UNIPROT:P04141 - FACTA Search

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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 biological effects of recombinant hematopoietic factors, which are considered to stimulate megakaryocytopoiesis in vitro or in vivo, were studied utilizing purified rat megakaryocytes. Recombinant human erythropoietin (rhEPO), recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF), and recombinant murine interleukin 3 (rmIL-3) stimulated both [3H]thymidine and [3H]leucine incorporation into purified rat megakaryocytes. In contrast, recombinant human interleukin 6 (rhIL-6) did not stimulate [3H]thymidine uptake but did increase [3H]leucine incorporation into purified rat megakaryocytes. These in vitro data suggest that DNA synthesis in megakaryocytes may be regulated by EPO, GM-CSF, and IL-3, and that protein synthesis is stimulated by EPO, GM-CSF, IL-3, and IL-6 in vitro.
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PMID:Biological effects of recombinant erythropoietin, granulocyte-macrophage colony-stimulating factor, interleukin 3, and interleukin 6 on purified rat megakaryocytes. 189 46

An in vitro colony assay was used to examine the growth stimulatory effects of a variety of recombinant human lymphohemopoietic cytokines on human precursor-B acute lymphoblastic leukemia (ALL) cells. Of 23 cases evaluated, 16 formed significant numbers of colonies (mean 280, range 36-939) when cultured in 10% fetal calf serum in 0.8% methylcellulose containing 10% partially purified B-cell growth factor (BCGF). Immunoperoxidase staining of cells from cultures confirmed a precursor-B phenotype (HLA-DR+, CD-10+, CD-19+, CD-34+, Ig-, CD-3-, CD-11C-). When these cases were cultured with recombinant human cytokines (but without BCGF) only a minority showed colony formation, in all instances less than seen with BCGF. Three cases were stimulated both by interleukin 3 (IL-3) and the putative pre-B growth factor interleukin 7 (IL-7). One case was stimulated both by tumor necrosis factor alpha and by interleukin 6 (IL-6); these results were confirmed on highly purified CD-10+, CD-19+ cells prepared by fluorescence-activated cell sorting. A further case was stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF), including CD-10+, CD-19+ purified cells. All cases responding to recombinant cytokines were heavily pretreated patients at relapse, whereas none of the newly diagnosed untreated cases showed any response. These results confirm that activities present in BCGF are the major stimulant for precursor-B ALL proliferation in vitro. None of the recombinant cytokines examined, including IL-7, appeared to have consistent activity under these culture conditions. The molecules regulating growth of ALL remain to be more precisely defined.
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PMID:Effects of recombinant human cytokines on precursor-B acute lymphoblastic leukemia cells. 189 54

Human interleukin 6 (IL-6) produced by molecular cloning was administered to nonhuman primates to assess its biological activities in vivo. Rhesus monkeys were treated s.c. with recombinant human (rh) IL-6 at 3 and 30 micrograms/kg body weight/day for 11 days, followed by the administration of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) at 5.5 micrograms/kg/day for 5 days. Serum levels of positively regulated acute phase proteins (APP) (C-reactive protein, alpha 1-antitrypsin, haptoglobin, and ceruloplasmin) increased, whereas negatively regulated APP (prealbumin) decreased in response to rhIL-6 treatment in a dose-dependent manner. Platelet counts rose after a latent period of 4-5 days following the start of rhIL-6 treatment, resulting in a maximum twofold increase above normal levels 2-3 days after the termination of the rhIL-6 treatment. Recombinant human IL-6 treatment induced a two to threefold rise in myeloid progenitor blood cell levels. The subsequent administration of rhGM-CSF to rhIL-6-pretreated animals did not increase the progenitor cell levels in blood above those found with rhGM-CSF treatment alone, indicating that rhIL-6 compared to recombinant human interleukin 3 (rhIL-3) has a minor proliferative effect on hematopoietic precursors in vivo. In conclusion, rhIL-6 was shown to be a potent stimulator of APP and was able to increase the number of platelets in circulation in nonhuman primates.
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PMID:Recombinant human interleukin 6 is a potent inducer of the acute phase response and elevates the blood platelets in nonhuman primates. 190 69

