Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Mast cells (MC) are proinflammatory immune cells residing in various organs. Tissue-specific heterogeneity of MC has been described. The aim of this study was to establish the phenotype and functional profile of human tonsillar mast cells (ToMC) and to compare ToMC with lung-, skin-, and uterus MC. Tonsillar tissue was obtained from 23 patients suffering from hyperplastic tonsils and dispersed by enzymatic digestion. With the use of a combined toluidine blue/immunofluorescence staining technique, isolated ToMC were found to react with monoclonal antibodies (mAb) to immunoglobulin E, CD9, CD43, CD44, CD46, CD54, CD55, and CD59, as well as mAb to stem cell factor (SCF) receptor (CD117/c-kit). ToMC were not recognized by mAb to other cytokine receptors or mAb to CD3, CD11b, CD14, CDw17, the skin MC marker CD88 (C5aR) or CD89 (Fc alphaR). Activation of ToMC by recombinant human (rh) SCF or anti-IgE resulted in histamine secretion, whereas no effects were seen with rhC5a, rh granulocyte-macrophage colony-stimulating factor, or rh interleukin-1 through -10. In summary, ToMC exhibit functional and phenotypic properties similar to lung- or uterus MC. Unlike skin MC, ToMC lack C5aR and are unresponsive to rhC5a.
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PMID:Immunophenotypic and functional characterization of human tonsillar mast cells. 912 8

Chronic infection with Schistosoma mansoni induces in humans and mice a Th2-dominant immune response in which eosinophils and IgE are conspicuously elevated. Human eosinophils express IgE receptors that participate in an IgE-dependent eosinophil-mediated ADCC reaction against Schistosomula larvae in vitro. To investigate the expression of IgE receptors on murine eosinophils, they were purified (>95% pure by Giemsa-stained cytospin preparations) from liver granulomas of Schistosoma-infected mice. Flow cytometric analysis showed the absence of the low-affinity IgE receptor Fc-epsilon RII (CD23) and Mac-2 and the absence of binding of murine IgE. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of granuloma eosinophil mRNA did not detect transcripts for Fc-epsilon RII or the alpha-chain of the high-affinity IgE receptor Fc-epsilon RI, but did detect transcripts that encode Mac-2 and the low-affinity IgG receptors Fc-gamma RIIb2, Fc-gamma RIII, and the FcR-associated gamma-chain. In vitro stimulation of granuloma eosinophils with interleukin-4 (IL-4) did not induce IgE binding, surface expression of Mac-2, or the transcription of Fc-epsilon receptors (Fc-epsilon RI, Fc-epsilon RII/CD23). To investigate normal murine eosinophils, we cultured normal mouse bone marrow cells with recombinant IL-3, recombinant IL-5, and recombinant granulocyte-macrophage colony-stimulating factor, conditions that promote eosinophil differentiation. Flow cytometric analysis of bone marrow-derived eosinophils failed to detect IgE binding or cell surface expression of Fc-epsilon RII and Mac-2, and RT-PCR analysis of fluorescence-activated cell sorted bone marrow-derived eosinophils failed to detect transcripts that encode Fc-epsilon RI or Fc-epsilon RII. These findings show that, in contrast to human eosinophils, murine eosinophils do not express cell surface receptors that bind IgE. However, because IgG receptors (Fc-gamma RIIb2, Fc-gamma RII) were present on eosinophils purified from granulomas, we investigated whether they might be involved in eosinophil activation. We found that an oxidative burst in eosinophils could be triggered through their IgG receptors.
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PMID:Lack of Fc-epsilon receptors on murine eosinophils: implications for the functional significance of elevated IgE and eosinophils in parasitic infections. 916 Jun 53

