and the size of secondary colonies. Moreover, the majority of secondary colonies were CFU-GEMM-derived. Although the percentages of bone marrow CFU-GEMM that replate was similar to that for CB CFU-GEMM and the sizes of secondary bone marrow and CB CFU-GEMM were also similar, replated CB CFU-GEMM gave rise to far greater numbers of secondary colonies. No tertiary colonies were observed when secondary CFU-GEMM were replated. Detection of extensive secondary replating potential was enhanced by the addition of CB plasma to the cultures. This activity was not found in either adult blood (PB) plasma, umbilical cord vein endothelial cell-conditioned medium (ECCM), FBS plus ECCM, or FBS plus the combination of interleukin-1 (IL-1), IL-3, IL-6, IL-11, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor. Whether the CB plasma-enhancing activity for CFU-GEMM replating capacity is attributable to a novel factor or factors, or represents effects of other known cytokines, alone or in combination, remains to be determined. Of particular relevance, these studies suggest that human CFU-GEMM have some degree of stemness and perhaps should be classified as a subset of stem cells.
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PMID:Human multipotential progenitor cells (CFU-GEMM) have extensive replating capacity for secondary CFU-GEMM: an effect enhanced by cord blood plasma. 767 10

We have studied the effects of recombinant human interleukin-11 (rhIL-11), alone and combined with stem cell factor (SCF or c-kit ligand), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) on the proliferation of highly enriched human hematopoietic CD34+ and CD34+CD33-DR- progenitor cells. CD34+ cells were purified using the avidin-biotin immunoabsorption technique and CD33+DR+ cells were subsequently removed by immuno-magnetic separation. The colony assays were performed in the presence and absence of exogenous serum. IL-11, as a single agent, induced the growth of a small number of colony-forming units-granulocyte/macrophage (CFU-GM) derived from purified CD34+ cells and failed to support the colony growth of CD34+CD33-DR- cells. The addition of erythropoietin (Epo) to IL-11 induced the growth of erythroid progenitors (BFU-E) derived from CD34+ cells but not from the same population depleted of CD33+DR+ cells. The combination of IL-11 with SCF, IL-3, or GM-CSF, in the presence of Epo, resulted in a synergistic or additive increase in the number of CFU cells (CFU-C) derived from both cell fractions. Moreover, the addition of SCF to IL-11 stimulated the development of macroscopic erythroid and multilineage colonies (CFU-GEMM) containing more than 10(4) cells. A combination of three factors (IL-11, SCF, and IL-3) resulted in the increase of the number of colonies arising from CD34+ and CD34+CD33-DR- cells (but not of their size) compared to the cultures treated with IL-11 plus SCF or IL-11 plus IL-3. The pattern of proliferative response of primitive hematopoietic progenitor cells to IL-11 in serum-free conditions was very similar to the cultures grown in serum-containing medium. It is noteworthy that IL-11 and SCF yielded colony formation that was comparable to that observed in the presence of serum. The effects of IL-11 on CD34+CD33-DR- cells were also studied in a short-term suspension culture system, which was shown to be specific for evaluating the proliferation of pluripotent hematopoietic precursors (Delta assay). In this system, IL-11 had a minimal effect on its own, whereas IL-11 plus SCF acted synergistically and their proliferative activity was improved by the addition of GM-CSF. These experiments indicate that IL-11 may be considered a "permissive" cytokine, capable of initiating the proliferation of very primitive human hematopoietic cells, which are then able to respond to late-acting CSFs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interleukin-11 stimulates the proliferation of human hematopoietic CD34+ and CD34+CD33-DR- cells and synergizes with stem cell factor, interleukin-3, and granulocyte-macrophage colony-stimulating factor. 769 67

When 15-deoxyspergualin (DSG) was administered into [BALB/c-->C3H/He] bone marrow (BM) chimeras from day 14 to day 25, increased platelet counts were observed from day 25 to day 33. Twofold increase of platelet counts was observed in DSG-treated BM chimeras compared with phosphate buffered saline (PBS)-treated BM chimeras. By using reverse transcriptase-polymerase chain reaction (RT-PCR), several cytokine mRNA expressions were analyzed in order to clarify which cytokines are involved in thrombopoiesis. So far, interleukin-6 (IL-6), leukemia inhibitory factor (LIF), stem cell factor (SCF), and IL-11 have been reported to have potent thrombopoietic activity in vivo. Although some other cytokines such as IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) possess the capacity of thrombopoiesis, megakaryocytopoiesis is more marked in these cytokines. IL-6 mRNA expression was increased in spleen cells from DSG-treated BM chimeras from day 25 to day 32 and in bone marrow cells from day 19 to day 28. LIF mRNA expression was not significantly increased compared with PBS control. Although SCF mRNA expression was increased, the kinetics of increased SCF mRNA expression did not fit the kinetics of increased platelet counts. Increased mRNA expression in other hematopoietic cytokines, such as IL-3, granulocyte-colony stimulating factor (G-CSF) and GM-CSF were also observed, thus suggesting that these cytokines may synergistically support thrombopoiesis in concert with IL-6. These results suggest that IL-6 and other hematopoietic cytokines might induce increased platelet counts, although the involvement of thrombopoietin (TPO) and IL-11 should be analyzed in the future.
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PMID:A novel immunosuppressant 15-deoxyspergualin and thrombopoiesis. 795 88

We investigated the effects of stem cell factor (SCF) on the growth of blast clonogenic cells from 27 patients with acute myeloblastic leukemia (AML) and 3 patients with chronic myelocytic leukemia in myeloid crisis. SCF alone showed a significant stimulatory activity in 15 of 30 patients (50%). A marked reduction in the number of blast cell colonies supported by SCF alone was noted by the addition of neutralizing antibody (Ab) against granulocyte-macrophage colony-stimulating factor (GM-CSF). Ab against interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) also moderately reduced the number of colonies, whereas Ab against granulocyte CSF (G-CSF) failed to do so. All four Ab together completely abolished the growth in 5 of 6 patients tested. c-kit antisense oligonucleotides reduced the colony formation supported by IL-3 or G-CSF or, in the absence of growth factor, in only 2 of 10 patients tested. SCF caused stimulation by acting synergistically with G-CSF, GM-CSF, IL-3, IL-6, IL-9, IL-11, and IL-12 in 20 of 27 (74%), 17 of 27 (63%), 14 of 28 (50%), 9 of 28 (32%), 1 of 15 (7%), 3 of 28 (11%), and 2 of 15 (13%) patients, respectively. Thus, SCF alone or in combination with some other factor stimulated the growth in 27 of 30 (90%) patients. Of 3 nonresponders, 2 were AML, M3 at presentation. G-CSF at the optimal concentration increased the sensitivity of blasts to SCF. Taken together, SCF acting in combination with other factors, but not alone, stimulates the growth of blast clonogenic cells. GM-CSF, IL-6, and TNF-alpha may be produced endogenously, whereas G-CSF and SCF may be supplied exogenously. Autocrine regulation of the growth of blasts seems to increase the responsiveness of the cells to any of these factors, allowing them to achieve a highly active growth state.
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PMID:Roles of stem cell factor in the in vitro growth of blast clonogenic cells from patients with acute myeloblastic leukemia. 856 3


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