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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 influence of cytokines on extracellular superoxide dismutase (EC-SOD) expression by human dermal fibroblasts was investigated. The expression was markedly stimulated by interferon-gamma (IFN-gamma), was varying between fibroblast lines stimulated or depressed by interleukin-1 alpha (IL-1 alpha), was intermediately depressed by tumor necrosis factor-alpha (TNF-alpha), and markedly depressed by transforming growth factor-beta (TGF-beta). TNF-alpha, however, enhanced the stimulation by a high dose of IFN-gamma, whereas TGF-beta markedly depressed the stimulations given by IFN-gamma and IL-1 alpha. The ratio between the maximal stimulation and depression observed was around 30-fold. The responses were generally slow and developed over periods of several days. There were no effects of IFN-alpha, IL-2, IL-3, IL-4, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, human growth hormone, Escherichia coli lipopolysaccharide, leukotriene B4, prostaglandin E2, formylmethionylleucylphenylalanine, platelet-activating factor, and indomethacin. The cytokines influencing the EC-SOD expression are also known to influence superoxide production by leukocytes and other cell types, and the EC-SOD response pattern is roughly compatible with the notion that its function is to protect cells against extracellular superoxide radicals. The results show that EC-SOD is a participant in the complex inflammatory response orchestrated by cytokines. The CuZn-SOD activity of the fibroblasts was not influenced by any of the cytokines, whereas the Mn-SOD activity was depressed by TGF-beta. TNF-alpha, IL-1 alpha, and IFN-gamma stimulated the Mn-SOD activity, as previously known, and these responses were reduced by TGF-beta. The different responses of the three SOD isoenzymes illustrate their different physiological roles.
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PMID:Regulation by cytokines of extracellular superoxide dismutase and other superoxide dismutase isoenzymes in fibroblasts. 155 78

CD28 is a 44-kDa glycoprotein expressed as a homodimer on the surface of a major subset of human T cells. Previous studies have demonstrated that the binding of monoclonal antibodies to the CD28 surface antigen can augment the proliferation of purified human T cells stimulated with suboptimal doses of mitogens or anti-T-cell receptor/CD3 complex antibodies. In this report, we show that CD28 stimulation augments T-cell immune responses by specifically inducing a 5- to 50-fold enhancement in the expression and secretion of interleukin 2, tumor necrosis factor type alpha, lymphotoxin, interferon gamma, and granulocyte-macrophage colony-stimulating factor in normal human T cells stimulated to proliferate by crosslinking of the T-cell receptor/CD3 complex. This CD28-mediated induction of lymphokine/cytokine gene expression occurred even in T cells stimulated with optimal concentrations of mitogens or anti-T-cell receptor/CD3 antibodies, although under these conditions CD28 activation failed to enhance the proliferative response. The activation pathway induced by stimulation of CD28 is distinct from other biochemical pathways that induce lymphokines/cytokines because CD28 stimulation can induce lymphokine/cytokine gene expression in the presence of the immunosuppressant cyclosporine. Together these data suggest that the CD28 cell surface molecule is part of a distinct activation pathway that specifically modulates the expression of multiple lymphokine/cytokine genes.
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PMID:CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. 246 50

A cDNA coding for murine interleukin-5 (IL-5) was isolated from the EL4.ExC5 cell line. With the exception of a single amino acid substitution at position 79 (Arg----His), it is identical to a published sequence. The coding sequence for human IL-5 was synthesized chemically, allowing the introduction of strategically located restriction enzyme cleavage sites. Both cDNAs were expressed in various eukaryotic systems. Deletion of the 3' untranslated region of the murine IL-5 gene led to a 5- to 10-fold increase in expression in Xenopus laevis oocytes and in NIH-3T3 cells. The highest production, however, was obtained in Sf9 cells using a baculovirus vector. Human IL-5 was obtained from transformed Saccharomyces cerevisiae as a secreted, mature form using an in-frame fusion to the leader sequence of alpha-mating type factor, and was purified to homogeneity. In all cases mentioned, IL-5 was found to be glycosylated, and its biological activity was dependent on a 40- to 50-kD homodimer configuration, linked together by disulfide bridges. Deglycosylation did not affect the biological activity. Recombinant human IL-5 is biologically active on some human B-CLL cells (proliferation in the presence of IL-2) and on murine BCl1 cells (proliferation) at a low specific activity (about 1-2 x 10(3) U/mg) and on human eosinophils (eosinophil peroxidase assay) at a high specific activity (at least 5 x 10(6) U/mg). Recombinant murine IL-5 from Sf9 cells has a specific activity of 1-2 x 10(7) U/mg in the BCl1 proliferation assay. An additive effect is seen in the presence of murine granulocyte-macrophage colony-stimulating factor (GM-CSF) and a synergistic effect in the presence of murine IL-4.
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PMID:Expression of human and murine interleukin-5 in eukaryotic systems. 267 Apr 97

