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)

In order to investigate differences in control mechanisms between embryonic and adult hemopoiesis, we have studied the sensitivity of human embryonic progenitors (5-8 weeks postconception) to either positive (erythropoietin (Ep), granulocyte-macrophage colony-stimulating factor (GM-CSF) and insulin-like growth factor 1 (IGF-1] or negative (tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma] in vitro regulators of adult hemopoietic differentiation. Growth stimulators were analyzed under serum-deprived conditions whereas growth inhibitors were investigated in serum-supplemented culture. Formation of granulocyte-macrophage colonies from embryonic progenitors was induced by GM-CSF but inhibited by TNF and IFN-gamma. Early erythroid progenitors resemble adult erythroid burst-forming cells (BFU-E) in their sensitivity to Ep and TNF but differ in their lack of response to GM-CSF or other adult sources of burst-promoting activity, and absence of inhibition by IFN-gamma. IGF-1 promoted erythroid burst formation in the absence of insulin, but did not have Ep-like activity. These data indicate that embryonic and adult erythroid progenitors differ at least in terms of in vitro sensitivity to GM-CSF and IFN-gamma and suggest that different cellular response to control signals may underlie the differences observed in vivo between embryonic and adult hemopoiesis.
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PMID:Human embryonic hemopoiesis: control mechanisms underlying progenitor differentiation in vitro. 311 98

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

A new serum-free culture (SFC) system for human AML-CFU was established and the colony-promoting activity of four recombinant human hematopoietic growth factors (rhHGFs) including granulocyte-macrophage colony-stimulating factor (rhGM-CSF), interleukin-3 (rhIL-3), erythropoietin (rhEPO) and newly developed stem cell factor (rhSCF) were investigated in this SFC system. Under the orthogonal design condition, it was found that human AML-CFU presented optimal clonal growth in an environment of bovine serum albumin (0.6%), saturated human transferrin (2 x 10(-6) mol/L), cholesterol (2.8 micrograms/ml), bovine insulin (15 micrograms/ml), bovine hemin (0.05 mmol/L), linoleic acid (2.8 micrograms/ml), and IMDM. Spontaneously growing colonies were observed in 11 out of 14 cases studied. The plating efficiencies obtained by culturing with rhGM-CSF, rhIL-3, and rhSCF were 0.776 +/- 0.621%, 0.574 +/- 0.510%, and 0.647 +/- 0.543% (mean +/- s), respectively. There was one case (M3b) showing no response to all HGFs in both SFC ad SCC. The clonal growth of AML-CFU obtained from peripheral blood of the patient with M6 was unexpectedly marked. As a whole, the newly designed SFC system has been demonstrated to be useful for culture of human AML-CFU from both bone marrow and peripheral blood.
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PMID:A newly developed serum-free culture system: clonal growth of human acute myelogeneous leukemia (AML) progenitors--a report of 14 AML cases. 780 5

Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have previously been reported to induce rapid phosphorylation of the mitogen-activated protein (MAP) kinase. However, little is known about signaling events initiated by both hematopoietins that occur downstream of the MAP kinase. MAP kinase has been shown to phosphorylate the AP-1 transcription factor and also to activate two kinases designated insulin-stimulated protein kinase-1 and MAP kinase-activated protein (MAP-KAP) kinase 2. We show here that IL-3 and GM-CSF induce MAPKAP kinase 2 activity in the human megakaryoblastic leukemia cell line MO7 and phosphorylate the human small heat shock protein Hsp 27 on serine residues in vitro. GM-CSF also induced Hsp 27 phosphorylation in neutrophils in a range similar to that observed in MO7 cells, suggesting that MAPKAP kinase 2-mediated Hsp 27 activation occurs independently of proliferation. Hsp 27 phosphorylation was dose-dependent, occurred as early as 5 minutes after factor exposure, and was inhibited by the tyrosine kinase inhibitors genistein and herbimycin A. Furthermore, the protein phosphatase A2 abolished IL-3- and GM-CSF-induced serine phosphorylation of Hsp 27. Taken together, our findings indicate that tyrosine phosphorylation of MAP kinase is a prerequisite for serine phosphorylation of Hsp 27, which is mediated by MAPKAP kinase 2. Hsp 27 has shown activation-dependent translocation from the cytosolic to the nuclear region and has been linked to the cellular stress response. However, its precise function is largely unknown. Our data identify Hsp 27 as a target of the IL-3/GM-CSF stimulation pathway that involves MAP kinase and MAPKAP kinase 2. In addition, our results indicate that Hsp 27 may be target of phosphorylation events not only in the stress response but also in unstressed cells responding to cytokine stimulation.
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PMID:Interleukin-3 and granulocyte-macrophage colony-stimulating factor induce activation of the MAPKAP kinase 2 resulting in in vitro serine phosphorylation of the small heat shock protein (Hsp 27). 1101 49