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

In a placebo-controlled double-blind dose-finding trial, 15 patients with ovarian cancer stage III or IV received daily s.c. 1.5, 3, or 6 micrograms/kg recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). At each dose step three patients received recombinant human GM-CSF, and two received placebo. Chemotherapy comprised 6 cycles of carboplatin, 300 mg/m2, and cyclophosphamide, 750 mg/m2, by i.v. bolus on day 1 every 4 weeks. GM-CSF, given on days 6-12 on an outpatient basis, raised the mean leukocyte count on days 7, 10, and 15 and the mean neutrophil count on days 7 and 10 at all dose levels as compared with the control group. Neutrophil counts of less than 0.5 x 10(9)/liter occurred in 20 of 22 cycles in the control group and in 5 of 17 cycles at the 6-micrograms/kg/day GM-CSF dose level (P less than 0.0005). In comparison with the control group, the mean eosinophil count was higher on days 10 and 15 at all GM-CSF doses, as was the mean monocyte count on day 15. The mean platelet count was raised at the 3- and 6-micrograms GM-CSF doses on days 15 and 22. Chemotherapy dose reduction or postponement due to myelotoxicity occurred in 9 of 28 cycles in the placebo groups versus 5 of 44 cycles in the GM-CSF group (not significant). Local skin infiltrates at the GM-CSF injection sites occurred in 8/9 patients, leading to premature removal of two patients from the study. Capillary leakage of 131I-albumin was increased in all patients 5 days after the first chemotherapy course but was not significantly affected by 4 days of GM-CSF treatment. Tumor necrosis factor alpha and C-reactive protein serum levels increased during GM-CSF administration at the 6-micrograms dose level, but interleukin 6 serum levels were not affected. We conclude that a dose of 3 and 6 micrograms/kg/day GM-CSF reduces the severity of neutropenia and thrombocytopenia after carboplatin-cyclophosphamide. This GM-CSF dose does not induce additional capillary leakage.
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PMID:A double-blind placebo-controlled study with granulocyte-macrophage colony-stimulating factor during chemotherapy for ovarian carcinoma. 198 77

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes the proliferation and differentiation of hematopoietic progenitor cells. Although preliminary data are available from clinical trials, the effect of GM-CSF on gene expression of immunocompetent cells in treated patients has not been studied. We previously demonstrated that in vitro treatment with GM-CSF also enhances maturation-related anti-tumor activities in mononuclear phagocytes. The purpose of the present study was to examine the effects of in vivo recombinant GM-CSF therapy on alveolar macrophages and blood monocytes, to determine if these cells demonstrated differential expression of cytokine genes, cytokine production, and tumoricidal activity. Alveolar macrophages and blood monocytes were isolated from 13 patients receiving a range of GM-CSF doses (60-250 micrograms/m2/day) by continuous infusion over a 2-week period. Both monocytes and macrophages were isolated prior to therapy and at day 10 of the infusion. Monocytes, in addition, were isolated on day 3 of infusion. Results indicated that GM-CSF therapy enhanced expression of tumor necrosis factor, interleukin 1, and interleukin 6 mRNA in both monocytes and alveolar macrophages. Differential responses, however, were observed in cytokine secretion; monocytes demonstrated enhanced secretion of all three cytokines by day 3 of treatment, but alveolar macrophages showed only enhanced interleukin 6 secretion at day 10. Monocyte tumoricidal activity after in vitro lipopolysaccharide stimulation was also significantly elevated by day 3 of treatment, but at day 10 activity was not statistically different from pretreatment values in either monocytes or alveolar macrophages. These data indicate that GM-CSF exerts striking time-dependent modulatory effects on gene expression and functional activities of monocytes and alveolar macrophages in vivo, although the responses of the two cell types differ with respect to cytokine secretion.
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PMID:Induction of cytokine messenger RNA and secretion in alveolar macrophages and blood monocytes from patients with lung cancer receiving granulocyte-macrophage colony-stimulating factor therapy. 198 25

The immunostimulant poly(A)-poly(U) induces a rapid enhancement of circulating colony-stimulating activity (CSA) in normal mice, culminating 2 h after i.v. injection. A dose of 200 micrograms per mouse is sufficient for a maximal effect. The colonies formed in response to sera from poly(A)-poly(U)-injected mice are mainly granulocytic with few macrophages. These sera are devoid of detectable interleukin 3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF), but contain large amounts of interleukin 6 (IL-6) that are perfectly correlated with circulating CSA levels. Although, in our hands, IL-6 alone induces no colony formation in the standard methylcellulose colony assay, it is nevertheless requisite for this biological activity because 1) monoclonal antibodies against IL-6 strongly diminish colony formation in response to sera from poly(A)-poly(U)-injected mice, and 2) recombinant (r)IL-6 induces colonies when tested in combination with low amounts of normal murine serum. At the concentrations used (0.3%-2.5%), the latter has no or a very slight effect alone. Low amounts of hematopoietic growth factors, that is, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), GM-CSF, or IL-3 that are almost ineffective in the absence of IL-6 can replace normal serum. Taken together, these data suggest that circulating IL-6, induced by i.v. injection of poly(A)-poly(U), promotes colony formation by interacting with serum components that might be identical with hematopoietic growth factors present in normal serum at subliminal concentrations. Finally, the involvement of lipopolysaccharide (LPS) in this phenomenon has been ruled out by the use of the low responder strain of mice (C3H/HeJ) that leads to similar results.
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PMID:Poly(A)-poly(U) induces circulating colony-stimulating activity resulting from interactions between endogeneous interleukin 6 and serum components. 205 90