Selective accumulation of eosinophils and activated CD4+ cells is now considered a central event in the pathogenesis of asthma, and this process is thought to be mediated by a number of cytokines including tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), and the Type 2 cytokines interleukin-4 (IL-4) and IL-5. To carry out a detailed time-course analysis of cellular changes in the bronchoalveolar lavage fluid (BAL), peripheral blood (PB), and bone marrow (BM), and of changes in the aforementioned cytokines in BAL and serum, Balb/c mice were sensitized by intraperitoneal injection with ovalbumin (OVA) adsorbed to aluminum hydroxide on two occasions 5 days apart, and were subjected to an OVA aerosol challenge 12 days after the second sensitization. This resulted in an airways inflammatory response characterized by early transient neutrophilia, marked eosinophilia, and, to a lesser extent, lymphocytosis in the BAL. Inflammatory events were first observed 3 h and 24 h after antigen challenge in the lung tissue and BAL, respectively, and lasted for 21 days. In the BM, we detected a 1.5- and 5-fold increase in the total number of cells and eosinophils, respectively, 4 days after the second sensitization. This was followed by a decrease, although BM eosinophilia remained clearly present at the time of antigen challenge. A second eosinopoietic event was observed in the BM shortly after challenge and reached a peak at day 3. BM cellularity returned to normal at day 21 after challenge. Serum OVA-specific IgE was first detected 3 days following the second sensitization (150 ng/ml). IgE levels then decreased but remained at the 75 ng/ml range at the time of the aerosol challenge. During the sensitization period, TNF-alpha (approximately 25 pg/ml), IL-4 (approximately 40 pg/ml), and IL-5 (approximately 250 pg/ml) were detected in serum, but not in the BAL fluid (BALF) and returned to background levels at the time of the antigen challenge. After antigen challenge, TNF-alpha, IL-4, IL-5, and GM-CSF were detected in serum. Peak levels were observed at 3 h (approximately 40 pg/ml), 3 h (approximately 120 pg/ml), 12 h (approximately 350 pg/ml), and 3 h (approximately 10 pg/ml), respectively, and returned to background levels 24 h after challenge. In the BALF, we detected peak levels of TNF-alpha, IL-4, IL-5, and GM-CSF at 6 h (approximately 250 pg/ml), 24 h (approximately 140 pg/ml), 24 h (350 pg/ml), and 3 h (approximately 10 pg/ml), respectively, with a return to background levels 5 days after challenge. No IL-10 could be detected at any time point during sensitization or after challenge in either serum or BAL. We also detected approximately 40 pg/ml of interferon-gamma (IFN-gamma) in the serum of normal untreated mice. Serum IFN-gamma levels fluctuated during sensitization and after challenge, but never exceeded those observed in untreated mice. Thus, the cytokine profile observed in this experimental model of allergic inflammation is characterized by IL-4 and IL-5 dominance, with an apparently minor TNF-alpha and GM-CSF contribution and relatively low or undetectable levels of IFN-gamma and IL-10.
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PMID:Cytokine and eosinophil responses in the lung, peripheral blood, and bone marrow compartments in a murine model of allergen-induced airways inflammation. 916 Aug 31

By using reverse transcription-PCR, in situ hybridization, enzyme-linked immunosorbent assay and immunocytochemistry, we have studied the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) in human lung mast cells induced by cross-linkage of high-affinity Fc epsilon receptors (Fc epsilonRI). We have also confirmed the bioactivity of GM-CSF released from lung mast cells by investigating the effect of the supernatant from lung mast cells activated with anti-IgE on the release of eosinophil cationic protein (ECP) from eosinophils. Mast cells were purified using affinity magnetic selection with monoclonal antibody (mAb) YB5.B8 (93-99% pure). Purified mast cells were precultured with IgE for 16 h before challenge with 1 microg/ml anti-IgE with or without stem cell factor (SCF). Eosinophils were purified by immunomagnetic negative selection (> 98% pure). The activation of mast cells via Fc epsilonRI enhanced the intensity of the GM-CSF signal within 2 h and the cells produced GM-CSF protein 4 h after the activation. In the absence of recombinant human (rh) SCF, anti-IgE induced a median GM-CSF response of 202 (< 15 to approximately 681) pg/10(6) mast cells/24 h, whereas in the presence of rhSCF the median IgE-dependent GM-CSF release was 356 (152 to approximately 1216) pg/10(6) mast cells/24 h. This difference was statistically significant (p = 0.0029, n = 12). In contrast, mast cells produced only a small amount of GM-CSF in the absence of anti-IgE. The mast cell supernatant induced ECP release from eosinophils and the release was significantly inhibited by blocking mAb against GM-CSF. These findings indicate that human mast cells are an important cellular source of GM-CSF and as such may contribute to chronic eosinophil-mediated inflammation.
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PMID:Human lung mast cells are enriched in the capacity to produce granulocyte-macrophage colony-stimulating factor in response to IgE-dependent stimulation. 952 Oct 81

We have previously shown that mouse bone marrow-derived mast cells (BMMC) can process and present immunogenic peptides to CD4 T cells. Here, we report on a T cell-dependent MHC class II-mediated mast cell activation resulting in IL-4 transcription and protein release. Presentation of optimal doses of ovalbumin peptide 323-339 resulted in IL-2 production by a specific T cell hybridoma and increase in IL-4 mRNA transcription in mast cells. IL-4 mRNA transcription increased by 200-fold in mast cells treated in IL-3/IL-4/granulocyte-macrophage colony-stimulating factor (high presenters) whereas only a tenfold increase or no increase were obtained with IL-3/IL-4/IFN-gamma- or IL-3-treated mast cells (low presenters), respectively. Induction of IL-4 mRNA transcription in purified mast cells by direct ligation of MHC class II molecules, using anti-I-A and anti-I-E-coated beads, indicates that MHC class II molecules are critical in this signaling pathway. However, when compared to T cells, anti-MHC class II-coated beads were less efficient, indicating a potential role of accessory molecules in this mast cell activation process. IgE-independent IL-4 production by mast cells as a result of cognate interaction with CD4 T cells could be critical for the development of type 2 responses. This novel mechanism may contribute to the induction and/or amplification of specific IgE-mediated allergic responses.
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PMID:IL-4 mRNA transcription is induced in mouse bone marrow-derived mast cells through an MHC class II-dependent signaling pathway. 954 79

