UNIPROT:P04141 - FACTA Search

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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
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The disruption of the cutaneous permeability barrier results in metabolic events that ultimately restore barrier function. These include increased epidermal sterol, fatty acid, and sphingolipid synthesis, as well as increased epidermal DNA synthesis. Because tumor necrosis factor (TNF) and other cytokines are known products of keratinocytes and have been shown to modulate lipid and DNA synthesis in other systems, their levels were examined in two acute models and one chronic model of barrier perturbation in hairless mice. Acute barrier disruption with acetone results in a 72% increase in epidermal TNF 2.5 h after treatment, as determined by Western blotting. Furthermore, epidermal TNF mRNA was elevated ninefold over controls 2.5 h after acetone treatment. This elevation in TNF mRNA was maximal at 1 h after acetone, and decreased to control levels by 8 h. After tape stripping, a second acute model of barrier disruption that avoids application of potentially toxic chemicals, TNF mRNA was elevated fivefold over controls at 2.5 h. Moreover, the mRNA levels for epidermal IL-1 alpha, IL-1 beta, and granulocyte macrophage-colony-stimulating factor (GM-CSF) also were elevated several-fold over controls, after either acetone treatment or tape stripping, but their kinetics differed. GM-CSF mRNA reached a maximal level at 1 h after acetone, while IL-1 alpha and IL-1 beta were maximal at 4 h after treatment. In contrast, mRNAs encoding IL-6 and IFN gamma were not detected either in control murine epidermis or in samples obtained at various times after tape stripping or acetone treatment. The relationship of the cytokine response to barrier function is further strengthened by results obtained in essential fatty acid deficient mice. In this chronic model of barrier perturbation mRNA levels for epidermal TNF, IL-1 alpha, IL-1 beta, and GM-CSF were each elevated several-fold over controls. These results suggest that epidermal cytokine production is increased after barrier disruption and may play a role in restoring the cutaneous permeability barrier.
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PMID:Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice. 164 19

Resting natural killer (NK) cells express the p75 chain of the IL-2 receptor (IL-2R beta) and most NK cells express the CD2 (erythrocyte rosette) receptor. The cell adhesion molecule, LFA-3, is a natural co-ligand for CD2. Tac antigen (IL-2R alpha), a p55 IL-2R subunit, can be expressed after NK activation and may play a role in IL-2-induced NK proliferation. Little is known of the molecular mechanisms underlying cytokine production in NK cells. We investigated the roles of IL-2R alpha, IL-2R beta, and CD2/LFA-3 in the molecular regulation of NK cell granulocyte/macrophage-colony-stimulating factor (GM-CSF) production. Enriched populations of peripheral blood NK cells were separated into CD16-positive and CD16-negative fractions by flow cytometry; positively selected cells were greater than 97% positive for CD16 (the FcIII receptor for IgG which is present on almost all NK cells), less than 1% positive for the T cell antigen CD3, and did not demonstrate rearrangement of the T cell receptor beta chain gene by Southern blot. NK cell supernatants were harvested after 3-4 d of incubation with 0-100 U/ml IL-2, or after incubation with anti-CD2 (T11(3] MAb and sheep red blood cells (SRBC are a homologue for LFA-3). Parallel cell aliquots were harvested at 3-16 h for transcriptional run-on assays, S1 nuclease assays, and actinomycin D mRNA t1/2 determinations. IL-2-activated NK supernatants contained large amounts of GM-CSF (178 +/- 35 pg/ml) by ELISA as did supernatants from CD2-activated NK cells (T11(3) MAb + SRBC: 212 +/- 42) vs. less than 20 pg/ml for NK cells incubated alone or with either SRBC or T11(3) MAb alone. Sepharose-linked anti-CD3 MAb did not induce GM-CSF release from NK cells. By S1 analysis, both IL-2 and CD2 stimulation markedly augmented GM-CSF mRNA expression but with very different latencies of onset. IL-2R beta MAb inhibited greater than 85% of GM-CSF release from IL-2-activated NK cells and markedly suppressed IL-2-induced GM-CSF mRNA expression, whereas IL-2R alpha MAb even at 2,000-fold molar excess of IL-2 had little effect (less than 10%) on either GM-CSF release or mRNA expression. Run-on assays showed that GM-CSF is constitutively transcribed in NK cells and that IL-2 and CD2-activated cells had a three- to fourfold increased rate of GM-CSF transcription compared to nonstimulated cells. The t1/2 of GM-CSF mRNA in IL-2-activated NK cells was identical to that of unstimulated NK cells (15 min), whereas GM-CSF mRNA t1/2 in CD2-activated NK cells was increased 2.5-fold. We conclude that GM-CSF production in NK cells is regulated by both the IL-2Rbeta and the CD2 receptor but not by IL-2Ralpha, that both transcriptional and posttranscriptional signals act together to modulate the level of GM-CSF mRNA in NK cells, and that the molecular mechanisms underlying NK cell GM-CSF production are dependent in part on differential surface receptor activation.
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PMID:Production of granulocyte/macrophage-colony-stimulating factor by human natural killer cells. Modulation by the p75 subunit of the interleukin 2 receptor and by the CD2 receptor. 167 38