Signaling by a wide variety of cytokines, including interferons, interleukins, and growth factors, involves activation of JAK kinases and Stat (Signal transducers and activators of transcription) proteins. At present, not much is known about the molecular mechanisms by which interleukin-5 (IL-5) exerts its diverse biologic effects. Human eosinophils are one of the most important target cells for IL-5 and were used here to study IL-5 signaling in a primary human cell. IL-5 induced rapid and transient tyrosine phosphorylation of JAK2. Moreover, IL-5 induced at least two DNA-binding complexes, using nuclear extracts from normal human eosinophils and the IL-6/interferon-gamma response element of the ICAM-1 promoter (ICAM-1 pIRE) in an electromobility shift assay. From supershift experiments it was concluded that one DNA-binding complex contained Stat1 alpha, probably as a homodimer. Both DNA-binding complexes were inhibited by a phosphotyrosine antibody (4G10), suggesting that tyrosine phosphorylation is required for complex formation. IL-3 and granulocyte-macrophage colony-stimulating factor induced, similar to IL-5, two DNA-binding complexes in human eosinophils, including Stat1 alpha. These data show for the first time that molecular mechanisms of IL-5 signaling in human eosinophils involve members of the JAK kinase family as well as members of the Stat family.
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PMID:Interleukin-5 signaling in human eosinophils involves JAK2 tyrosine kinase and Stat1 alpha. 788 66

The mechanism of growth inhibition mediated by tumor necrosis factor (TNF) is unclear. Since recent data strongly suggested that generation of superoxide is a key step in cytotoxicity of TNF, we reasoned that cells expressing high levels of enzymes that degrade superoxide radicals would be resistant to TNF. Therefore, we examined the TNF-sensitivity of bone marrow progenitor cells of transgenic mice that expressed the gene for human copper zinc-superoxide dismutase (CuZn-SOD). The CuZn-SOD is a key enzyme in the metabolism of superoxide radicals. Heterozygous and homozygous transgenic mice had 3- and 5-fold increased levels of CuZn-SOD activity, respectively. Bone marrow cells of transgenic and nontransgenic mice were plated in soft gel culture with TNF (0.01-100 ng/ml). TNF inhibited myeloid colony formation supported by either granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF from nontransgenic mice in a dose-dependent manner. In contrast, the myeloid clonal growth of homozygote transgenic mice was not inhibited by TNF at concentrations up to 100 ng/ml. As expected, the effects of TNF on erythroid clonogenic cells, which do not produce superoxide, and the action of transforming growth factor-beta on myeloid progenitor cells, were similar in both transgenic and nontransgenic mice. These results suggest that the mechanism of TNF-mediated growth inhibition of hematopoietic cells occurs through production of superoxide.
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PMID:Hematopoietic progenitor cells of transgenic mice with increased copper/zinc-superoxide dismutase activity are resistant to tumor necrosis factor. 804 Jan 83

Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) receptor (hGMR) consists of alpha and beta subunits, and the precise stoichiometry of these subunits has remained to be determined. In this work, oligomerization of the beta subunit was studied using a chemical cross-linker. In Ba/F3, a mouse interleukin-3-dependent cell line expressing both subunits of hGMR (Ba/F3-alpha,beta), a protein with a molecular mass corresponding to that of a homodimer of the beta subunit (beta homodimer) was detected only when cells were treated with the cross-linker. Dimerization of the beta subunit was confirmed by coimmunoprecipitation of a tagged beta subunit with the wild type beta subunit COS7 cells. The beta homodimer had already formed in the absence of hGM-CSF, whereas stimulation with the ligand brought both alpha and beta subunits into a complex, the result being tyrosine phosphorylation of the beta homodimer. Tyrosine phosphorylation of the subunit was impaired by deletion of the cytoplasmic domain of the alpha subunit without interfering with the association of both subunits. These results indicate that the beta homodimer, which alone is insufficient for signaling, forms the functional hGMR with the alpha subunit in response to hGM-CSF.
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PMID:The beta subunit of human granulocyte-macrophage colony-stimulating factor receptor forms a homodimer and is activated via association with the alpha subunit. 866 48

Colony-stimulating factor (CSF-1) activates several members belonging to the STAT (signal transducers and activators of transcription) family of transcription factors. We investigated the DNA binding complexes activated by CSF-1 in several cell lines and compared them with complexes activated by platelet-derived growth factor and interleukin 3. Our results indicate that the SIF-A complex activated by CSF-1 and platelet-derived growth factor may contain STAT3/STAT5 heterodimers binding to the high affinity SIF binding site, m67. In addition, both growth factors activate one or several STAT5-containing protein complexes binding to the prolactin-inducible element, PIE. The formation of these complexes was cell type and growth factor specific. Interleukin 3 activated only PIE binding complexes containing STAT5A and STAT5B and did not activate m67 binding complexes. It appears, therefore, that STAT5 cannot bind to m67 as a homodimer, but it can bind if it is dimerized with STAT3, whereas it can bind to the PIE element without being either complexed with STAT3 or any other known STAT protein, possibly as a homodimer or as STAT5A/STAT5B heterodimer. However, in addition, STAT5 may heterodimerize with other proteins and form novel PIE binding complexes.
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PMID:Formation of STAT5-containing DNA binding complexes in response to colony-stimulating factor-1 and platelet-derived growth factor. 870 76

