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)

Oxidized lipoproteins have been identified in atherosclerotic plaques and in early lesions in humans as well as in animals. There is accumulating evidence that such oxidized lipoproteins have an important role in atherosclerosis. Treatment of endothelial cells with altered lipoproteins stimulates monocyte binding as well as the production of chemotactic factors for monocytes. Both these findings could be relevant to the accumulation of monocytes-macrophages in the arterial wall during the early stages of lesion development. We now report that treatment of endothelial cells (EC) with modified low-density lipoproteins obtained by mild iron oxidation or by prolonged storage, results in a rapid and large induction of the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage CSF (M-CSF) and granulocyte CSF (G-CSF). These growth factors affect the differentiation, survival, proliferation, migration and metabolism of macrophages/granulocytes, and G-CSF and GM-CSF also affect the migration and proliferation of EC. Because EC and macrophages are important in the development of atherosclerosis, the expression of the CSFs by these cells could contribute to the disease.
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PMID:Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. 169 Mar 54

Purified recombinant human (rhu) interleukin (IL)-1 alpha, rhuIL-6, iron saturated lactoferrin (LF), and T-lymphocytes were assessed for their effects on the survival of granulocyte-macrophage (granulocyte-macrophage colony-forming units, CFU-GM) and erythroid (erythroid burst-forming units, BFU-E) progenitor cells from human low-density (LD) and nonadherent LD T-lymphocyte-depleted (NALT-) bone marrow (BM) cells. Colony-stimulating factor (CSF) deprivation studies showed that 10 ng/ml IL-1 alpha could promote the survival of CFU-GM and BFU-E from NALT- BM cells. Concentrations of 1 ng/ml IL-1 alpha and 1-100 ng/ml IL-6 alone could not promote progenitor cell survival from NALT- BM cells; however, concentrations of 1 ng/ml each of IL-1 alpha and IL-6 could synergize to promote the survival of CFU-GM but not of BFU-E. The combination of these low concentrations of IL-1 alpha and IL-6 could, however, support the survival of BFU-E in the presence of purified T-lymphocytes. LF could decrease the survival of CFU-GM and BFU-E from LD but not from NALT- BM cells, apparently due to the inhibition of IL-1 release from monocytes in this cell population. The suppressive effect of LF on the survival of those progenitor cells was abolished by concentrations of 10 ng/ml IL-1 alpha or 1 ng/ml each of IL-1 alpha and IL-6. These results demonstrate that the survival of human marrow CFU-GM and BFU-E can be influenced by IL-1, IL-6, LF, and T-lymphocytes.
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PMID:Influence of T-lymphocytes and lactoferrin on the survival-promoting effects of IL-1 and IL-6 on human bone marrow granulocyte-macrophage and erythroid progenitor cells. 189 56

The production of colony-stimulating factors (CSFs) by murine bone marrow stromal cells was studied with Dexter long-term bone marrow culture (LTBMC). For induction of CSF release, various concentrations (0.5-40.0 microgram/ml) of bacterial lipopolysaccharide (LPS) were added to nonrecharged 3-week-old LTBMCs consisting of an intact or macrophage-depleted adherent cell layer. The depletion of monocytes/macrophages from freshly prepared bone marrow cell suspension was performed by carbonyl-iron incorporation before establishment of LTBMC. The supernatants (Sup) of normal LTBMCs contained a low level of macrophage colony-stimulating factor (M-CSF) that was produced by the adherent cells but not by the nonadherent cell elements. No colony inhibitor was found in the Sup of LTBMCs, whereas a colony-promoting activity (CPA) was detected in medium conditioned by the adherent marrow cells (AC-CM). CPA could enhance the colony formation of myeloid progenitor cells when used in combination with recombinant murine granulocyte-macrophage colony-stimulating factor (GM-CSF). The production of CSFs peaked at about 24 h after refeeding, but it then declined to only half the optimal activity at the end of the week. Addition of LPS to the intact LTBMC invariably increased the production of a GM-CSF-like cytokine. The release of this cytokine was dose dependent and peaked at a dosage of 20 micrograms/ml of LPS at 24 h after treatment. In contrast, macrophage-depleted marrow-adherent cells failed to respond to LPS for CSF secretion. These results suggest that LPS can stimulate marrow macrophages to directly release CSF or to potentiate the production of CSF by other stromal cells.
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PMID:Effect of lipopolysaccharide on the production of colony-stimulating factors by the stromal cells in long-term bone marrow culture. 199 94