Normal hematopoiesis is controlled by a cascade of interacting hormones collectively referred to as cytokines. These growth factors have been studied both individually and in specific combinations to determine their optimal clinical use. In some cases, the combination of certain cytokines produces a synergistic effect enhancing their efficacy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has demonstrated the ability to stimulate early- and late-phase granulocyte and macrophage progenitor cells, activate mature neutrophils and macrophages, and enhance their peripheral infection fighting performance. Interleukin-3 (IL-3), currently undergoing clinical evaluation, acts early in the development of multiple types of white blood cells and, when used in combination with GM-CSF, also produces a synergistic effect in raising white blood cell and platelet levels. A recombinant protein, PIXY321, has recently been developed that contains both IL-3 and GM-CSF domains. The development of this molecule was supported by the discovery of a dual IL-3-GM-CSF receptor on the surface of hematopoietic progenitor cells. PIXY321 provides a significantly enhanced biologic effect (10-fold greater proliferation) via multiple cross-linking of GM-CSF, IL-3, and dual receptor binding sites. PIXY321 has the same molecular weight as the equivalent molar concentrations of GM-CSF and IL-3 combined and offers the advantage of combination therapy in an easy-to-administer regimen. Another recombinant cytokine, mast cell growth factor (MGF), has shown profound hematopoietic activity in vitro and has the ability to enhance proliferation of hematopoietic stem cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preclinical studies and future directions in the development of new hematologic growth factors. 168 5

Colony-stimulating factors (CSFs) are a class of glycoprotein hormones that stimulate production of the cellular elements of blood. Two of these hormones, granulocyte macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), have shown promise in clinical trials for the treatment of various neutropenic states. This article reviews the published experience in treating patients with GM-CSF and G-CSF and points out potential applications of these drugs in clinical practice.
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PMID:The promise of colony-stimulating factors in clinical practice. 168 43

Severe congenital neutropenia (SCN) is a disorder of myelopoiesis characterized by severe neutropenia secondary to a maturational arrest at the level of promyelocytes. We treated five patients with SCN with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for 42 days and subsequently, between 1 and 3 months later, with rhG-CSF for 142 days. The objective was to evaluate the safety and ability of these factors to elicit a neutrophil response. rhGM-CSF was administered at a dose of 3 to 30 micrograms/kg/d (30 to 60 minutes, intravenously). In all patients, a specific, dose-dependent increase in the absolute granulocyte counts was observed. However, in four patients this increase was due to an increase in eosinophils, and in only one patient it was due to an increase in the absolute neutrophil counts (ANC). Subsequently, all patients received rhG-CSF at a dose of 3 to 15 micrograms/kg/d subcutaneously. In contrast to rhGM-CSF treatment, all five patients responded to rhG-CSF during the first 6 weeks of treatment with an increase in the ANC to above 1,000/microL. The level of ANC could be maintained during maintenance treatment. In one patient, the increase in ANC was associated with an improvement of a severe pneumonitis caused by Peptostreptococcus and resistant to antibiotic treatment. No severe bacterial infections occurred in any of the patients during CSF treatment. All patients tolerated rhGM-CSF and rhG-CSF treatment without severe side effects. These results demonstrate the beneficial effect of rhG-CSF in SCN patients.
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PMID:Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia. 168 95

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

A possible role for calmodulin in the colony growth of human hematopoietic progenitor cells was investigated using pharmacologic approaches. We obtained evidence for a dose-dependent inhibition of colony formation of myeloid progenitor cells (CFU-C) stimulated by interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte CSF (G-CSF) by three calmodulin antagonists, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide hydrochloride (W-13), and trifluoperazine. Chlorine-deficient analogs of W-7 and W-13, with a lower affinity for calmodulin, did not inhibit the growth of CFU-C colonies. W-7, W-13, and trifluoperazine inhibited the colony formation of immature erythroid progenitor cells (BFU-E) stimulated by IL-3 plus erythropoietin (Ep) or GM-CSF plus Ep, in a dose-dependent manner, while they did not affect the colony formation of mature erythroid progenitor cells (CFU-E) induced by Ep. W-7, W-13, and trifluoperazine also led to a dose-dependent inhibition of GM-CSF-induced colony formation of KG-1 cells. Calmodulin-dependent kinase activity derived from the KG-1 cells was inhibited by these three calmodulin antagonists in a dose-dependent manner. These data suggest that calmodulin may play an important regulatory role via a common process in the growth of hematopoietic progenitor cells stimulated by IL-3, GM-CSF, and G-CSF. Mechanisms related to the growth signal of Ep apparently are not associated with calmodulin-mediated systems.
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PMID:A role for calmodulin in the growth of human hematopoietic progenitor cells. 169 May 78

