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 interleukin (IL)-3 family of cytokines mediates its numerous effects on myeloid growth and maturation by binding a family of related receptors. It has been shown recently that IL-3 induces the activation of two distinct cytoplasmic signal transducing factors (STFs) that are likely to mediate the induction of immediate early genes. In immature myeloid cells, IL-3 activates STF-IL-3a, which comprises two tyrosine-phosphorylated DNA binding proteins of 77 and 80 kDa. In mature myeloid cells, IL-3 and granulocyte-macrophage colony-stimulating factor activate STF-IL-3b, which consists of a 94 and 96 kDa tyrosine-phosphorylated DNA binding protein. Peptide sequence data obtained from the purified 77 and 80 kDa proteins (p77 and p80) indicate that they are closely related but are encoded by distinct genes. Both peptide and nucleotide sequence data demonstrate that these two proteins are the murine homologs of ovine mammary gland factor (MGF)/Stat5. The peptide data also indicate that p77 and p80 are phosphorylated on tyrosine 699, a position analogous to the tyrosine that is phosphorylated in Stat1 and Stat2 in response to interferon. Additionally, antiserum raised against bacterially expressed p77/p80 recognizes the 94 and 96 kDa protein components of STF-IL-3b, suggesting that these may be additional isoforms of Stat5. These studies indicate that the IL-3 family of ligands is able to activate multiple isoforms of the signal transducing protein Stat5.
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PMID:Interleukin-3 signals through multiple isoforms of Stat5. 753 13

The effects of transforming growth factor (TGF) beta 1 on cytokine-enhanced eosinophil survival and degranulation were investigated in vitro to determine whether it is an inhibitory regulator of allergic inflammation. Peripheral blood eosinophils purified by Percoll density gradient centrifugation and the CD16 negative selection technique were incubated in the presence of eosinophil-activating cytokines (interleukin-5 (IL-5), IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-gamma) with and without TFG-beta 1 for 1-3 days. On day 1, eosinophil protein X release was measured by radioimmunoassay. Eosinophil viability on day 3 was determined by staining the cells with fluorescein diacetate and propidium iodide, and on the same day DNA was extracted and subjected to gel electrophoresis to test for fragmentation. TGF-beta 1 significantly inhibited eosinophil survival enhanced by IL-5, IL-3, GM-CSF and IFN-gamma in a dose-dependent manner. The inhibitory effects of TGF-beta 1 on IL-5-enhanced survival was partially reversed by high concentrations of IL-5 and was completely neutralized with anti-TGF-beta antibody. IL-5 inhibited DNA fragmentation of eosinophils in vitro. TGF-beta reversed the effect of IL-5, indicating that TGF-beta 1 activates the pathway of apoptosis. TGF-beta 1 significantly suppressed eosinophil protein X release induced by IL-5. These results suggest that TGF-beta 1 may play a role in the modulation of allergic inflammation.
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PMID:Inhibitory effect of transforming growth factor beta 1 on cytokine-enhanced eosinophil survival and degranulation. 754 18

T-lymphocyte proliferation is suppressed by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D3, and is associated with a decrease in interleukin 2 (IL-2), gamma interferon, and granulocyte-macrophage colony-stimulating factor mRNA levels. We report here that 1,25(OH)2D3-mediated repression in Jurkat cells is cycloheximide resistant, suggesting that it is a direct transcriptional repressive effect on IL-2 expression by the vitamin D3 receptor (VDR). We therefore examined vitamin D3-mediated repression of activated IL-2 expression by cotransfecting Jurkat cells with IL-2 promoter/reporter constructs and a VDR overexpression vector and by DNA binding. We delineated an element conferring both DNA binding by the receptor in vitro and 1,25(OH)2D3-mediated repression in vivo to a short 40-bp region encompassing an important positive regulatory element, NF-AT-1, which is bound by a T-cell-specific transcription factor, NFATp, as well as by AP-1. VDR DNA-binding mutants were unable to either bind to this element in vitro or repress in vivo; the VDR DNA-binding domain alone, however, bound the element but also could not repress IL-2 expression. These results indicate that DNA binding by VDR is necessary but not sufficient to mediate IL-2 repression. By combining partially purified proteins in vitro, we observed the loss of the bound NFATp/AP-1-DNA complex upon inclusion of VDR or VDR-retinoid X receptor. Order of addition and off-rate experiments indicate that the VDR-retinoid X receptor heterodimer blocks NFATp/AP-1 complex formation and then stably associates with the NF-AT-1 element. This direct inhibition by a nuclear hormone receptor of transcriptional activators of the IL-2 gene may provide a mechanistic explanation of how vitamin derivatives can act as potent immunosuppressive agents.
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PMID:Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. 756 32

