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)

Umbilical cord blood (CB) has been identified as a potential source of hematopoietic stem cells suitable for clinical transplantation. We used long-term cord blood cultures (LTCBC) to evaluate the hematopoietic potential of populations of umbilical CB cells phenotypically defined and isolated by flow cytometry. LTCBC initiated with CD34+HLA-DR+ and CD34+HLA-DR- CB cells were examined over a period of 8 weeks for the production of assayable burst-forming units-erythroid (BFU-E), colony-forming units-granulocyte/macrophage (CFU-GM), and colony-forming units-mixed (CFU-GEMM) in response to repeated additions of stem cell factor (SCF), interleukin-3 (IL-3), IL-6, and either erythropoietin (Epo) or granulocyte-macrophage colony-stimulating factor (GM-CSF). The LTCBC-initiating cell (LTCBC-IC) appeared to be present among CD34+HLA-DR+ cells, in contrast to our previous findings in adult bone marrow (BM), where the long-term culture initiating cells were shown to be CD34+HLA-DR-. In addition, production of BFU-E, CFU-GM, and CFU-GEMM in CB CD34+HLA-DR+ cells displaying low uptake of the supravital dye rhodamine 123 (Rh123) exceeded those detected in the fraction of cells with high uptake of Rh123. Furthermore, on day 21 of LTCBC, the production of the high proliferative potential colony-forming units (HPP-CFC) by CB CD34+HLA-DR+Rh123dull cells was five-fold greater than that detected in cultures initiated with their Rh123bright counterparts. Collectively, these data show that, contrary to what has been documented in adult human BM, LTCBC-IC and presumably CB cells capable of in vivo engraftment reside in the CD34+HLA-DR+Rh123dull fraction of CB. Although the functional significance of these differences between the in vitro behavior of phenotypically defined populations of CB and BM remains to be determined, these findings constitute an objective parameter with which the suitability of CB for clinical transplantation may be assessed.
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PMID:Evaluation of the in vitro behavior of phenotypically defined populations of umbilical cord blood hematopoietic progenitor cells. 750 62

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

Previously, we have shown that Escherichia coli alpha-hemolysin represents a potent stimulus for inflammatory mediator release (O2- release, beta-glucuronidase release, and leukotriene generation) from human polymorphonuclear granulocytes (PMN) as well as for histamine release from a human lymphocyte-monocyte-basophil cell suspension (LMB). In contrast, the E. coli alpha-hemolysin leads to a downregulation of cytokine release (interleukin 6 [IL-6], tumor necrosis factor alpha, and IL-1 beta) from human LMB. This study was undertaken (i) to analyze the priming efficacy of growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF] and granulocyte CSF [G-CSF]) on inflammatory mediator release from human PMN and LMB challenged with hemolysin-producing E. coli bacteria as well as with cell-free E. coli alpha-hemolysin and (ii) to identify major components involved in GM-CSF and G-CSF priming. GM-CSF pretreatment led to an increased chemiluminescence response from human PMN by up to 100%, leukotriene B4 generation was enhanced up to fivefold, and histamine release from human LMB increased from 45% +/- 15% to 75% +/- 5% (mean +/- standard distribution) of the total histamine content. G-CSF priming induced an increase in the chemiluminescence response by up to 50% +/- 5% from human PMN and an increase in histamine release from human LMB by 20% +/- 5%. The growth factors, GM-CSF and G-CSF, modulated neither beta-glucuronidase release from human PMN nor IL-8 release from human PMN and LMB challenged with the E. coli alpha-hemolysin. GM-CSF and G-CSF pretreatment increased the fluoride (NaF)-induced chemiluminescence response by up to 10-fold; the serine/threonine phosphatase inhibitor okadaic acid inhibited GM-CSF- and G-CSF-induced priming. NaF-induced histamine release was enhanced up to 60 and 30% by GM-CSF and G-CSF priming, respectively. GM-CSF and G-CSF pretreatment did not modulate phorbol 12-myristate 13-acetate-induced chemiluminescence response or histamine release. GM-CSF by itself induced an increase in 5-lipoxygenase-specific mRNA expression within 5 min. Our results indicate that (i) GM-CSF and G-CSF interact with inflammatory cells via distinct cellular signalling, (ii) the signal transduction pathway is dependent on the cellular mediator, and (iii) the use of growth factors may be a potent tool to influence the clinical outcome in infectious diseases.
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PMID:Effect of growth factors on Escherichia coli alpha-hemolysin-induced mediator release from human inflammatory cells: involvement of the signal transduction pathway. 751 12

