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)

Previous experiments have revealed the expression of tumor necrosis factor alpha (TNF-alpha) transcripts in all murine bone marrow-derived macrophage colonies isolated from days 5 through 9 of differentiation in vitro. These results implicated a role for TNF-alpha gene expression during macrophage differentiation. Antisense oligomers to the initiation region of the TNF-alpha message were used to inhibit its expression, thus allowing the role of TNF-alpha gene expression in controlling the differentiation of macrophages to be determined. Results showed that TNF-alpha regulated the proliferation of macrophages during differentiation. Cells isolated on day 3 were exclusively vulnerable to the effects of blocking TNF-alpha gene expression, displaying a 30% increase in proliferation over control cells or sense oligomer-treated cells. Thus, in the absence of TNF-alpha gene expression, cells maintained proliferation instead of undergoing terminal differentiation. Exogenous TNF-alpha was capable of rescuing day 3 antisense-treated cells, therefore maintaining normal levels of proliferation. In contrast, blocking interleukin 1 beta gene expression by antisense oligonucleotide treatment had no effect on proliferation. Addition of exogenous recombinant murine or human TNF-alpha decreased the total cell number 25-50% regardless of whether cells were grown in medium containing colony-stimulating factor 1 (CSF-1) or granulocyte-macrophage colony-stimulating factor (GM-CSF). These results suggested that exogenous TNF-alpha suppressed proliferation of early hematopoietic progenitors, whereas endogenous TNF-alpha regulated proliferation of macrophage progenitors. The number of differentiated, adherent macrophages on day 5 of differentiation in vitro was increased by TNF-alpha treatment of GM-CSF-induced macrophages but was suppressed in CSF-1-induced macrophages. These findings suggest that distinct TNF receptor expression and/or signaling is induced in differentiating macrophages stimulated with either growth factor.
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PMID:Tumor necrosis factor alpha is an autocrine growth regulator during macrophage differentiation. 850 31

Production of interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), interleukin 2 (IL-2), interferon gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) after stimulation by lipopolysaccharide (LPS) and phytohemagglutinin (PHA) was studied in 1/10 diluted whole blood (WB) culture and in peripheral blood mononuclear cell (PBMC) culture. Cytokines IL-1 beta, TNF-alpha and IL-6 are preferentially stimulated by LPS whereas IL-2, IFN-gamma and GM-CSF are stimulated by PHA. Combination of 5 micrograms/ml PHA and 25 micrograms/ml LPS gave the most reliable production of the six cytokines studied. IL-1 beta, TNF-alpha and IL-6 represent a homogeneous group of early-produced cytokines positively correlated among themselves and with the number of monocytes in the culture (LeuM3). Furthermore, IL-1 beta was negatively correlated with the number of T8 lymphocytes. IL-2, IFN-gamma and GM-CSF represent a group of late-produced cytokines. Kinetics and production levels of IL-6 and GM-CSF are similar in WB and PBMC cultures. In contrast, production levels of TNF-alpha and IFN-gamma are higher in WB than in PBMC whereas production levels of IL-6 and IL-2 are lower in WB than in PBMC. Individual variation in responses to PHA + LPS was always higher in PBMC cultures than in WB cultures. The capacity of cytokine production in relation to the number of mononuclear cells is higher in WB, or in PBMC having the same mononuclear cell concentration as WB, than in conventional cultures of concentrated PBMC (10(6)/ml). Because it mimics the natural environment, diluted WB culture may be the most appropriate milieu in which to study cytokine production in vitro.
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PMID:Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood. I. Comparison with isolated PBMC stimulation. 149 59