The product of the c-raf-1 proto-oncogene, Raf-1, is known to encode a 74-kDa ubiquitously expressed cytoplasmic serine/threonine kinase. Various growth factors such as epidermal growth factor, acidic fibroblast growth factor, platelet-derived growth factor, insulin, granulocyte-macrophage colony-stimulating factor, interleukin (IL)-2, IL-3 and erythropoietin have been shown to induce phosphorylation of Raf-1, thereby activating Raf-1 kinase. Raf-1 is, thus, believed to play a role in coupling growth factor receptors to proliferation. We have examined the role of Raf-1 in the mitogenic response of human peripheral blood-derived IL-2 receptor expressing T cells to human recombinant IL-2 employing c-raf antisense (AS) oligodeoxyribonucleotide. Uptake studies of oligonucleotides indicated that incorporation of oligomers was maximal at 4 h and oligodeoxynucleotides remained stable in these cells for up to 24 h. Treatment of T cells with the AS oligodeoxyribonucleotide in intracellular duplex formation followed by efficient translation blockade of c-raf-1. In contrast, sense (S) and nonsense (NS) oligodeoxynucleotides failed to form intracellular duplexes and did not interfere with translation of c-raf-1, suggesting specific elimination of c-raf-1 by the AS oligomer. Proliferation of T cells ([3H]thymidine incorporation) following exposure to IL-2 was substantially reduced when the c-raf-1 AS oligodeoxyribonucleotide was added to cultures, while the mitogenic response to this factor remained almost unaffected in the presence of S and NS oligodeoxyribonucleotides.
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PMID:The mitogenic response of T cells to interleukin-2 requires Raf-1. 825 28

Tumor metastasis is the primary cause of death for cancer patients. The metastatic cascade requires successful tumor cell invasion into and through vascular and parenchymal barriers. We have shown that autocrine motility factor (AMF, autotaxin) and the insulin-like growth factors (IGFs) induce tumor-cell migration. Since granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to prime neutrophils for chemotaxis, we have therefore studied the influence of GM-CSF upon tumor cells and report that GM-CSF stimulates migration of these cells in a dose-dependent fashion. The ED50 for A2058 human melanoma cell line chemotaxis to GM-CSF is approx. 60 pM. The motile response to GM-CSF was additive to that of IGF-I and AMF, both of which are potent attractants for tumor cells. Pre-treatment of cells for 2 hr with non-toxic concentrations of pertussis toxin (PT) or amiloride resulted in a 50% inhibition of chemotaxis to GM-CSF. Therefore, GM-CSF, through PT- and amiloride-sensitive signal pathways, is a potent attractant for melanoma cells, the response to which is additive to that of other attractants. The presence of the GM-CSF receptor in A2058 melanoma cells was indicated by Northern-blot analysis which identified message transcripts of 2.1 and 3.0 kb. These data emphasize the versatility of the melanoma cell migration response to an array of cytokines, including GM-CSF.
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PMID:Granulocyte-macrophage colony-stimulating factor induces human melanoma-cell migration. 847 54

A large body of clinical experience on the adverse consequences of cytokine administration has accumulated since the last decade. Side-effects reported after the therapeutic use of cytokines has provided evidence that activation of the immune response may sometimes have deleterious consequences. Several effects appeared as a direct consequence of the immune activation induced by cytokines, e.g. flu-like reactions, vascular leak syndrome. Cytokine-induced exacerbation of underlying diseases or immune dysregulation were other complications of growing concern. Interferon-alpha (IFN-alpha) treatment has now been clearly linked with the exacerbation or the occurrence of several types of autoantibodies or autoimmune diseases (thyroiditis, systemic lupus erythematosus, hematologic disorders, insulin-dependent diabetes mellitus) or diseases involving altered cell-mediated immune functions (inflammatory dermatologic diseases, nephritis, pneumonitis, colitis). By contrast immunological side-effects of IFN-beta and IFN-gamma have been seldom reported. However, the extent of clinical experience with both of these cytokines is still very limited. Interleukin-2 (IL-2) has also been implicated in various conditions that may involve immunopathological processes (thyroid disorders, rheumatoid arthritis, dermatological diseases, interstitial nephritis). Growth factors have been more specifically linked with the development or the exacerbation of dermatological inflammatory diseases through neutrophils, monocytes/macrophages or eosinophils activation (e.g. cutaneous vasculitis and generalized cutaneous eruption, Sweet's syndrome, bullous eruption, psoriasis). Exacerbation of autoimmune thyroiditis was described with granulocyte-macrophage colony-stimulating factor (GM-CSF) only. The immunogenicity of cytokines is also of great relevance and the occurrence of antibodies binding IFN-alpha and IFN-beta, IL2 and GM-CSF have been reported. While the clinical significance of non-neutralizing antibodies is not clearly established, an absence of response or reversal of clinical efficacy has been described in patients developing neutralizing antibodies. Finally, several isolated reports have recently suggested that IFN-alpha treatment may be associated with several immunosuppressive effects while IL-2 is clinically associated with an increased incidence of infectious complications.
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PMID:Immune-mediated side-effects of cytokines in humans. 863 83