In long-term human bone marrow cultures, stromal cells of human origin are usually used on the assumption that human primitive progenitor cells do not respond to cytokines produced by stromal cells from other species. There is accumulating evidence, however, that murine stromal cells also promote maintenance and differentiation of very primitive human stem cells, which suggests the existence of novel stromal activities that cross species barriers. In this study, we show that a murine bone marrow-derived stromal cell line, MS-5, allows the proliferation of the human leukemic cell line UT-7. The long-term growth of UT-7 is usually supported only by human interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or erythropoietin (Epo). None of these three cytokines was involved in the observed effect, since murine GM-CSF and IL-3 do not act on human cells and MS-5 cells do not produce Epo. Soluble stem cell factor (SCF) induced UT-7 cell proliferation. However, S1/S1 mutant fibroblasts also supported UT-7 cell growth and anti-c-kit antibodies only partially abolished UT-7 cell proliferative response to MS-5 cells. These observations excluded a major role of SCF in this system. MS-5-derived growth-promoting activity was diffusible, but attempts to grow UT-7 cells in high levels of known soluble murine stromal-derived cytokines active on human cells showed no or minimal response, suggesting that MS-5's proliferative effect was not mediated by known cytokines. Finally, involvement of an autocrine loop of activation induced by MS-5 was excluded: RT-PCR analysis did not detect increased transcripts for GM-CSF, IL-3, IL-6, SCF, or Epo in UT-7 cells cocultured for 2 to 6 days with MS-5. In addition, UT-7 cell proliferation on MS-5 was not inhibited by neutralizing antibodies against the human GM-CSF receptor or the human IL-6 receptor alpha chain. Whether UT-7 cell proliferation triggered by MS-5 reflects the existence of novel stromal cytokines or results from synergistic interactions on the MS-5 cell surface between extracellular matrix proteins and cytokines will require further investigation.
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PMID:A murine stromal cell line promotes the proliferation of the human factor-dependent leukemic cell line UT-7. 751 51

Previous work has shown that part of the hierarchical structure of the hematopoietic system can be described by HPP-CFC-1 (primitive high proliferative potential colony-forming cells responding to colony-stimulating factor-1 [CSF-1] + interleukin-3 [IL-3] + IL-1), HPP-CFC-2 (more mature HPP-CFC responding to CSF-1 + IL-3), and mature HPP-CFC responding to the single factors, CSF-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), or IL-3. In this study, we have attempted to relate the murine HPP-CFC, stimulated by various combinations of growth factors (GFs)--CSF-1, GM-CSF, IL-3, IL-6, IL-1, stem cell factor (SCF), and transforming growth factor-beta (TGF-beta)--and by CSF-1, GM-CSF, and IL-3 on their own, to these known progenitors. Studies involving regeneration of the bone marrow after 5-fluorouracil (5-FU) treatment, generation of progenitors in liquid cultures in response to different GF combinations, and the HPP-CFC content of lineage-negative rhodamine-sorted bone marrow (BM) fractions have indicated that: 1. the combinations CSF-1 + IL-3 + IL-1 + SCF and CSF-1 + IL-3 + IL-1 + IL-6, and possibly CSF-1 + GM-CSF + IL-3 + IL-1, stimulate pre-HPP-CFC-1; 2. the combinations CSF-1 + IL-1 + GM-CSF, CSF-1 + IL-1 + IL-6, CSF-1 + IL-1 + SCF, CSF-1 + IL-3 + SCF, CSF-1 + IL-6 + SCF, and IL-3 + SCF, appear to overlap with the CSF-1 + IL-3 + IL-1 combination to stimulate the more mature cells of the HPP-CFC-1 compartment; 3. the combinations CSF-1 + GM-CSF, CSF-1 + IL-1, CSF-1 + IL-6, and CSF-1 + SCF may stimulate the more mature cells of the HPP-CFC-2 population, while the single factors CSF-1, GM-CSF, and IL-3, as suggested in other reports, may stimulate HPP-CFC that are more mature than the HPP-CFC-2; 4. the combinations IL-3 + IL-6 and SCF + IL-6 appear to stimulate HPP-CFC that overlap with the HPP-CFC-1 population, while those responding to the combination GM-CSF + TGF-beta overlap with the HPP-CFC-2 population within the hematopoietic hierarchy; and 5. CSF-1 and GM-CSF appear to be interchangeable in the combinations studied.
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PMID:The relationship between different high proliferative potential colony-forming cells in mouse bone marrow. 751 52

A model of murine heterotopic allogeneic transplantation was used to study the rejection characteristics of three tissues--adult cornea, fetal pancreas, and fetal skin--for attributes that might explain their variation in rejection rates and help define the determinants of graft immunogenicity. Under identical conditions, tissues were transplanted to the renal subcapsular space and their base-line rejection rates compared. The expression of MHC class I and II and intercellular adhesion molecule-1 (ICAM-1), was determined for each tissue, as was their ability to produce interleukin-6, IL-3, interferon-gamma, and granulocyte-macrophage colony-stimulating factor in vitro. These studies were performed under basal conditions and after stimulation with concanavalin A-stimulated spleen cell supernatant (CAS) or INF gamma. Corneal grafts had a slow rejection rate compared with pancreas and skin. While all three tissues had low basal expression of MHC class II, both fetal skin and pancreas, but not adult cornea, were able to increase this under our experimental conditions. Pancreas and skin produced IL-6 under basal conditions and could be stimulated to increase production 2-3-fold but the cornea did not basally produce IL-6 and showed minimal upregulation. We postulate that delayed corneal rejection, compared with pancreas and skin, results from two compounding deficiencies: the relative lack of class II MHC-positive APC and the inability to overcome this deficiency by upregulating class II expression and producing accessory molecules for antigen presentation.
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PMID:A comparison of corneal, pancreas, and skin grafts in mice. A study of the determinants of tissue immunogenicity. 751 13

