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 crystal structure of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has been determined at 2.8 A resolution using multiple isomorphous replacement techniques. There are two molecules in the crystallographic asymmetric unit, which are related by an approximate non-crystallographic 2-fold axis. The overall structure is highly compact and globular with a predominantly hydrophobic core. The main structural feature of rhGM-CSF is a four alpha-helix bundle, which represents approximately 42% of the structure. The helices are arranged in a left-handed antiparallel bundle with two overhand connections. Within the connections is a two-stranded antiparallel beta-sheet. The tertiary structure of rhGM-CSF has a topology similar to that of porcine growth factor and interferon-beta. Most of the proposed critical regions for receptor binding are located on a continuous surface at one end of the molecule that includes the C terminus.
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PMID:Three-dimensional structure of recombinant human granulocyte-macrophage colony-stimulating factor. 156 68

The recombinant cytokines are increasingly important therapeutic agents for patients with AIDS. Recombinant interferon-alpha has demonstrated antitumor and antiretroviral activities in patients with Kaposi's sarcoma. Limited studies with interferon-beta suggest that it also has antitumor effects in patients with Kaposi's sarcoma, but interferon-gamma appears to be ineffective in controlling this tumor. The hematopoietic growth factors, including erythropoietin, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been evaluated in several populations of human immunodeficiency virus (HIV)-infected individuals. The combination of G-CSF and recombinant human erythropoietin completely reversed the zidovudine-induced neutropenia of AIDS patients but was only partially effective in reversing anemia. In several clinical trials, GM-CSF induced marked increases in leukocyte counts and improved neutrophil function in some AIDS patients. In severely immunocompromised patients with disease caused by HIV who were receiving therapy with either G-CSF or GM-CSF, opportunistic infections continued to occur despite increases in circulating white blood cell counts. Recombinant cytokines may be used in the future in AIDS patients as adjunctive treatment with myelosuppressive antibiotics and chemotherapeutic drugs, as a possible means of enhancing host defense, or as agents of immune reconstitution.
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PMID:Use of recombinant interferons and hematopoietic growth factors in patients infected with human immunodeficiency virus. 196 13

The K562 cell line provides a unique population of primitive human myeloid leukaemia cells which can be induced to differentiate along the erythroid, granulocytic, macrophage and megakaryocytic lineages in response to several agents. Cytarabine is not only the most widely used drug in the treatment of myeloid leukaemia but also the most effective agent in K562 cells. The effects of five recombinant human cytokines - interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-alpha, interferon-beta and interferon-gamma on cytarabine-induced growth inhibition and differentiation of K562 cells was studied in liquid suspension cultures. GM-CSF and to a lesser extent IL-3 enhanced the antiproliferative effect of cytarabine in K562 cells, whereas the three interferons reduced it. The efficacy of cytarabine in inhibiting the growth of K562 cells was doubled by its combination with GM-CSF or IL-3 but was halved by its combination with interferons. The five cytokines did not significantly affect cytarabine-induced erythroid differentiation of K562 cells. The present results appear to favour the use of GM-CSF and IL-3 but not of interferons in future treatment strategies based on a combined cytokine and chemotherapy approach for myeloid leukaemia.
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PMID:Effects of recombinant human cytokines on cytarabine activity in K562 human myeloid leukaemia cells. 176 Sep 44

Interleukin-1 (IL-1) has been reported previously to inhibit the in-vitro decidualization of human endometrial stromal cells as assessed by progesterone-induced prolactin production and morphological transformation. In this study we examined whether other cytokines, such as tumour necrosis factor-alpha (TNF alpha), interferon-beta (IFN beta), IFN gamma or granulocyte-macrophage colony-stimulating factor (GM-CSF), could affect the decidualization of human endometrial stromal cells in vitro. Of these cytokines, TNF alpha significantly suppressed prolactin production in a dose-dependent manner, with no apparent effect on cell number. The morphological transformation of endometrial stromal cells was also inhibited by TNF alpha. TNF alpha and IL-1 significantly suppressed cAMP-stimulated prolactin production by endometrial stromal cells. Neither the progesterone concentration in the supernatant of the endometrial stromal cell culture system nor intracellular calcium concentration of the endometrial stromal cells were affected by the addition of TNF alpha or IL-1. These results indicated that TNF alpha and IL-1 suppress both progesterone-induced and cAMP-mediated prolactin production in endometrial stromal cells, and that this inhibition was not attributable to direct effects on progesterone metabolism or related to Ca(2+)-mediated signal transduction. These experiments suggested that a local increase of TNF alpha and IL-1 under certain pathological conditions in vivo may disturb blastocyst implantation and/or the maintenance of pregnancy by inhibiting the decidualization of endometrial stromal cells.
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PMID:Tumour necrosis factor alpha inhibits in-vitro decidualization of human endometrial stromal cells. 771 66

To evaluate the effects of inflammatory cytokines on oxidative production in normal neutrophils, seven kinds of cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin-2 (IL-2), IL-6, IL-1 alpha, IL-1 beta, and interferon-beta (IFN-beta) were tested. The intracellular hydrogen peroxide (H2O2) in individual cells was determined by flow cytometry. According to the levels of intracellular H2O2 enhanced by cytokines, these seven cytokines were classified into three types: (1) prominently effective--GM-CSF; (2) moderately effective--G-CSF, IL-6, and IL-2; (3) weakly or ineffective--IFN-beta, IL-1 alpha, and IL-1 beta. Changes in cell size and cell surface structure after stimulation of those seven cytokines were simultaneously measured by flow cytometry. The most prominently effective cytokine, GM-CSF, initially caused enlargement of cell size and irregularity of the cell surface and subsequently increased H2O2 production by neutrophils. In contrast, the weakly or ineffective cytokines, like IL-1 beta, had no effects on cell size or cell surface. Our study indicates that some kinds of cytokines enhance oxidative production and cause morphological changes in neutrophils.
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PMID:An evaluation of the effects of cytokines on intracellular oxidative production in normal neutrophils by flow cytometry. 826 56

