UNIPROT:P04141 - FACTA Search

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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
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The repertoire of cytokine and cytokine receptor mRNA expressed by unstimulated human thymocytes and thymic stromal cells was explored by a quantitative polymerase chain reaction (PCR) using sequence specific internal standards. Of the 18 cytokines tested we found a considerable overlap in the expression of cytokines by human thymocytes and by thymic stromal cells; both cell types express the mRNA for interleukin-1 beta(IL-1, IL-6, IL-7 and tumour necrosis factor-alpha (TNF-alpha). However, there are substantial differences in the levels of cytokine mRNA expressed in these two types of cells as revealed by the quantitative PCR assay. Stromal cells express considerably higher levels of IL-1 beta and IL-6 than thymocytes (14- and 27-fold respectively). In addition, a number of cytokines such as lymphotoxin and interferon-gamma (IFN-gamma), are expressed exclusively in thymocytes whereas others such as stem cell factor (SCF), IL-1 receptor antagonist-2 (IRAP-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are produced only in stromal cells. There is a complete overlap in the expression of a group of cytokine receptors tested in thymocytes and thymic stromal cells; these include IL-1R, IL-2R, IL-6R, IL-7R, TNFR and stem cell growth factor receptor (c-KIT). The expression of specific cytokines by thymic stromal cells and the parallel expression of their receptors on thymocytes under physiological conditions, support the hypothesis that these cytokines participate in paracrine interactions between these two cell populations during thymocyte differentiation.
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PMID:Expression of cytokines and their receptors by human thymocytes and thymic stromal cells. 133 59

The objective of these experiments was to evaluate the production of IL-1ra, a specific receptor antagonist of IL-1, by human in vitro-derived macrophages, a model for differentiated macrophages. IL-1ra protein levels in supernatants and lysates of cultured cells were determined by a specific ELISA. Relative steady-state IL-1ra mRNA levels were measured using a specific cDNA probe. Human monocytes were differentiated by 6 days culture in either medium or granulocyte-macrophage colony-stimulating factor (GM-CSF), after which the effects of subsequent LPS and/or GM-CSF on the production of IL-1ra were evaluated. In vitro-derived macrophages cultured in medium for 6 days constitutively produced IL-1ra protein during the 24-h period of the 7th day in culture. The constitutive production of IL-1ra by medium-aged cells correlated with low steady-state IL-1ra mRNA levels determined over this same time period. In contrast, cells cultured for 6 days in GM-CSF synthesized significantly increased levels of IL-1ra protein during the 7th day in culture but the secreted levels remained unchanged. Cells differentiated in GM-CSF displayed enhanced steady-state levels of IL-1ra mRNA in comparison with cells aged in medium. Stimulation of in vitro-derived macrophages aged for 6 days in medium or in GM-CSF, with LPS or adherent IgG, did not result in increased levels of IL-1ra protein production in comparison with non-LPS stimulated cells. The IL-1ra protein detected in the supernatants of cells differentiated in GM-CSF was biologically active in the IL-1-augmented murine thymocyte proliferation assay. By Western blot analysis, the IL-1ra protein in the in vitro-derived macrophage supernatants was predominantly the 22- to 24-kDa glycosylated species, whereas the lysates contained additional lower molecular weight forms. These results suggest that as monocytes differentiate in vitro into macrophages, they constitutively produce IL-1ra protein and that this production is enhanced by the continuous presence of GM-CSF.
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PMID:Production of IL-1 receptor antagonist by human in vitro-derived macrophages. Effects of lipopolysaccharide and granulocyte-macrophage colony-stimulating factor. 183 81