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

To extent our knowledge on the cytokines possibly involved in the pathophysiology of B-cell chronic lymphocytic leukemia (B-CLL), the mRNA expression of a panel of 10 cytokines was investigated on purified B-CLL cells using a reverse-transcriptase polymerase chain reaction method. Whereas negative RT-PCR signals were recorded for interleukin-1 alpha (IL-1 alpha), IL-2, IL-3, IL-4, IL-5, IL-7, tumor necrosis factor beta (TNF beta), and granulocyte-macrophage colony-stimulating factor, we detected the expression of IL-1 beta, IL-6 and TNF alpha. Furthermore, the constitutive expression of IL-8 mRNA was observed in all 17 B-CLL samples analyzed. mRNA expression was associated with the capacity of the leukemic cells to release IL-8 both constitutively (4.6 +/- 8.1 SD ng/mL) and, to a further extent, after stimulation (14.5 +/- 19.4 ng/mL). The circulating levels of IL-8 were also evaluated in 12 untreated B-CLL sera samples and the overall mean level was significantly higher (P < .01) than in normal sera. In addition, supernatants of purified B-CLL cells cultured in the presence of 12-O-tetradecanoylphorbol-13-acetate showed chemotactic activity towards neutrophils; this activity was neutralized in the presence of an anti-IL-8 antiserum. The mRNA for IL-8 was absent in five B-cell preparations from hairy cell leukemia cases and in four B-cell lines. Normal tonsil CD5+ B cells showed a low expression of IL-8 mRNA only in two of the nine preparations tested and the overall quantity of IL-8 released by these cells after 3 days' incubation was significantly lower compared with that released by B-CLL cells (0.4 +/- 0.3 and 1.6 +/- 0.9 ng/mL under basal and stimulated conditions, respectively). These findings point to an involvement of a member of the proinflammatory chemokine supergene family in human CD5+ B lymphocytes. The different IL-8 behavior observed between B-CLL cells and their normal counterpart is likely to reflect an activation state of the leukemic population.
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PMID:Cytokine gene expression in B-cell chronic lymphocytic leukemia: evidence of constitutive interleukin-8 (IL-8) mRNA expression and secretion of biologically active IL-8 protein. 751 9

Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect interleukin-1 beta (IL-1 beta) mRNA in candidate human hematopoietic stem cells. The cells, obtained from adult bone marrow (BM) or umbilical cord blood, had a CD34+ CD45RAlo CD71lo phenotype and were further fractionated into CD38+ and CD38- or Thy-1+ and Thy-1- subpopulations. The purity of these fractions was always more than 99%. IL-1 beta and CD34 mRNA were detected in pools of 30 BM-derived CD34+ CD45RAlo CD71lo cells. To further exclude any contribution by contaminating cells, individual cells were analyzed for CD34 and IL-1 beta mRNA. Positive results were obtained with 2 of 5 individual BM-derived CD34+ CD45RAlo CD71lo CD38+ cells isolated by micromanipulation after overnight culture in serum-free medium without any exogenous cytokines, and 1 of 10 individual CD34+ CD45RAlo CD71lo CD38- cells isolated immediately after sorting. Moreover, of 10 pools of three BM-derived CD34+ CD45RAlo CD71lo cells cultured overnight in the presence of a mixture of various cytokines (Steel factor, IL-3, IL-6, macrophage colony-stimulating factor [M-CSF], erythropoietin, and IL-3/granulocyte-macrophage colony-stimulating factor [GM-CSF] fusion protein), 5 were positive for IL-1 beta mRNA. This result was compatible with more than 20% (95% confidence limit 0.06-0.61) of the BM cells with the CD34+ CD45RAlo CD71lo phenotype expressing IL-1 beta mRNA. IL-1 beta expression was also consistently observed from day 0 to day 9 in liquid cultures of cord-blood-derived CD34+ CD45RAlo CD71lo Thy-1+ or Thy-1- cells. The cultures contained the same combination of cytokines and resulted in an expansion of cell numbers of up to 400-fold. GM-CSF mRNA was not detected in the equivalent of 75 cells at any day, even though it could be detected with high sensitivity in control stromal cells. Because IL-1 beta is a powerful and pleiotropic biomodulator of cytokines and adhesion molecules, our observations suggest that at least some primitive hematopoietic cells do not merely respond passively to signals from their environment, but may themselves regulate the paracrine production of cytokines from neighboring stromal cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Expression of interleukin-1 beta gene in candidate human hematopoietic stem cells. 751 16

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


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