Granulocyte-macrophage colony-stimulating factor receptor signals by a complex which includes the ligand and two different receptor subunits: a low affinity alpha receptor binding chain (granulocyte-macrophage colony-stimulating factor receptor alpha subunit (GM-Ralpha)) and a signal-transducing beta chain (GM-Rbeta). To investigate two unresolved issues in the initiation of signaling, the role of receptor extracellular domains and receptor stoichiometry, we replaced the mouse GM-Ralpha and GM-Rbeta extracellular domains with the leucine zipper domain of either the Fos or Jun molecule. We co-transfected combinations of chimeric receptors into Ba/F3 cells and found that both simple heterodimers of the GM-Ralpha and GM-Rbeta intracellular domains and homodimers of the GM-Rbeta intracellular domain signaled for proliferation. Surprisingly, homodimers of the GM-Ralpha intracellular domain also signaled for prevention of apoptosis in transfected cells. We similarly engineered dimers of the intracellular domain of the human interferon gamma receptor beta subunit and found that homodimers of the intracellular domain signaled for proliferation. When Fos peptide was added to Ba/F3 cells expressing the human interferon gamma receptor beta subunit construct, thereby preventing homodimer formation, the cells no longer proliferated in the absence of mouse interleukin 3.
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PMID:Functional replacement of cytokine receptor extracellular domains by leucine zippers. 894 1

The stoichiometry of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor complex is still unresolved. We have utilised a sensitive, functional assay for receptor homodimerisation to show that GM-CSF induces dimerisation of the common signalling subunit, hbeta(c). We generated a chimeric cytokine receptor in which the extracellular and transmembrane domains of hbeta(c)are fused to the cytoplasmic domain of erythropoietin receptor (EPO-R). Given that to induce EPO-R activation and mitogenic signalling there is a requirement for formation of a specific homodimeric complex, we reasoned that the cytoplasmic domain of EPO-R could be utilised as a highly sensitive reporter for functional homodimer formation. We show that, in the presence of a cytoplasmically truncated GM-CSF alpha-subunit, the hbetac-EPO receptor chimera transduces a mitogenic signal in BaF-B03 in response to GM-CSF. This is consistent with formation of a hbeta(c)homodimer following GM-CSF binding and implies that ligand stimulation induces formation of a higher order complex that contains the hbeta(c)homodimer.
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PMID:GM-CSF binding to its receptor induces oligomerisation of the common beta-subunit. 1123 32

Interleukin-3 (IL-3) is a cytokine produced by activated T-cells and mast cells that is active on a broad range of hematopoietic cells and in the nervous system and appears to be important in several chronic inflammatory diseases. In this study, alanine substitutions were used to investigate the role of residues of the human beta-common (hbetac) receptor and the murine IL-3-specific (beta(IL-3)) receptor in IL-3 binding. We show that the domain 1 residues, Tyr(15) and Phe(79), of the hbetac receptor are important for high affinity IL-3 binding and receptor activation as shown previously for the related cytokines, interleukin-5 and granulocyte-macrophage colony-stimulating factor, which also signal through this receptor subunit. From the x-ray structure of hbetac, it is clear that the domain 1 residues cooperate with domain 4 residues to form a novel ligand-binding interface involving the two protein chains of the intertwined homodimer receptor. We demonstrate by ultracentrifugation that the beta(IL-3) receptor is also a homodimer. Its high sequence homology with hbetac suggests that their structures are homologous, and we identified an analogous binding interface in beta(IL-3) for direct IL-3 binding to the high affinity binding site in hbetac. Tyr(21) (A-B loop), Phe(85), and Asn(87) (E-F loop) of domain 1; Ile(320) of the interdomain loop; and Tyr(348) (B'-C' loop) and Tyr(401) (F'-G' loop) of domain 4 were shown to have critical individual roles and Arg(84) and Tyr(317) major secondary roles in direct murine IL-3 binding to the beta(IL-3)receptor. Most surprising, none of the key residues for direct IL-3 binding were critical for high affinity binding in the presence of the murine IL-3 alpha receptor, indicating a fundamentally different mechanism of high affinity binding to that used by hbetac.
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PMID:Interleukin-3 binding to the murine betaIL-3 and human betac receptors involves functional epitopes formed by domains 1 and 4 of different protein chains. 1506 62


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