Recent studies have indicated that airway inflammation in atopic asthma is characterized by T-cell activation and local eosinophilia, but it is unknown whether this also applies to nonatopic asthma. In this study, the cytokine mRNA profile and activation status of inflammatory cells in bronchoalveolar lavage fluid (BALF) of eight nonallergic patients with symptomatic asthma and eight nonallergic healthy controls were compared using the message amplification phenotyping (MAPPing) with the polymerase chain reaction (PCR) procedure and immunocytochemical evaluation. Asthmatics had an increasing number of inflammatory cells in BALF, including activated eosinophils (EG2-positive) (p less than 0.001) and activated T cells (CD25-positive) (p less than 0.001). Activated T cells from five of the eight asthmatic patients and from one control subject expressed high levels of interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF). All the asthmatic patients had increased numbers of monocytes in their BALF (p less than 0.002) and those cells invariably showed increased expression of interleukin 1 beta (IL1 beta) transcripts. In five patients they also expressed appreciable levels of IL-6 and GM-CSF mRNA. IL-5 and GM-CSF can induce local activation of eosinophils, and IL-1 beta and IL-6 are known to promote T-cell activation and proliferation. Thus, there is an increased production of cytokines with inflammatory properties in the airways of patients with nonatopic symptomatic asthma, which may contribute to the persistence of inflammation, and monocytes and activated T cells are important sources of these cytokines.
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PMID:Cytokine mRNA profile and cell activation in bronchoalveolar lavage fluid from nonatopic patients with symptomatic asthma. 151 85

An in vitro system allowing the culture of ovine bone marrow-derived macrophages (BMMs) is described. Bone marrow (BM) cells from the sternum of 4- to 9-month-old sheep were cultured in liquid suspension in hydrophobic bags with medium containing 20% autologous serum and 20% fetal calf serum (FCS). Cells with macrophage characteristics were positively selected and increased four- to five-fold between day (d) 0 and d18. Granulocytes and cells of lymphoid appearance including progenitor cells were negatively selected and were diminished 50-fold during this 18-d culture. The addition of macrophage colony-stimulating factor (M-CSF)-containing supernatants to liquid cultures did not significantly improve the yield of BMM in 18-d cultures. In contrast, cell survival at d6 and macrophage cell yield at d18 depended on the concentration and source of serum in the culture medium. FCS and 1:1 mixtures of FCS and autologous serum were superior to autologous serum alone. Analysis of growth requirements of ovine BMMs suggested that they are under more complex growth control than their murine counterparts. In an [3H]thymidine incorporation assay with BM cells collected at different times of culture, d3 or d4 BM cells responded to human recombinant M-CSF, human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF), bovine GM-CSF, murine M-CSF or murine M-CSF-containing supernatants, and bovine interleukin 1 beta (IL-1 beta) in decreasing order of magnitude. Likewise, pure murine BMM populations harvested at d6 responded to homologous GM-CSF, IL-3, and human or murine M-CSF. FCS did not stimulate the proliferation of murine BMMs (d6) and of ovine BM cells (d3 or d4). In contrast, ovine BM cells harvested at d12 responded to FCS by proliferation in a dose-dependent manner but failed to proliferate in the presence of human or murine M-CSF or M-CSF-containing supernatants of mouse and sheep fibroblasts containing mouse macrophage growth-promoting activity. Likewise, various cytokine-containing supernatants and recombinant cytokines (murine IL-3, murine and human GM-CSF, murine and bovine IL-1 beta) did not promote proliferation of ovine d12 BM cells to an extent greater than that achieved with 15% FCS alone. Thus, ovine BMM proliferation is under the control of at least two factors acting in sequence, M-CSF and an unidentified factor contained in FCS. The ovine BMM culture system may provide a model for the analysis of myelomonocytopoiesis in vitro.
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PMID:Culture of ovine bone marrow-derived macrophages and evidence for serum factors distinct from M-CSF contributing to their propagation in vitro. 161 90

There are clones of myeloid leukemic cells that can be induced to undergo terminal cell differentiation to macrophages by normal hemopoietic regulatory proteins. Induction of differentiation in two different clones of myeloid leukemic cells with interleukin 6 (IL-6) or granulocyte-macrophage colony-stimulating factor (GM-CSF) resulted in induction of mRNA for the hemopoietic regulatory proteins IL-6, GM-CSF, interleukin 1 alpha and interleukin 1 beta, tumor necrosis factor, and transforming growth factor beta 1. In one of these clones, induction of differentiation with GM-CSF was also associated with induction of mRNA for macrophage colony-stimulating factor (M-CSF) but not for the receptor for M-CSF (c-fms), whereas in the other clone, induction of differentiation with IL-6 was associated with induction of mRNA for both c-fms and M-CSF. The clones also differed in their responsiveness to these regulators. There was no induction of mRNA for granulocyte colony-stimulating factor or interleukin 3 during differentiation of either clone. The results indicate that the genes for a nearly normal network of positive and negative hemopoietic regulatory proteins are induced during differentiation of these myeloid leukemic cells and that there are leukemic clones with specific defects in this network.
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PMID:The network of hemopoietic regulatory proteins in myeloid cell differentiation. 175 9