Circulating and tissue-specific monocytes/macrophages, through production of hydrolytic enzymes and growth factors, can dramatically affect the local tissue environment. Colony-stimulating factor-1 (CSF-1) is a key regulator of monocyte/macrophage cell activity. CSF-1 is produced by stromal elements, including fibroblasts, which are found in all tissues. To understand at the molecular level how changes in CSF-1 gene transcription are initiated in fibroblasts, we set out to identify the cis-acting elements and cognate trans-acting factor(s) that bind regulatory regions of the mouse CSF-1 gene. Analysis of heterologous reporter constructs containing the mouse CSF-1 promoter linked to the bacterial chloramphenicol acetyltransferase (CAT) gene in transiently transfected fibroblasts identified a cis-acting element located between base pairs -88 and -43 of the CSF-1 gene. Electrophoretic mobility-shift assays (EMSAs) and DNase I protection assays with nuclear extracts isolated from proliferating fibroblasts revealed distinct protein binding to the region spanning base pairs -90 to -68. Results from methylation interference assays suggest CTF/NF1 or a CTF/NF1-like factor is the cognate trans-acting factor. Mutation of the putative CTF/NF1 binding site in the CSF-1 promoter lead to a modest decrease in promoter activity in transiently transfected fibroblasts and monocytes. Therefore, we have demonstrated that CTF/NF1 or a CTF/NF1-like protein binds to the CSF-1 gene promoter; however, binding of the CTF/NF1-like protein alone does not significantly effect changes in CSF-1 gene promoter activity.
DNA Cell Biol 1995 Nov
PMID:Binding of a CTF/NF1-like protein to the mouse colony-stimulating factor-1 gene promoter. 757 83

Although human eosinophils express low concentrations of CD4, the capacity of mature, non-replicating eosinophils to be infected with human immunodeficiency virus-1 (HIV-1) has not been established. Using peripheral blood eosinophils isolated free of contaminating lymphocytes and mononuclear leukocytes, we evaluated eosinophil infection with HIV-1. Eosinophils could be infected with strains of HIV-1 as evidenced by HIV-induced cytolytic effects, progressive release of p24 antigen in cultures of infected eosinophils, recovery of HIV from infected eosinophils by co-cultivation, and detection of HIV-1 gag viral DNA from infected eosinophils by polymerase chain reaction (PCR) amplification. Greater p24 antigen release from infected eosinophils was elicited by the phorbol ester, PMA; and eosinophil killing by HIV-1 was enhanced by the cytokine GM-CSF. By light and electron microscopy, HIV-infected eosinophils demonstrated apoptosis and necrosis. Apoptotic subdiploid nuclear staining was detected by flow cytometric analyses of propidium iodide-stained nuclei from HIV-infected eosinophils, and DNA isolated from HIV-infected eosinophils showed both nucleosomal fragmentation and diffuse degradation. Thus, mature eosinophils, non-replicating terminally differentiated leukocytes, can be infected with HIV-1. HIV-1 expression in eosinophils is promoted by increased granulocyte-macrophage colony-stimulating factor (GM-CSF) and can cause eosinophils to undergo death due to apoptosis and necrosis.
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PMID:Infection, apoptosis, and killing of mature human eosinophils by human immunodeficiency virus-1. 757 98