The presence of heterogeneous erythroid progenitor cells, contaminant cells, or serum may alter erythroid colony development in vitro. To obtain highly purified colony-forming units-erythroid (CFU-E), we cultured partially purified human blood burst-forming units-erythroid (BFU-E) in methylcellulose with recombinant human erythropoietin (rHuEPO) for 7 d and generated cells that consisted of 30-60% CFU-E, but no BFU-E. A serum-free medium was used that allowed development of the same number of erythroid colonies as serum containing medium, but with a greater percentage of larger colonies. This medium consisted of delipidated crystalline bovine serum albumin, iron saturated transferrin, lipid suspension, fibrinogen, thrombin, Iscove's modified Dulbecco's medium/F-12[HAM], and insulin plus rHuEPO. When CFU-E were cultured in a limiting dilution assay and the percentage of nonresponder wells was plotted against cell concentration, both serum-free cultures and serum-containing cultures yielded overlapping straight lines through the origin indicating that CFU-E development did not depend on accessory cells and that insulin acted directly on the CFU-E. Human recombinant interleukin 3 (IL-3) and/or granulocyte-macrophage colony-stimulating factor had no effect on CFU-E growth, while they markedly enhanced BFU-E growth. Physiological concentrations of recombinant human insulin-like growth factor I (IGF-I) enhanced CFU-E growth in the absence of insulin and, together with rHuEPO in serum-free medium, provided a plating efficiency equal to that of serum-containing medium. Limiting dilution analysis in serum-free medium with IGF-I showed a straight line through the origin indicating that IGF-I also acted directly on the CFU-E and not through an effect on accessory cells. These data demonstrate that CFU-E do not require accessory cells, but do require IGF-I and/or insulin which act directly on the CFU-E.
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PMID:Human colony-forming units-erythroid do not require accessory cells, but do require direct interaction with insulin-like growth factor I and/or insulin for erythroid development. 265 78

The different 3' noncoding AU-rich elements (ARE) that mediate the degradation of many short-lived mRNAs may function through distinct decay pathways; translation-dependent and -independent mechanisms have been proposed. To investigate the cotranslational model, we designed an expression system that exploits the properties of the ferritin iron-responsive element to shuttle chimeric mRNAs from ribonucleoproteins to polyribosomes. The iron-responsive element was introduced in the 5' untranslated regions of alpha-globin mRNAs that harbored in their 3' untranslated regions either the c-fos ARE or the granulocyte-macrophage colony-stimulating factor ARE as prototypes of the different ARE subsets. The cytoplasmic location of the transcripts was controlled by intracellular iron availability and monitored by polysomal profile analysis. We report that these two mRNA subsets behaved identically in this system. Iron deprivation by desferrioxamine treatment stabilized both transcripts by sequestering them away from polyribosomes. Sequential treatments with desferrioxamine, followed by hemin to concentrate the mRNAs in the ribonucleoprotein pool prior to translation, showed that rapid degradation occurred only upon redistribution of the transcripts to polyribosomes. Deletion of a critical cytosine in the iron-responsive element abolished targeted sequestration and restored high-level constitutive mRNA instability. These observations demonstrate that the c-fos and granulocyte-macrophage colony-stimulating factor ARE subsets mediate selective mRNA degradation through similar polysome-associated mechanisms coupled with ongoing translation.
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PMID:Rapid mRNA degradation mediated by the c-fos 3' AU-rich element and that mediated by the granulocyte-macrophage colony-stimulating factor 3' AU-rich element occur through similar polysome-associated mechanisms. 754 Jul 19