Nine patients with progressive, metastatic disease from primary carcinoma of the colon were entered into a phase I/II study using continuous intravenous infusions of granulocyte-macrophage colony-stimulating factor (GM-CSF) and high dose melphalan (120 mg m-2). GM-CSF was given alone to six patients during the first part of the study to determine a dose that would produce a peripheral leucocyte count (WCC) greater than or equal to 50 X 10(9) 1(-1) and was initially given at 3 micrograms kg-1 day-1 and escalated to 10 micrograms kg-1 day-1 after 10 days. The infusion was discontinued when the WCC exceeded 50 X 10(9) 1(-1) and after a gap of one week, melphalan was given over 30 min. GM-CSF was recommenced 8 h later and was continued until the neutrophil count had exceeded 0.5 X 10(9) 1(-1) for greater than 1 week. One patient achieved a WCC greater than 50 X 10(9) 1(-1) with GM-CSF 3 micrograms kg-1 day-1, but the other five who entered this phase of the study required dose escalation to 10 micrograms kg-1. No toxicity attributed to GM-CSF was seen. After melphalan, the median times to severe neutropenia (less than 0.5 X 10(9) 1(-1] and thrombocytopenia (greater than 20 X 10(9) 1(-1] were 6 and 9 days respectively. The median durations of neutropenia and thrombocytopenia were 14 and 10 days respectively. All patients required intensive support with a median duration of inpatient stay of 24 days. There was one treatment related death due to renal failure. One complete and two partial remissions (33% response rate) were seen but these were of short duration (median of 10 weeks). This study demonstrates that GM-CSF given by continuous intravenous infusion produces significant increments of peripheral granulocyte counts at 3 and 10 micrograms kg-1 day-1 and is not associated with any toxicity. The duration of neutropenia and thrombocytopenia induced by high-dose melphalan appears to be reduced by the subsequent administration of GM-CSF to times which are at least as short as have been reported in historical series which have used autologous bone marrow rescue.
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PMID:Granulocyte-macrophage colony stimulating factor (GM-CSF) after high-dose melphalan in patients with advanced colon cancer. 169 72

The pathogenic effects of human cytomegalovirus (CMV) infection in vitro on hematopoiesis were investigated. Normal human bone marrow cells from both seronegative and seropositive donors were challenged with CMV (Towne or wild-type strain) and tested for their responsiveness to the recombinant hematopoietic growth factors granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-CSF (G-CSF), respectively. Regardless of the serostatus of the donor, infection with CMV resulted in a significant decrease in the proliferation and colony formation of hematopoietic progenitor cells in response to both growth factors, with more pronounced suppression in response to G-CSF being observed. Evaluation of the colony composition revealed a profound decrease in colonies of the granulocytic (CFU-G), or granulocyte-macrophage (CFU-GM) lineages, while suppression of multipotential (CFU-GEMM) and erythroid (BFU-E) colony-forming cells occurred after infection with wild-type but not the laboratory strain of CMV. Although no evidence of productive virus infection could be seen in colony-forming cells, in situ hybridization studies and immunohistochemical staining revealed the presence of CMV-specific mRNA and immediate-early antigens, demonstrating that a small proportion of cells were abortively infected. These studies demonstrate that CMV can infect bone marrow progenitor cells and interfere with normal hematopoiesis in vitro, which may help to explain the hematologic defects seen during acute infections with CMV in vivo.
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PMID:Preferential suppression of myelopoiesis in normal human bone marrow cells after in vitro challenge with human cytomegalovirus. 169 91

The recent demonstration of the ability of human polymorphonuclear neutrophils (PMN) to secrete various cytokines in response to the granulocyte activator granulocyte-macrophage colony-stimulating factor (GM-CSF) but not to other cytokines, has led to the identification of PMN as biosynthetically active cells. In this study we have investigated the ability of PMN to secrete interleukin-6 (IL-6), a molecule known to be involved in inflammatory reactions. Using RNA blotting analysis and bioassays, we show that PMN could be induced to synthesize transcripts specific for IL-6, indistinguishable in size from IL-6 mRNA produced by activated human macrophages. Consequently, PMN released IL-6-like activity into their culture supernatants that could be neutralized by monospecific anti-IL-6 antibody. Interleukin-6 secretion by PMN, however, required previous stimulation with GM-CSF or tumor necrosis factor-alpha (TNF-alpha), whereas other cytokines, including interleukin-3 (IL-3), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), interferon gamma (IFN-gamma), and lymphotoxin (LT), failed to induce IL-6 mRNA accumulation and protein secretion by PMN. Similar to GM-CSF and TNF-alpha, other compounds, including the inhibitor of protein synthesis cyclohexemide (CHX), endotoxin (Escherichia coli-derived lipopolysaccharide), and phorbol myristate acetate (PMA) (but not the chemoattractant N-formyl-methionyl-leucyl-phenylalanine [FMLP]), induced detectable levels of IL-6 transcripts in PMN.
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PMID:Inducible production of interleukin-6 by human polymorphonuclear neutrophils: role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha. 169 93

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