An immunohistochemical technique was used to examine whether there was a colocalization of cytokine-specific receptors with cytokine-expressing cells. We have previously shown that there is extensive cytokine production and secretion in the rectal mucosa in shigellosis (interleukin 1 alpha [IL-1 alpha], IL-1 beta, IL-1ra, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha [TNF-alpha], TNF-beta, gamma interferon, granulocyte-macrophage colony-stimulating factor, and transforming growth factor beta [TGF-beta]) (R. Raqib, A. A. Lindberg, B. Wretlind, P. K. Bardhan, U. Andersson, and J. Andersson, Infect. Immun. 63:289-296, 1995; R. Raqib, B. Wretlind, J. Andersson, and A. A. Lindberg, J. Infect. Dis. 171:376-384, 1995). Kinetics for receptor expression was compared with that for cytokine synthesis in the inflamed rectal mucosa from Shigella-infected patients during acute (2 to 6 days after onset of diarrhea) and convalescent (30 to 40 days after onset) stages. Quantification of receptor expression was assessed by computer-assisted analysis of video microscopic images. A selective down-regulation of the receptors for gamma interferon, tumor necrosis factor (TNF receptor [TNFR] type I), IL-1 (IL-1 receptor [IL-1R] types I and type II), IL-3, IL-4, and TGF-beta (TGF-beta receptor type I) was observed at the onset of the disease, with a gradual reappearance during the convalescent stage. However, IL-2R, IL-6R, granulocyte-macrophage colony-stimulating factor receptor, TNFR type II, and TGF-beta receptor type II showed no change in expression during the study period and were comparable to controls. Cytokine receptors were predominantly located to the epithelial layer of the mucosal surface and crypts, with variable expression patterns in the lamina propria. A time-dependent kinetic curve was seen for the soluble IL-2R (sIL-2R), sIL-6R, and sTNFR types I and type II shed in stool at the acute stage similar to that observed for cytokine secretion in stool but at four- to six-times-lower concentration. In contrast, soluble receptor levels in plasma were 100-fold higher than the cytokine levels. The results suggest a dissociation in immune regulation between cytokine production and cytokine receptor expression. The down-regulation of the receptors in acute shigellosis was probably a consequence of cytokine-induced internalization and shedding of the receptors during signal transduction as well as due to programmed regulatory roles played by cytokines and the bacterial antigens.
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PMID:Down-regulation of gamma interferon, tumor necrosis factor type I, interleukin 1 (IL-1) type I, IL-3, IL-4, and transforming growth factor beta type I receptors at the local site during the acute phase of Shigella infection. 762 34

Accumulating data indicate that cytokines, peptides involved in regulation of both physiological and pathological immune responses, are produced predominantly at the site of local antigen stimulation. Cytokine-producing cells were detected at the protein level in human tonsil tissue obtained from children with recurrent tonsillitis or infectious mononucleosis (IM). Concomitant production of 19 different human cytokines, interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-1 receptor antagonist (ra), IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, tumour necrosis factor-alpha (TNF-alpha), TNF-beta, interferon-gamma (IFN-gamma) and transforming growth factor-beta 1-3 (TGF-beta 1-3), was identified at a single-cell level by indirect immunohistochemical staining procedures and use of carefully selected cytokine-specific antibodies (Ab). Fresh frozen sections were fixed with 4% paraformaldehyde and permeabilized by 0.1% saponin treatment, eluting cholesterol from the cell-surface membrane and the Golgi complex. The intracellular localization of all cytokines, except IL-1 and IL-1ra, was demonstrated by a characteristic local cytoplasmic perinuclear configuration in producer cells. In addition, the immunoreactivity for certain cytokines (IL-2, IL-4, IL-5, G-CSF and GM-CSF) was expressed on the cell membranes and extended over a large extracellular area encompassing the producer cell. Localization of the cytokine to the Golgi organelle was established by co-staining with a monoclonal antibody (mAb) specific to the Golgi complex. Both the extra- and intracellular cytokine staining reactions could be blocked by preincubation of the cytokine-specific Ab with the corresponding purified natural or recombinant cytokine. A complex cytokine pattern was established in both groups studied, where most T-helper type 1 (Th1) and Th2 lymphokines were expressed in the tonsils but at different frequencies and localizations. Cells expressing IL-4, IL-5, IL-10 and IL-13, (Th2 response) were evident at higher frequencies in recurrent tonsillitis compared to sections from IM, which were associated with a more pronounced IL-2, IFN-gamma and TNF-beta expression.
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PMID:Concomitant in vivo production of 19 different cytokines in human tonsils. 782 61