Hallmarks of central nervous system (CNS) disease in AIDS patients are headaches, fever, subtle cognitive changes, abnormal reflexes, and ataxia. Dementia and severe sensory and motor dysfunction characterize more severe disease. Autoimmune-like peripheral neuropathies, cerebrovascular disease, and brain tumors are also observed. Histological changes include inflammation, astrocytosis, microglial nodule formation, and diffuse de- or dysmyelination. Focal demyelination can also be seen. It is clear that AIDS-associated neurological diseases are correlated with greater levels of HIV-1 antigen or genome in tissues. In AIDS dementia, macrophages and microglial cells of the CNS are the predominant cell types infected and producing HIV-1. However, manifestations of the disease make it unlikely that direct infection by HIV-1 is responsible. It seems more likely that the effects are mediated through secretion of viral proteins or viral induction of cytokines that bind to glial cells and neurons. HIV-1 induction of such cytokines as interleukin 1 (IL 1) and tumor necrosis factor-alpha (TNF alpha) may lead to an autocrine feedback loop involving further productive virus replication and induction of other cytokines such as interleukin 6 (IL 6) and granulocyte-macrophage colony-stimulating factor (GMCSF). Interleukin 1 and TNF alpha in combination with IL 6 and GMCSF could account for many clinical and histopathological findings in AIDS nervous system diseases. As HIV-1 infected patients produce elevated levels of IL 1, TNF alpha, and IL 6, it will be important to make a formal connection between the presence of these factors in the CNS, which are all products of activated macrophages, astroglia, and microglia, their in vivo induction directly by virus or indirectly by virus-induced intermediates, and the clinical and pathological conditions seen in the nervous system in this disease.
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PMID:HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease. 206 87

Arachidonic acid (AA) metabolism is implicated as an intracellular and/or intercellular second messenger system for the transmission of cytokine-initiated signals that affect neutrophils and mediate systemic toxicity. The purpose of the present study is to ascertain if cytokines that are known to affect neutrophil function in vivo and in vitro directly stimulate neutrophil AA metabolism in vitro. The recombinant human cytokines multi-colony stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1, tumor necrosis factor (TNF), and interleukin 6 and the calcium ionophore A23187 were incubated with purified 14C-AA radiolabeled human peripheral blood neutrophils and the effects were assayed by one- and two-dimensional thin layer lipid chromatography. None of the cytokines appeared to induce the release of cell-incorporated AA or to increase the level of radiolabeled phosphatidic acid. TNF induces severe systemic toxicity that is inhibited by cyclooxygenase inhibitors, which suggests a role for AA metabolites in the pathophysiologic effects of TNF; we have confirmed that TNF and endotoxin act synergistically to induce indomethacin-inhibitable fatal shock in rats. However, when in 3H-AA radiolabeled human neutrophils were incubated with TNF in kinetic, cold-chase, and TNF preincubation experiments, TNF was not found to increase AA metabolism, although changes in the intracellular neutral lipid content were noted. GM-CSF, which has been reported by previous investigators to directly induce the release of AA, did not release neutrophil-associated 3H-AA. In conclusion, the direct release of AA from membrane-associated phospholipids does not appear to be a major second messenger pathway for cytokine-initiated activation of neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokine- and calcium ionophore A23187-mediated arachidonic acid metabolism in neutrophils. 212 4

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a small glycoprotein growth factor which stimulates the production and function of neutrophils, eosinophils and monocytes. GM-CSF can be produced by a wide variety of tissue types, including fibroblasts, endothelial cells, T cells, macrophages, mesothelial cells, epithelial cells and many types of tumor cells. In most of these tissues, inflammatory mediators, such as interleukin 1, interleukin 6, tumor necrosis factor or endotoxin, are potent inducers of GM-CSF gene expression, which occurs at least partly by post-transcriptional stabilization of the GM-CSF mRNA. The biological effects of GM-CSF are mediated through binding to cell surface receptors, which appear to be widely expressed by hematopoietic cells and also by some non-hematopoietic cells, such as endothelial cells. Receptor expression is characterized by low number (20-200/cell) and high affinity (Kd = 20-100 pM). At least two different functional classes of GM-CSF receptor have been identified. The neutrophil GM-CSF receptor exclusively binds GM-CSF, while interleukin 3 competes for binding of GM-CSF to a second class of receptors detected on some leukemic cell lines, such as KG1 and MO-7E. Signal transduction involves activation of a tyrosine kinase and possibly G protein-coupled stimulation of Na+/H+ exchange. The exact relationship of the two receptors needs further clarification.
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PMID:The biology of GM-CSF: regulation of production and interaction with its receptor. 215 77

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