Chronic sinusitis and its associated eosinophilic infiltrate are believed to be mediated, at least in part, by the upregulation of Th-2 cytokines, including interleukin-4, interleukin-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Interleukin-4 is involved in IgE production and in eosinophil recruitment through upregulation of vascular cell adhesion molecule-1. Interleukin-5 and GM-CSF are involved in eosinophil growth and survival. The aim of this study was to investigate the expression of receptors for these cytokines in the sinus mucosa of subjects with chronic sinusitis. Using the technique of in situ hybridization to detect specific cytokine receptor messenger RNA, we studied the sinus mucosa of subjects with nonallergic chronic sinusitis, subjects with allergic chronic sinusitis, subjects with allergic chronic sinusitis treated with topical steroids, and normal controls. Our data demonstrate higher expression of interleukin-4 receptor in subjects with allergic chronic sinusitis than in controls (p < 0.001) and higher expression of interleukin-5 receptor in both subjects with nonallergic chronic sinusitis and subjects with allergic chronic sinusitis than in controls (p < 0.001, p < 0.001). The expression of interleukin-4 receptor and interleukin-5 receptor was higher in subjects with allergic chronic sinusitis than in subjects with nonallergic chronic sinusitis (p < 0.001). GM-CSF receptor expression was also found to be higher in subjects with allergic chronic sinusitis and subjects with nonallergic chronic sinusitis than in controls (p < 0.001, p < 0.001). In contrast to interleukin-4 receptor and interleukin-5 receptor, however, expression of GM-CSF receptor was higher in subjects with nonallergic chronic sinusitis than in subjects with allergic chronic sinusitis (p < 0.001). In subjects with allergic chronic sinusitis treated with topical corticosteroids, the expression of interleukin-4 receptor and interleukin-5 receptor messenger RNA levels was significantly lower than levels in patients with allergic chronic sinusitis who were not taking topical steroids (p < 0.001, p < 0.001). Steroid treatment had no effect on GM-CSF receptor messenger RNA expression. In conclusion, our data support a role for Th-2 cytokine receptors in the pathophysiology of chronic sinusitis. Further, our data lend support to the theory that differential activation of distinct cytokine pathways mediates inflammation in chronic sinusitis depending on whether there is associated allergy. Finally, treatment with topical corticosteroids has been demonstrated in chronic sinusitis to downregulate receptors for interleukin-4 and interleukin-5.
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PMID:Interleukin-4, interleukin-5, and granulocyte-macrophage colony-stimulating factor receptor expression in chronic sinusitis and response to topical steroids. 956 Jan 1

Granulocyte-macrophage colony-stimulating factor (GM-CSF) could in theory attract antigen-presenting cells in muscle following intramuscular DNA immunization, resulting in enhanced antigen-specific immune responses. Thus, such adjuvants could constitute an important addition to a herpes vaccine by amplifying specific immune responses. Here we investigate the utility of GM-CSF cDNA as a vaccine adjuvant for herpes simplex virus (HSV)-2 in a mouse challenge model. GM-CSF cDNA co-injection enhanced levels of specific IgG, IgE and IgA against HSV-2 gD protein significantly higher than gD plasmid vaccination alone. Moreover, GM-CSF co-injection induced a dramatic increase in IgG1 levels, as compared to IgG2a levels, suggesting a Th2 bias in the response. T helper cell proliferation and secretion of cytokines (IL-2 and IFN-gamma) were significantly increased by GM-CSF cDNA co-injection. When challenged with a lethal dose of HSV-2, GM-CSF co-injection increased survival rates to 90%, an improvement as compared to gD vaccination alone (60-63%). Furthermore, GM-CSF cDNA co-injection reduced herpetic lesions and resulted in a faster recovery from lesions. These data indicate that GM-CSF cDNA enhances both humoral and cellular immune responses and enhances vaccine efficacy, resulting in reduced HSV-2-derived morbidity as well as mortality.
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PMID:Enhancement of protective humoral (Th2) and cell-mediated (Th1) immune responses against herpes simplex virus-2 through co-delivery of granulocyte-macrophage colony-stimulating factor expression cassettes. 984 96