In this study, we demonstrate that mononuclear cells of human milk have a potential for production of many different cytokines. We applied a technique for cytokine detection at the single-cell level using cytokine specific MAb and immunofluorescence. The characteristic staining pattern obtained represents intracellular cytokine production, which allows for the assessment of the cellular origin of production. Milk mononuclear cells were mitogen-stimulated in vitro and cultured for 4 h and then stained for 13 cytokines. Lipopolysaccharide stimulation induced extensive production of the following monokines: IL-1 alpha, IL-1 beta, IL-1ra, IL-6, IL-8, and tumor necrosis factor-alpha. IL-10 and granulocyte-macrophage colony-stimulating factor were smaller products, although detectable in most samples. The abundant monokine production correlated with the high number of macrophages in milk. Spontaneous monokine production in unstimulated cells could be detected in six out of 11 samples. The highest incidence was evident for IL-8. No spontaneous lymphokine production was detected. Considering the low proportion of lymphocytes, stimulation with phorbol myristate acetate in combination with ionomycin resulted in considerable production of the following lymphokines: IL-2, IL-3, IL-4, IL-10, interferon-gamma, tumor necrosis factor-alpha. Macrophages contributed to the high production of tumor necrosis factor-alpha and GM-CSF. IL-5 synthesis was detectable in only one sample. This work reveals that human milk mononuclear cells are potent producers of cytokines when mitogen stimulated in vitro. The in vivo implications of these findings remain to be investigated further.
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PMID:Cytokine production in mononuclear cells of human milk studied at the single-cell level. 823 27

Bacterial superantigens are the most potent known activators of human T lymphocytes. To engineer superantigens for immunotherapy of human colon carcinoma, the superantigen, staphylococcal enterotoxin A (SEA) was genetically fused to the Fab region of the colon carcinoma-reactive monoclonal antibody C242. In the present study the effector mechanisms involved in the anti-tumor response to C242 Fab-SEA were characterized. Immunohistochemistry and computer-aided image analysis were used in studies of cryopreserved tumor tissue to evaluate the phenotype of infiltrating cells and their cytokine profiles in response to therapy. Human T cells and monocytes were recruited to the tumor area and penetrated the entire tumor mass within hours after injection of C242 Fab-SEA. The production of cytokines at the single-cell level was found to be dominated by tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor, and transforming growth factor-beta, whereas IL-1-alpha, IL-1ra, IL-1 beta, TNF-beta, IL-3, IL-6, and IL-8 were undetectable. Most of the TNF-alpha, IL-2, IL-12, and IFN-gamma were made by the infiltrating human leukocytes, while the colon carcinoma cells were induced to produce IL-4, IL-10, and TNF-alpha. Up-regulation of IFN-gamma receptors and TNF R p60 receptors was found, while the TNF R p80 receptor was absent. The cytokine production, T cell infiltration, and CD95 Fas receptor expression concomitantly occurred to induce programmed cell death in the tumor cells. This was followed by a strong reduction of the tumor mass that was seen within 24 h after C242 Fab-SEA infusion. These findings demonstrate that antibody-superantigen proteins efficiently recruit tumor-infiltrating lymphocytes actively producing a variety of cytokines likely to be essential for the therapeutic effects observed in the model. Although the humanized SCID model has obvious limitations in its predictive value for treatment of human cancer, we believe that these results encourage clinical evaluation of antibody-targeted superantigens.
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PMID:Antibody-targeted superantigen therapy induces tumor-infiltrating lymphocytes, excessive cytokine production, and apoptosis in human colon carcinoma. 856 49

A technique using a computerized image analysis system was developed for evaluating and quantifying human cytokine production. This system registered single cells as positive or negative cytokine producers based on a specific juxtanuclear staining pattern generated by accumulation of the proteins in the Golgi-endoplasmatic reticulum compartment. The characteristic morphology of the immunocytochemical staining offered the opportunity to register individual producer cells within multicomponent cell populations. A color camera was then adapted to transfer on-line images directly into the computer-controlled operating system. In this study cultured human peripheral blood mononuclear cells were polyclonally stimulated and then analyzed for interleukin-1alpha (IL-1alpha), IL-1beta, IL-1ra, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-alpha), TNF-beta, interferon-gamma, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor production. The image-analyzing system detected cytokine-producing cells in a sensitive and reproducible manner, which was in total congruence with enumeration by conventional microscopy. Furthermore, accurate assessments of cell distributions by signal intensity and cell area were applied at the single-cell level. The image-analyzing system allowed the detection of at least 1 in 1,000 events by using unique cytokine-associated morphometric criteria. The results of kinetic studies measuring cytokine production following activation and cell transformation provided data supporting increases in intensity of intracellular localized specific immunostaining and in cell size within the cytokine-producing cells.
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PMID:Computerized assessment of production of multiple human cytokines at the single-cell level using image analysis. 860 2