Apoptotic cell death induced by cross-linking Fas receptor (FasR/CD95) has been investigated in human acute myelogenous leukemia (AML) cells. FasR-mediated growth inhibition and DNA fragmentation could be induced in certain cases of AML. Interestingly, when DNA synthesis and G1 -> S transition in the cell cycle were enhanced by interleukin-3 or granulocyte-macrophage colony-stimulating factor, Fas-insensitive blast cells acquired cellular susceptibility toward FasR-mediated growth inhibition. To further evaluate an association between the Fas-R-mediated action and a specific phase of the cell cycle, a FasR+ leukemic cell line, MML-1, was established from a patient with AML. The morphologic feature of dying cells and DNA fragmentation indicated that FasR cross-linking induced apoptotic cell death in MML-1 cells. Cell cycle arrest in G1A phase with the treatment of phorbol 12-myristate 13-acetate or thymidine rendered MML-1 cells resistant to FasR-mediated apoptosis without downregulation of surface FasR expression. However, S-phase arrest with 5-fluorouracil could neither enhance nor inhibit FasR-mediated apoptosis. Simultaneous DNA/RNA quantification analysis revealed the selective loss of cells in G1B compartment, accompanied by the increase of apoptotic nuclei in sub-G1 fraction. These findings suggested that FasR-mediated apoptotic signals could be transduced into cells in G1B compartment and G1A -> G1B transition might augment the induction of FasR-mediated apoptosis.
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PMID:Fas receptor (CD95)-mediated apoptosis is induced in leukemic cells entering G1B compartment of the cell cycle. 757 53

The upstream regulatory region of the c-fos promoter contains two growth factor-regulated promoter elements: the serum response element, which binds a ternary complex comprising serum response factor (SRF) and a ternary complex factor (TCF); and the sis-inducible element (SIE) which binds STAT transcription factors. We used transient transfection of c-fos promoter mutants in NIH 3T3 cells to assess the contributions of these elements to activation by different extracellular stimuli. Colony-stimulating factor-1, platelet-derived growth factor and epidermal growth factor activate the c-fos promoter via cooperation of the SIE and the SRE; however, mutants that can bind SRF but not STATs or TCF remain inducible by whole serum. Activation by the SIE is context-dependent: interferons activate STAT DNA binding activity and transcription of SIE reporter genes, but not the c-fos promoter, which requires an additional ras-dependent signal. SRE activation by receptor tyrosine kinases requires TCF binding, and can be mediated by the TCF Elk-1. In contrast, SRE activation following activation of heterotrimeric G proteins by lysophosphatidic acid or aluminium fluoride ion requires SRF but is independent of TCF binding. These results suggest that heterotrimeric G proteins activate a signalling pathway distinct from those that activate the STATs and the TCFs, that controls SRF activity.
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PMID:Differential activation of c-fos promoter elements by serum, lysophosphatidic acid, G proteins and polypeptide growth factors. 758 32

Human natural killer cells (NK) respond to interleukin-2 (IL-2) with augmented cytolytic activity, cytokine secretion and cell proliferation. Here we show that IL-2 protects NK cells from death by apoptosis (programmed cell death; PCD). Highly purified NK cells (CD3- CD56+) were isolated from peripheral blood lymphocytes (PBL) of either control donors or of an asymptomatic donor with 60% NK cells. Glucocorticosteroids (GCS) induced PCD in NK cells, as shown by nuclear condensation and DNA fragmentation. IL-2 completely prevented GCS-induced PCD in a dose-dependent manner without overcoming GCS-induced inhibition of NK cell proliferation. The IL-2 protective effect was mediated through the p75 beta chain of the IL-2R, as neutralizing monoclonal antibody (mAb) to the p75 beta chain but not to the p55 alpha chain completely abolished the IL-2 anti-apoptotic activity. In addition to IL-2, the cytokines IL-7 and IL-12 have been reported to regulate NK cell functions. Our present data showed that IL-7 but not IL-12 rescued NK cells from apoptosis, but to a lesser extent than IL-2. Although IL-4 had a marginal protective effect, IL-1, IL-3, IL-6, IL-8, interferon-gamma (IFN-gamma) and IFN-alpha, tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and granulocyte-macrophage colony-stimulating factor (GM-CSF) displayed no significant activity. Finally, we report that IL-2 and IL-7 enhanced bcl-2 expression in NK cells, suggesting the existence of a bcl-2-dependent survival pathway. In addition to regulating various functions, it is concluded that IL-2 and IL-7 have the ability to prevent PCD in NK cells.
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PMID:IL-2 and IL-7 but not IL-12 protect natural killer cells from death by apoptosis and up-regulate bcl-2 expression. 764 25