There is increasing evidence that the asthma process is 'driven' and maintained by persistence of a subset of chronically activated T memory cells, sensitized against allergenic, occupational or viral antigens which 'home' to the lung after antigen exposure or viral infection. In general, allergens induce a CD4 T helper (Th) cell response, whereas viruses recognize CD8+ cytotoxic (Tc) T cells. In the asthmatic airways, there are CD4+ and, to a lesser number CD8+ cells with a type 2 cytokine phenotype (i.e., Th-2 and Tc-2 type). These cells produce interleukin (IL) 3 and 5 and granulocyte-macrophage colony-stimulating factor which recruit, mobilize and activate eosinophils for subsequent mucosal damage, as well as IL-4, an essential cofactor for local or generalized IgE production. This leads to epithelial shedding, mucus hypersecretion and bronchial muscle contraction. Thus, although the eosinophil may damage the mucosal surfaces in asthma, its function appears to be under T cell control. Support for this hypothesis includes: (1) activated T cells and their products can be identified in biopsies from the major variants of the disease (atopic, non-atopic and occupational asthma); (2) colocalization of mRNA for type 2 cytokines to CD4+ and CD8+ cells in atopic and non-atopic asthma; (3) the presence of activated cytokine-producing T cells in corticosteroid-resistant asthma; (4) the association of disease severity with type 2 cytokines, especially IL-5; and (5) the efficacy of cyclosporin A and a monoclonal anti-CD4 in chronic steroid-dependent disease. Inhibitors and/or antagonists directed against more precise T cell associated molecular targets hold promise for the future treatment of chronic asthma.
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PMID:T cells and chronic asthma. 1022 60

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) are recognized as enhancers, but not as inducers, of histamine release from normal human basophils. However, when extracellular Na+ is removed IL-3 acquires the capacity to induce histamine release. The aim of this study was to evaluate whether GM-CSF can induce basophil histamine release using the same pathway of IL-3. Leucocyte suspensions from normal human subjects were stimulated with GM-CSF, IL-3 and anti-IgE, and histamine release was evaluated by an automated fluorometric method. In a physiological medium, GM-CSF (10 ng/ml) and IL-3 (10 ng/ml) did not provoke histamine release, in spite of an efficient response to anti-IgE (10 micrograms/ml). However, when extracellular Na+ was substituted iso-osmotically with N-methyl-d-glucamine+ or with choline+, GM-CSF and IL-3 were able to trigger histamine release from either mixed leucocyte suspensions or purified human basophils. The effect of GM-CSF on basophil histamine release was dose dependent, with optimal release at a dose of 1 ng/ml after incubation at 37 degrees for 60-120 min. The kinetics of IL-3-induced histamine release were similar, whereas anti-IgE-induced histamine release was more rapid, being almost maximal after incubation for 30 min. A good correlation was found between GM-CSF-induced and IL-3-induced histamine release; furthermore, the combined effects of the two cytokines were less than additive, suggesting that they share the same pathways leading to histamine release. When extracellular Na+ concentration was increased from 0 to 140 mm, histamine release induced by GM-CSF, IL-3 and anti-IgE was reduced progressively. In contrast, histamine release induced by these stimuli was upregulated when the concentration of extracellular Ca2+ was increased. These results provide indirect evidence that GM-CSF and IL-3 can induce basophil histamine release by a common pathway that is downregulated by Na+.
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PMID:Granulocyte-macrophage colony-stimulating factor and interleukin-3 cause basophil histamine release by a common pathway: downregulation by sodium. 1023 91

Mast cells (MC) are stem cell factor-dependent tissue-based hematopoietic cells with substantial functional heterogeneity. Cord blood-derived human MC (hMC) express functional receptors for IL-5, and IL-5 mediates stem cell factor-dependent comitogenesis of hMC in vitro. Although IL-5 is not required for normal hMC development, we considered that it might prime hMC for their high-affinity Fc receptor for IgE (FcvarepsilonRI)-dependent generation of cytokines, as previously demonstrated for IL-4. Compared with hMC maintained in stem cell factor alone, hMC primed with IL-5 expressed 2- to 4-fold higher steady-state levels of TNF-alpha, IL-5, IL-13, macrophage inflammatory protein 1alpha, and granulocyte-macrophage colony-stimulating factor transcripts 2 h after FcvarepsilonRI crosslinking and secreted 2- to 5-fold greater quantities of the corresponding cytokines, except IL-13, at 6 h. Unlike IL-4, IL-5 priming did not enhance FcvarepsilonRI-dependent histamine release. Thus, IL-5 augments cytokine production by hMC by a mechanism distinct from that of IL-4 and with a different resultant profile of cytokine production. These observations suggest a potentially autocrine effect of IL-5 on hMC for amplification of allergic immune responses, in addition to its recognized paracrine effects on eosinophils, and implicate both IL-4 and IL-5 in the modulation of the hMC phenotype.
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PMID:IL-4 and -5 prime human mast cells for different profiles of IgE-dependent cytokine production. 1097 84


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