Developing megakaryocytes are distinguished from progenitor cells by the appearance of platelet proteins such as platelet factor 4 (PF 4). The human erythroleukemic cell line HEL can also be induced to produce PF 4 by incubation in phorbol esters. HEL cells were used here as a model system in which to study the phenomenon of inducible PF 4 production at both the mRNA and protein levels. The cytokines interleukin 1 beta (IL-1 beta), interleukin 3 (IL-3), interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), and transforming growth factor-beta (TGF-beta) were also evaluated for their effects on PF 4 mRNA induction in HEL cells.
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PMID:Platelet factor 4 mRNA expression in human erythroleukemic cells: regulation by phorbol esters and certain cytokines. 186 92

Juvenile chronic myelogenous leukemia (JCML) is a rare pediatric malignancy characterized by marked hepatosplenomegaly, leukocytosis with prominent monocytosis, elevated fetal hemoglobin, no Philadelphia chromosome, and generally a poor prognosis. In vitro, JCML peripheral blood granulocyte-macrophage progenitors (granulocyte-macrophage colony-forming units, CFU-GM) demonstrate the unique characteristic of "spontaneous" proliferation at very low cell densities in the absence of exogenous growth factors. The "spontaneous" CFU-GM proliferation can be abolished by prior adherent cell (monocyte) depletion, suggesting a paracrine mode of cellular proliferation. Although previous studies using a [3H]thymidine ([3H]TdR) incorporation assay suggested an important role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in JCML, many non-growth factor-related reasons for [3H]TdR incorporation and the relatively low level of inhibition of [3H]TdR uptake left those conclusions open to question. Therefore, we performed clonal CFU-GM assays, which more specifically reflect cytokine effects on CFU-GM, using JCML peripheral blood mononuclear cells (PBMNC) and neutralizing antibodies against GM-CSF, granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating (M-CSF), interleukin 3 (IL-3), interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), interleukin 4 (IL-4), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF alpha), and interferon gamma (IFN gamma). Cultures containing anti-GM-CSF alone inhibited "spontaneous" JCML CFU-GM by 87% +/- 9% (mean +/- standard error of the mean [SEM]). No other anti-cytokine antibody produced a significant inhibition of CFU-GM growth. Various combinations of antibodies, excluding anti-GM-CSF, failed to demonstrate any synergistic inhibitory effects upon CFU-GM. Because this apparent paracrine cellular stimulation could be due to excessive cytokine production, by monocytes or other accessory cells, we examined cytokine levels in conditioned media from various JCML cell populations using enzyme-linked immunosorbent assays (ELISAs). Monocytes from only a minority of JCML patients produced higher than normal quantities of GM-CSF, G-CSF, IL-1 beta, IL-6, and/or TNF alpha, but no obvious pattern could be discerned. Further, only 7 of 15 JCML monocyte-conditioned media (MCM) had elevated GM-CSF, and 6 of 15 JCML patients had normal levels of all nine cytokines tested. The monocyte depletion experiments and the inhibition experiments with anti-cytokine antibodies taken together demonstrate clearly that the "spontaneous" growth of JCML CFU-GM in vitro critically depends on at least one monocyte-derived growth factor, GM-CSF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of monocyte-derived hemopoietic growth factors in the regulation of myeloproliferation in juvenile chronic myelogenous leukemia. 191 2