Recently, a variety of growth factor-dependent subclones of the murine interleukin-3 (IL-3)-dependent cell line 32D have been isolated. These subclones include those dependent for growth on erythropoietin (Epo) (32D Epo), granulocyte-macrophage colony-stimulating factor (GM-CSF) (32D GM), or granulocyte colony-stimulating factor (G-CSF) (32D G). 32D Epo1.1 is a revertant of 32D Epo and is capable of growing in IL-3. These cell lines express the differentiation program appropriate to the specific growth factor and depend on the growth factors not only for proliferation but also for survival. To determine how the signal for proliferation is triggered by various growth factors, we examined the DNA histograms and the expression of cell cycle-specific genes in the different cell lines. The cell cycle-specific genes analyzed were myc (early G1), myb (late G1), and the structural genes for the calcium-binding protein 2A9 (middle G1) and histone H3 (G1-S boundary). The DNA histogram analysis of cells in the logarithmic phase of growth showed that approximately 40% of 32D, 32D GM, 32D G, and 32D Epo1.1 (growing in IL-3) were cells with a 2N DNA content (and therefore in G0/G1), and another 40% have a DNA content intermediate between 2N and 4N (in S phase). In contrast, 32D Epo and 32D Epo1.1 (growing in Epo) had fewer cells in the G0/G1 phase of the cell cycle compared with the number of cells that were in the S phase (19% to 31% v 69% to 78%, respectively). Because all the cell lines have comparable doubling times (15 to 18 hours), the cell distribution among the phases of the cell cycle is proportional to the length of the phase. Therefore, cells growing in IL-3 (32D and 32D Epo1.1), GM-CSF (32D GM), or G-CSF (32D G) progress along the cycle in a manner typical of previously reported nontransformed cell lines. In contrast, cells growing in Epo (32D Epo or 32D Epo1.1) spend relatively less time in G0/G1 and correspondingly more time in S. These data were confirmed by the analysis of the tritiated thymidine (3H-TdR) suicide rate and of the expression of cell cycle-specific genes. The 32D and 32D Epo1.1 cells growing in IL-3 had a suicide rate of congruent to 50%, whereas the suicide rate of 32D Epo and 32D Epo1.1 growing in Epo was higher than 75%.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Erythropoietin-specific cell cycle progression in erythroid subclones of the interleukin-3-dependent cell line 32D. 767 9

We have investigated the stimulative effects of mast cell growth factor (MGF) in primary acute myeloid leukemia (AML) in vitro. MGF stimulated DNA synthesis of purified leukemic blasts in eight out of 10 cases and colony formation in four cases in serum-free (SF) culture. MGF synergized with interleukin-3 (IL-3; four out of 10 cases), granulocyte-macrophage colony-stimulating factor (GM-CSF; three out of 10 cases), granulocyte colony-stimulating factor (G-CSF; six out of 10 cases), macrophage colony-stimulating factor (M-CSF; one out of 10 cases) and erythropoietin (EPO; one out of 10 cases) when added to culture in combination. Synergistic effects of MGF in combination with other CSFs were also seen in the colony assay. Antibodies against GM-CSF, M-CSF, G-CSF, and IL-6 did not inhibit the MGF response, suggesting that the stimulative effect of MGF was not mediated through autocrine release of those cytokines. Cell recovery data in liquid cultures that contained MGF, IL-3, or MGF + IL-3, indicated that both MGF and IL-3 augmented the maintenance of clonogenic cells as compared to nonsupplemented cultures, but the effect of the combination of IL-3 + MGF did not show synergy. In contrast, activation of DNA synthesis by MGF was abrogated in the presence of tumor necrosis factor (TNF; four out of 10 cases) and interleukin-4 (IL-4; two out of 10 cases). Fluorescence-activated cell sorting (FACS) analysis with anti c-kit antibodies revealed MGF receptor expression in eight out of nine cases, often in a subpopulation of the cells. Scatchard analysis of MGF receptors in two cases indicated the presence of 1460 and 41,500 (mean) binding sites, respectively, of high affinity (Kd 40-160 pmol/l). The MGF dose-response curve in the presence of IL-3 or GM-CSF resulted in a higher plateau of DNA synthesis, however no shift in the dose response was apparent. The respective reciprocal dose response relations to GM-CSF, IL-3, or G-CSF were similarly elevated when MGF was added. MGF did not alter IL-3 and GM-CSF receptor expression, nor did IL-3, GM-CSF, G-CSF, TNF, or IL-4 influence MGF binding to AML cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of mast cell growth factor on acute myeloid leukemia cells in vitro: effects of combinations with other cytokines. 768 Apr 1


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