A proportion of HIV-infected individuals experience episodes of localized or systemic bacterial infections caused by Gram-negative bacteria. Many of the clinical side effects of these infections are associated with the production of proinflammatory cytokines, which are induced primarily by LPS, a constituent of the bacterial cell wall of Gram-negative bacteria. The present study examines the mechanisms involved in LPS-mediated induction of HIV expression in U1 cells, a promonocytic cell line chronically infected with HIV. Stimulation of U1 cells by LPS alone induced minimal levels of HIV expression, which was significantly enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF). Costimulation of U1 cells with LPS plus GM-CSF resulted in the accumulation of steady-state levels of HIV RNA; however, only a weak induction of HIV long terminal repeat-driven transcription, which was not associated with the activation of the cellular transcription factor nuclear factor-kappa B, was noted. Costimulation of cells with LPS plus GM-CSF induced the production of proinflammatory cytokines, IL-8, IL-1 beta and IL-6, but not TNF-alpha. IL-1 receptor antagonist (ra) inhibited LPS enhancement of HIV expression in GM-CSF-stimulated cells, suggesting that endogenous IL-1 was involved in LPS-mediated viral production. In this regard, anti-inflammatory cytokines inhibited LPS plus GM-CSF-stimulated HIV expression, and this effect closely correlated with inhibition of IL-1 beta release and, in particular, with up-regulation of endogenous IL-1ra production. Thus, the balance between an endogenously produced viral inducer (IL-1 beta ) and an inhibitor (IL-1ra) may represent an important pathway leading to modulation of HIV expression from monocytic cells.
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PMID:Modulation of endogenous IL-1 beta and IL-1 receptor antagonist results in opposing effects on HIV expression in chronically infected monocytic cells. 861 79

Murabutide is a synthetic muramyl peptide which is in clinical stage of development. Its effect on cytokine production was analysed in human whole blood to reproduce the natural environment. Induced gene transcription within 2 h was associated with the release of cytokines such as tumour necrosis factor (TNF), interleukin-1 beta (IL-1 beta), IL-6, IL-8, and also the anti-inflammatory mediator IL-1ra. This synthesis was not associated with the release of IL-4, IL-12, interferon gamma (IFN-gamma), the three colony-stimulating factors (CSFs) or the soluble TNF receptors. The same series of cytokines were assayed to determine the effect of some recombinant cytokines in association with murabutide. Thus, in the presence of IL-2, IL-6, IL-3 or granulocyte-macrophage colony-stimulating factor (GM-CSF), the level of cytokines induced by murabutide was enhanced with no change in the other cytokines profile. IL-3 and GM-CSF were more potent in increasing the murabutide-induced response, eliciting synergistic effects on IL-8 and IL-1Ra production, at both the mRNA accumulation and the protein release. Although neither IL-12 nor IFN-gamma were produced in cells stimulated with murabutide alone, some mRNA expression was found with combined treatments. The results indicate that association of murabutide with a cytokine could exert synergistic effects, thus reducing effective doses of the recombinant protein, increasing the release of anti-inflammatory mediators, and triggering efficient cellular immunity.
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PMID:Selective potentiation of cytokine expression in human whole blood by murabutide, a muramyl dipeptide analogue. 889 42

With a short lifespan and containing only few ribosomes and endoplasmic reticulum structures, neutrophils are thought to have a limited capacity for protein synthesis. We here show that peripheral blood polymorphonuclear neutrophils (PMN) are able react to stimulants with differential production of two interleukin (IL)-1 receptor antagonist (IL-1ra) isoforms, secreted IL-1ra (sIL-1ra) and the 16kDa intracellular form of IL-1ra (icIL-1ra3), as well as IL-8. Neutrophils of a high purity and with a low degree of preactivation upregulate mRNA and de novo synthesize protein of both IL-1ra variants and IL-8 in response to granulocyte-macrophage colony-stimulating factor and lipopolysaccharide. The cytokines are differentially regulated and distributed in two intracellular compartments. In comparison with peripheral blood mononuclear cells (PBMC), PMN produce distinctly more sIL-1ra but significantly less IL-8. This may indicate an anti-inflammatory role, enabling PMN to antagonize proinflammatory signals. It is therefore possible that PMN play an important role in immune regulation by counteracting a dysregulation of the inflammatory process.
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PMID:Differential synthesis of two interleukin-1 receptor antagonist variants and interleukin-8 by peripheral blood neutrophils. 1634 27

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