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

An algorithm for the rigid-body superposition of proteins is described and tested. No prior knowledge of equivalent residues is required. To find the common structural core of two proteins, an exhaustive grid search is conducted in three-dimensional angle space, and at each grid point a fast translation search in three-dimensional space is performed. The best superposition at a given angle set is defined by that translation vector which maximizes the weighted number of equivalent C alpha atoms. Filters using the information about the sequential character of the polypeptide chain are employed to identify that rotation and translation which yields the highest topological similarity of the two proteins. The algorithm is shown to find the best superposition of distantly related structures, and to be capable of finding similar structures to a given atomic model in the Brookhaven Protein Data Bank. In a search using granulocyte-macrophage colony-stimulating factor as a template, all other four-helix bundle cytokines with up-up-down-down topology were found to give the highest values of a topological similarity score, followed by interferon-beta and -gamma and those four-helix bundles with the more common up-down-up-down topology. In another example, the insertion domain of the long variant adenylate kinases is demonstrated to share its fold with rubredoxin.
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PMID:Structural superposition of proteins with unknown alignment and detection of topological similarity using a six-dimensional search algorithm. 859

We studied the effects of interferon-beta (IFN-beta) on the differentiation of dendritic cells (DC) obtained by culturing plastic-adherent peripheral blood mononuclear cells (PBMC) from a total of 30 healthy volunteers in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). First, we found that the addition of IFN-beta at the initiation of the culture did not modify DC morphology but caused a reproducible and statistically significant upregulation of HLA-DR, CD86, and CD80 surface expression. CD1a expression was significantly reduced, and CD40 expression was unchanged. We then determined the influence of IFN-beta on the production of cytokines by DC. DC differentiated in the presence of IFN-beta secreted significantly less IL-12 (p40 and p70) both spontaneously and on activation by fibroblasts transfected with the CD40L gene. This effect of IFN-beta was dose dependent and selective, as it was not observed for IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha). As a consequence, DC differentiated in the presence of IFN-beta induced significantly less IFN-gamma secretion by alloreactive T cells, whereas they were more efficient than control DC in eliciting IL-5 secretion. We conclude that the direct action of IFN-beta on DC causes inhibition of their ability to secrete IL-12 in response to CD40 ligation and to elicit Th1 type responses.
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PMID:IFN-beta interferes with the differentiation of dendritic cells from peripheral blood mononuclear cells: selective inhibition of CD40-dependent interleukin-12 secretion. 1038 59

We studied the secretion of gelatinase B by dendritic cells (DC) generated by culturing human peripheral blood monocytes in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). First, we found the intracellular expression of gelatinase B on sections of fixed DC pellets. Zymography analysis of the supernatants of DC cultured for 72 h demonstrated the presence of gelatinase B. To determine if DC produce net enzymatic activity, bioactive gelatinase, a novel sensitive fluorescent-activated substrate conversion (FASC) assay was used to complement the zymography data. Culture media of unstimulated DC demonstrated reproducible net gelatinolytic activity. Tumor necrosis factor-alpha (TNF-alpha) IL-1beta but not lipopolysaccharide (LPS) stimulation caused a significant increase in gelatinase B production in zymography analysis. Both types of stimulation failed to increase net gelatinase activity in FASC assay. Interestingly, interferon-beta (IFN-beta) significantly diminished both the total zymolytic production and the net bioactive gelatinase produced by DC in a dose-dependent manner. We conclude that human monocyte-derived DC secrete bioactive gelatinase B and that IFN-beta inhibits this production.
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PMID:Human monocyte-derived dendritic cells produce bioactive gelatinase B: inhibition by IFN-beta. 1150 43

Dendritic cells (DCs) represent a promising tool for immunotherapy. A key feature in their action is to provide co-stimulatory signals for full activation of T cells. In view of recent studies demonstrating the critical role of 4-1BB co-stimulation in T cell response, it is of importance to optimize 4-1BB ligand (4-1BBL) expression on human monocyte-derived DCs (MDDCs), the DC source of many clinical studies. In this study, two types of MDDCs, generated in granulocyte-macrophage colony-stimulating factor and interleukin-4 (GM-CSF/IL-4-DCs) or in interferon-beta and IL-3 (IFN-beta/IL-3-DCs), were analyzed for 4-1BBL expression in response to several known DC activators. Immature MDDCs expressed 4-1BBLs at very low levels. Lipopolysaccharide (LPS) was the only activator that preferentially triggered 4-1BBL expression on either MDDCs, but 4-1BBL-positive cells were significantly more frequently observed on LPS-activated GM-CSF/IL-4-DCs (30.2+/-2.6% versus 14.3+/-1.2%). Combinations of multiple activating signals did not bring about enhanced 4-1BBL stimulatory capacity. In addition, plasmid DNA transfection and necrotic cell pulsing of GM-CSF/IL-4-DCs for antigen loading also resulted in 4-1BBL up-regulation. However, in all circumstances, the induced 4-1BBL levels were low in comparison with CD80 co-stimulatory molecule. Finally, by demonstrating LPS-matured GM-CSF/IL-4-DCs from sorted 4-1BBL(high) population augmented T cell expansion and survival, we propose that efforts are required to increase 4-1BBL levels on MDDCs achieved by current activation schemes.
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PMID:Lipopolysaccharide preferentially induces 4-1BB ligand expression on human monocyte-derived dendritic cells. 1468 28


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