Various concentrations of 1,25-dihydroxyvitamin D3 (vit D3; 10(-9)-10(-7) M) and recombinant human tumor necrosis factor alpha (rTNF-alpha; 60-960 U/ml) were used to induce growth inhibition and differentiation of the human promyelocytic leukemia cell line HL-60 based on growth kinetics, colony formation, morphological analysis, nonspecific esterase (NSE) activity, surface antigen expression, and cytokine release. Both vit D3 (10(-8)-10(-7) M) and rTNF-alpha (60-960 U/ml) were antiproliferative against the HL-60 cells, and a cooperative effect was noted when the two inducers were used in combination. After 5 days of incubation, vit D3 induced the HL-60 cells to differentiate into monocytes/macrophages, resulting in the formation of 3.0% +/- 0.4%, 18% +/- 2.0%, and 43% +/- 3.8% of morphologically mature cells at 10(-9), 10(-8), and 10(-7) M, respectively. The induced cells were NSE positive and expressed monocyte-associated antigens (EBM11, CD11b, and HLA-DR). Conversely, rTNF-alpha (60-960 U/ml) was unable to trigger the HL-60 cells to differentiate. However, rTNF-alpha could apparently increase the proportion of the morphologically mature and NSE-/antigen-positive cells when used in combination with vit D3 (10(-9)-10(-8) M). Following differentiation induction, HL-60 cells from vit D3-treated HL-60 cultures acquired the ability to secrete certain monokines, including interleukin 1 beta (IL-1 beta), prostaglandin E2 (PGE2), and granulocyte-macrophage colony-stimulating factor (GM-CSF), and adding rTNF-alpha in addition to vit D3 invariably increased the production of IL-1 beta and PGE2.
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PMID:Growth inhibition and differentiation in HL-60 leukemia cells induced by 1,25-dihydroxyvitamin D3 and tumor necrosis factor alpha. 191 3

The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF), a pluripotent cytokine, on tumoricidal activity of alveolar macrophages and monocytes from nonsmoking normal volunteers was compared using [3H]thymidine-labeled human tumor cells (SK-MEL-28, melanoma) as targets. A dose-response study (500-5000 units/ml) of recombinant GM-CSF indicated dramatic differences between cytotoxicity of alveolar macrophages and blood monocytes. Macrophages exhibited significant (P less than 0.01) tumoricidal activity at all GM-CSF doses tested. In contrast, monocytes showed no significant tumoricidal activity at 500 units/ml and significantly (P less than 0.01) less activity than alveolar macrophages at doses of 1000-5000 units/ml. Maximal activity in alveolar macrophages occurred 72-96 h after exposure to 1000-5000 units/ml GM-CSF. Tumoricidal activity may be related to the state of maturation, because monocytes matured in vitro for 7 days displayed enhanced tumoricidal activity after GM-CSF exposure. Tumor necrosis factor alpha and interleukin 1 beta were measured in supernatant fluids of 24-h GM-CSF-treated cells. No significant increase in either cytokine was detected after GM-CSF treatment of alveolar macrophages. Monocyte interleukin 1 beta secretion was not enhanced by GM-CSF; however, tumor necrosis factor alpha secretion was enhanced in some donors (three of five). Superoxide anion production of alveolar macrophages was not enhanced by GM-CSF. These data suggest that alveolar macrophage tumoricidal activity is induced by GM-CSF and is not dependent on oxidative metabolism or secreted forms of interleukin 1 beta or tumor necrosis factor alpha.
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PMID:Differential effect of recombinant granulocyte macrophage colony-stimulating factor on human monocytes and alveolar macrophages. 254 32

A group of cytokines characterized by a common set of target cells--namely, the pluripotential hemopoietic stem cells or their cellular derivatives--share similarities in the amino acid sequence at their N terminus or in the putative signal peptide immediately prior to the published N terminus. Murine P-cell-stimulating factor (PSF), murine and human interleukin 2 (IL-2), murine and human granulocyte-macrophage colony-stimulating factor (GM-CSF), human erythropoietin, and human interleukin 1 beta all share alanine as the N-terminal amino acid and have some similarities in the succeeding three or four amino acids. In the case of murine PSF and GM-CSF, the six N-terminal amino acids are readily cleaved from mature molecules and are lacking from the N-terminal amino acid sequences reported initially. A sixth cytokine, colony-stimulating factor 1, has an alanine followed by a similar pattern of five amino acids at the end of the putative signal peptide. GM-CSF and IL-2 have more extensive homology, about 25% of residues being identical in three regions that comprise about 70% of the molecules. Only minor similarities of uncertain significance were found among the complete amino acid sequences of the other cytokines. Although its evolutionary origin is uncertain, the homology around the N terminus may provide a structural marker for a group of cytokines active on the pluripotential hemopoietic stem cell and its derivatives.
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PMID:Structural homologies among the hemopoietins. 308 95


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