It has been proposed that cytokines mediate the acceleration of bone loss following menopause. Because of the intimate relationship between bone marrow stromal cells and bone tissue, it is possible that marrow cells and their products contribute to the bone microenvironment and influence the regulation of bone cell differentiation and activity. We examined the production of cytokines by bone marrow stromal cells from a total of 37 women and 15 men undergoing total hip replacement for noninflammatory joint disease. Low-density mononuclear cells were isolated from bone marrow and were cultured in phenol red-free alpha MEM medium supplemented with 10% FBS and antibiotics. Constitutive secretion of interleukin-6 (IL-6) was positively correlated with age in a series of 8 women and 5 men measured by bioassay (r = 0.98; P < 0.01) and in a series of 18 women and 10 men measured by immunoassay (r = 0.56; P < 0.01). The pattern of cytokine production by bone marrow stromal cells was examined in detail in 23 postmenopausal women, aged 49-88 yr. Basal secretion of immunoreactive IL-6 and IL-11, but not granulocyte-macrophage colony-stimulating factor, increased with time in culture. Exogenous IL-1 beta stimulated secretion of IL-6 and IL-11 in a saturable, dose-dependent manner. Secretion of soluble IL-6 receptor was not correlated with secretion of IL-6, either constitutively or in the presence of IL-1 beta. In 4 of 14 samples, IL-1 beta also stimulated secretion of granulocyte-macrophage colony-stimulating factor. IL-1 beta was undetectable in 7 of 9 cultures during the 2-week culture period. IL-6 did not stimulate secretion of IL-1 beta in the 7 cultures tested. Cells were dependent upon serum for viability and growth and were not sustained by a serum substitute (1% insulin-transferrin-selenium-BSA). Cells grown in medium with 10% FBS and supplemented with 1% insulin-transferrin-selenium-BSA secreted 10-fold more IL-6 than cells grown in serum alone. Marrow from 7 women receiving estrogen replacement therapy showed lower constitutive secretion of IL-6 (75%; P < 0.006) and IL-11 (43%; P < 0.05) than marrow from age-matched controls and had blunted stimulation of IL-6 and IL-11 secretion by exogenous IL-1 beta. These data indicate distinct patterns of cytokine production by human marrow stromal cultures dependent upon age and estrogen status.
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PMID:In vitro secretion of cytokines by human bone marrow: effects of age and estrogen status. 962 37

Human ovarian adenocarcinoma cells N.1 secrete an autocrine activity that stimulates active cell death under serum-reduced conditions. To substitute the autocrine activity by a single physiological component, 28 cytokines, growth factors and biomodulators were tested [interleukin 1alpha (IL-1alpha), IL-1beta, IL-2, IL-3, IL-4, IL-6, IL-10, IL-11, stem cell factor (SCF), platelet-derived growth factor (PDGF), acid fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF-1), IGF-2, insulin, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), oncostatin, RANTES (regulated on activation normal T cell expressed and secreted), angiogenin, leukaemia inhibitory factor (LIF), erythropoietin (EPO), interferon alpha (INF-alpha), INF-gamma, transferrin, tumour necrosis factor alpha (TNF-alpha, TNF-beta and bovine serum albumin for control reasons]. In these experiments, only TNF-alpha and TNF-beta rapidly induced apoptosis. TNF-alpha and TNF-receptor 1 were expressed by N.1 cells, and the secretion of TNF-alpha was verified by enzyme-linked immunosorbent assay (ELISA). Autocrine factor-triggered apoptosis was inhibited when conditioned supernatant was preincubated with anti-TNF-alpha antibody. These findings suggested that the apoptosis-inducing component of the N.1 autocrine activity was TNF-alpha. In the presence of antisense c-myc oligonucleotides, induction of cell death by autocrine factor was partly inhibited. Autocrine factor and TNF-alpha stimulated transcription of the invasiveness-related protease plasminogen activator/urokinase mRNA (upa) with similar kinetics. When N.1 cells were exposed to purified plasminogen activator/urokinase protein (uPA), cell matrix contact was disrupted. Thus, uPA might serve a physiological role during TNF-induced apoptosis by affecting the interactions between cells and the basal membrane, thereby facilitating anoikis. This mechanistic study, which was restricted to a single human ovarian carcinoma model cell line (N.1), provides evidence that N.1 maintains the capacity to undergo c-myc-dependent apoptosis by the TNF-TNF-receptor pathway, and no additional pharmacological stimuli for induction of apoptosis are required.
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PMID:Autocrine self-elimination of cultured ovarian cancer cells by tumour necrosis factor alpha (TNF-alpha). 976 76

Two young insulin-dependent diabetic patients suffering from chronic nonhealing leg ulcers of necrobiosis lipoidica diabeticorum were treated by applying topically recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) on the ulcer repetitively during 10 weeks. Evaluation of ulcer size was assessed with clinical examinations at 1-week or 2-week intervals. Topical GM-CSF healed the ulcers of both patients in 10 weeks. Decrease in the size of the ulcers was already evident after the first topical applications. During follow-up, the ulcers have remained healed for more than 3 years. This excellent treatment result suggests that topically applied GM-CSF may be a valuable drug for chronic, nonhealing ulcers in patients with diabetes.
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PMID:Healing of chronic leg ulcers in diabetic necrobiosis lipoidica with local granulocyte-macrophage colony stimulating factor treatment. 1043 76


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