Serum triglyceride levels are significantly higher and serum high-density lipoprotein cholesterol levels are lower in patients with gout compared with healthy individuals. Whereas increased serum triglyceride levels exist intrinsically in gout, serum uric acid concentration correlates inversely with insulin sensitivity and positively with serum triglycerides. Interaction of monosodium urate crystals with granulocyte-macrophage colony-stimulating factor and with tumor necrosis factor-activated neutrophils favored the production of interleukin-1 over that of interleukin-1-Ra, resulting in a proinflammatory imbalance. Interaction of the crystals with iron or tyrosine kinase may modify their inflammatory response and can be an important modulating mechanism in gouty arthritis. E-selectin is a specific marker for synovial fluid soluble endothelial activity and is increased in the synovial fluid of patients with gouty arthritis, as well as in that of patients with other inflammatory arthritides. Similarly, E-selectin was found to be high in joints with monosodium urate crystal-induced synovitis. In addition, synovial fluid levels of interleukin-8 were found to be high in gout, rheumatoid arthritis, and osteoarthritis.
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PMID:Gout, uric acid metabolism, and crystal-induced inflammation. 754 16

Minimally modified LDL (MM-LDL), obtained by mild iron oxidation or prolonged storage at 4 degrees C, has been shown to induce the expression of macrophage-colony stimulating factor (M-CSF) in cultured aortic endothelial cells. To examine whether other cell types also respond to MM-LDL, we investigated its effect on the expression of M-CSF mRNA in mouse L-cells and human aortic smooth muscle cells. Both L-cells and human aortic smooth muscle cells showed increased levels of M-CSF mRNA in response to 10 to 200 micrograms/mL MM-LDL in a dose-dependent manner. This allowed us to use mouse L-cells as a model to study the mechanism involved in MM-LDL-mediated increase in M-CSF mRNA. Nuclear runon assays showed that M-CSF gene transcription was activated by MM-LDL. In the present study, we identified specific elements that conferred MM-LDL-mediated transcriptional activation of the human M-CSF gene. Chimeric constructs containing sequential deletions in the 5'-promoter region of the M-CSF gene linked to a reporter chloramphenicol acetyltransferase (CAT) gene were transfected into mouse L-cells. The human M-CSF promoter region extending upstream from the transcription start site to nucleotide -406 showed maximum induction of CAT activity by MM-LDL. Induction of CAT activity was drastically reduced, with a deletion plasmid lacking the promoter region -406 to -344. A functional nuclear factor (NF)-kappa B binding site present in this critical region was required for MM-LDL-mediated induction of CAT activity since an internal deletion construct lacking this element showed significant loss of transcriptional activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transcriptional activation of the macrophage-colony stimulating factor gene by minimally modified LDL. Involvement of nuclear factor-kappa B. 758 32

The human neutrophil lactoferrin (Lf), a cationic iron-binding glycoprotein, has an inhibitor role on granulocyte macrophage colony-stimulating factor (GM-CSF) production via interleukin-1 (IL-1). The nuclear localization of Lf suggests that it may be involved in the transcriptional regulation of GM-CSF gene expression. To explore this possibility, the effect of Lf on GM-CSF gene expression was investigated in various cell lines and in primary cultures of fibroblasts. Down-regulation of GM-CSF mRNA level was observed in Lf-transfected embryonic fibroblasts induced to produce GM-CSF by IL-1 beta. In 5637 cell-line and in embryonic fibroblasts, co-transfection experiments, in which an Lf expression vector was used together with a vector carrying a reporter gene linked to the GM-CSF promoter, revealed that Lf reduces the activity of the GM-CSF promoter. This effect is marked in IL-1 beta-stimulated cells. These findings suggest that Lf plays a negative role in GM-CSF expression at the transcriptional level, perhaps through the mediation of IL-1 beta.
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PMID:Lactoferrin down-modulates the activity of the granulocyte macrophage colony-stimulating factor promoter in interleukin-1 beta-stimulated cells. 774 78

Erythropoiesis is controlled by different regulators. Interleukin 3, granulocyte-macrophage colony-stimulating factor and stem cell factor play regulatory functions in the early steps of erythropoiesis. Erythropoietin (Epo) is the main factor which acts positively on the last steps of the production of erythrocytes in mammals. Epo is specific for the erythroid progenitor cells and has only little effect on other cells. The target cells for Epo are the erythroid progenitors (BFUe and CFUe). Epo acts on these progenitors through surface receptors specific for Epo. Epo induces the proliferation and differentiation of erythroid progenitors leading finally to reticulocytes. During this process, certain conditions are required to permit this differentiation: progenitors must be present in sufficient numbers, the bone marrow environment must be normal, and nutrients such as folic acid, vitamin B12 and particularly iron must be available. Elemental iron is an absolute requirement for adequate haemoglobin formation. Indeed, in a normal adult, without any stimulation, the bone marrow synthesizes 4 x 10(14) molecules of haemoglobin per second, each molecule containing four atoms of iron, which roughly corresponds to 20 mg iron. On the other hand, erythropoiesis is negatively regulated by several cytokines. These are macrophage-derived cytokines, including tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta). All these factors are elevated in the inflammatory state and are implicated in the pathogenesis of anaemia of chronic disease. TNF-alpha has an inhibitory effect on erythroid progenitors either directly or mediated by interferon-beta (INF-beta). IL-1 inhibits erythropoiesis in vivo in mice and in vitro in humans.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cellular mechanism of resistance to erythropoietin. 852 90

Intermittent painful crises due to vasoocclusion are the major clinical manifestation of sickle cell disease (SCD), but subclinical episodes may also occur. There is sparse evidence for the involvement of neutrophils in the pathophysiology of SCD, but production of cytokines by the damaged endothelium might influence neutrophil function and modulate responses to subsequent cytokine exposure. In addition, the activation of neutrophils in the microcirculation could itself exacerbate vasoocclusion. To test whether neutrophil inflammatory responses were altered in SCD, neutrophil phospholipase A2 and NADPH oxidase activity in response to in vitro priming by granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) were measured both during and between painful crises. Resting levels of neutrophil phospholipase A2 activity in steady-state SCD (4.0% +/- 0. 5% of total cell radioactivity) were raised relative to control values (2.0% +/- 0.2%, n = 10, P = .008). There was no defect of agonist-stimulated phospholipase A2 or NADPH oxidase activity in steady-state SCD; however, the ability of phospholipase A2 to respond to priming with GM-CSF was attenuated to 63% +/- 17% of control values (n = 10, P = .04). Similarly, neutrophil NADPH oxidase activity after priming with GM-CSF and TNF-alpha was, respectively, 65% +/- 11% (n = 7, P = .03) and 57% +/- 7% of control (n = 10, P = .007) in steady-state disease, and was further reduced during painful vasoocclusive crises to 34% +/- 9% and 25% +/- 3% of control for GM-CSF and TNF-alpha, respectively. These data were not explained by poor splenic function or any racial factor, as normal cytokine responses were seen in splenectomized patients in remission from Hodgkin's disease and in healthy Afro-Caribbean subjects. Abnormal neutrophil cytokine priming responses were not observed in either patients with rheumatoid arthritis or iron-deficiency anemia. Our findings are indicative of an ongoing inflammatory state in SCD between painful crises involving neutrophil activation and an abnormality of cytokine-regulated neutrophil function, which may compromise the host defenses against certain microorganisms.
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PMID:Raised neutrophil phospholipase A2 activity and defective priming of NADPH oxidase and phospholipase A2 in sickle cell disease. 955 1


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