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)

This study examines the distribution of intraepithelial dendritic cells in eight atopic patients with symptomatic asthma and their ability to induce activation of autologous T lymphocytes in vitro. All subjects were sensitized to Dermatophagoides pteronyssinus. The incubation of asthmatic epithelial cells and dendritic cells with autologous resting CD4-positive T cells and purified extracts of D pteronyssinus induced T cell activation and release of high levels of interleukin-4 (IL-4) and interleukin-5 (IL-5). The antigen-presenting activity of dendritic cells was potentiated by epithelial cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF), since an antibody against GM-CSF reduced it. Circulating monocytes of the two groups of donors were equally effective in promoting selective activation of IL-4- and IL-5-producing T cells. Thus, an interaction between dendritic cells and allergens may favor local activation of CD4-positive T cells with Th2-like function in atopic asthmatic subjects, thereby promoting the expression of the disease.
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PMID:Intraepithelial dendritic cells and selective activation of Th2-like lymphocytes in patients with atopic asthma. 813 11

We have found increased concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the bronchoalveolar lavage fluid of 11 patients with nocturnal asthma (15.3 +/- 4.6 pg/ml) compared with normal subjects (2.3 +/- 6.1 pg/ml) (p = 0.03). In contrast to patients with asthma, low affinity IgE receptors (Fc epsilon RII or CD23) are not expressed on monocytes obtained from healthy, nonatopic donors. Fc epsilon RII expression was induced by the cytokines GM-CSF and interleukin (IL)-4 either alone or in combination. As assessed by flow cytometry, the combination of IL-4 and GM-CSF was found to be synergistic, inducing up to 54.8% +/- 4.6% Fc epsilon RII-positive monocytes compared with a maximum of 27.4% +/- 5.0% and 30.0% +/- 4.0% with IL-4 and GM-CSF alone, respectively (p < 0.05 compared with either cytokine alone). Human monocytes from the peripheral blood of seven normal subjects were cultured for 24 hours with and without IL-4 or GM-CSF. With IL-4, addition of IgE/anti-IgE complexes failed to induce IL-1 secretion and inhibited IL-1 secretion induced by lipopolysaccharides. The addition of GM-CSF or IgE immune complexes alone resulted in no additional IL-1 secretion in supernatants of the untreated monocytes, whereas the IgE complexes did stimulate IL-1 secretion by monocytes cultured in GM-CSF, as measured by ELISA (from 0.7 +/- 0.2 ng/ml to 2.3 +/- 0.5 ng/ml; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Granulocyte-macrophage colony-stimulating factor stimulates macrophages to respond to IgE via the low affinity IgE receptor (CD23). 815 Oct 65

CD69 is an early activation marker for T cells and cross-linking of CD69 on platelets triggers aggregation and mediator release. Expression of a number of membrane receptors is induced on eosinophils after culture with certain cytokines. Therefore, we investigated whether cytokine-activated eosinophils expressed CD69. Unstimulated, peripheral blood eosinophils did not express CD69, as determined by immunofluorescence and flow cytometry (n = 15). CD69 expression was induced on eosinophils by granulocyte-macrophage colony-stimulating factor (GM-CSF) in a time- and dose-dependent manner. After 1 day in culture, expression was significant at concentrations of 10(-11) M and above. CD69 expression could be detected after stimulation with GM-CSF for only 1 hr, was significant after 2 hr and was sustained over 1-2 days in culture. CD69 expression was also induced by interleukin-3 (IL-3), IL-5 and interferon-gamma (IFN-gamma), but stimulation of eosinophils with platelet-activating factor (PAF) (10(-6) M) for up to 2 hr did not induce CD69 expression. Cycloheximide (10(-6) M) significantly inhibited GM-CSF-induced CD69 expression, suggesting a requirement for protein synthesis. However, unlike up-regulation of CR3 expression, GM-CSF-induced CD69 expression was not inhibited by dexamethasone. CD69 was present on eosinophils from the bronchoalveolar lavage (BAL) fluid of patients with mild asthma (5/5), suggesting that the in vitro findings may have biological relevance in vivo. Therefore, CD69 can be used as a marker of eosinophil activation by cytokines and is a candidate receptor for triggering eosinophil mediator release in the airways in asthma.
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PMID:CD69 is expressed by human eosinophils activated in vivo in asthma and in vitro by cytokines. 826 55

Interleukin-8 (IL-8) is a neutrophil chemoattractant cytokine. Initially IL-8 appeared to exhibit specificity for neutrophils over other cells of the immune system. However, several recent studies have shown that this mediator can also activate other leucocyte types in vitro. In this study we have used an in vivo model of local [111In]leucocyte accumulation in the guinea-pig and an in vitro assay of leucocyte activation (changes in cytosolic-free Ca2+) to investigate the eosinophil chemoattractant activity of IL-8. The intradermal injection of recombinant human (rh)IL-8 induced a dose-dependent accumulation of intravenously administered [111In]eosinophils into the skin sites over 4 hr. Time-course experiments revealed that this cell infiltration was delayed in onset, occurring between 1 and 2 hr after injection of IL-8. The delay may indicate that IL-8 operates via an indirect mechanism. In contrast, eosinophil accumulation induced by the complement fragment C5a occurred within the first hour following injection. Other human cytokines, IL-1, IL-3, IL-5, tumour necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), were not eosinophil chemoattractants in this in vivo test system. Direct activation of eosinophils by IL-8 was demonstrated in vitro by a transient elevation in cytoplasmic-free Ca2+ levels where it was less potent than either rhC5a or leukotriene B4 (LTB4). Experiments using [111In]neutrophils in vivo indicated that rhIL-8 and rhC5a were similar in potency in inducing local neutrophil infiltration into guinea-pig skin. The demonstration of the eosinophil chemoattractant activity of IL-8 in vivo raises the possibility that this cytokine, or a structurally related molecule, contributes towards eosinophil infiltration in a number of inflammatory conditions such as asthma, helminthic infections and adult respiratory distress syndrome.
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PMID:Eosinophil accumulation induced by human interleukin-8 in the guinea-pig in vivo. 834 9

The presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) in airway epithelial cells in vivo was assessed in 15 asthmatic and 9 normal subjects. GM-CSF was analyzed using immunohistochemistry with a polyclonal and a monoclonal antibody. Hue saturation intensity color image analysis was used to quantify staining. Asthmatic airway epithelial cells stained significantly more with anti-GM-CSF than those from normal subjects (p = 0.0013 and p = 0.0003 for the polyclonal and monoclonal antibodies, respectively). Additionally, 8 asthmatic individuals inhaled 1,000 micrograms beclomethasone diproprionate per day for 8 wk and 6 asthmatic patients inhaled matching placebo. There was a significant reduction of GM-CSF in the epithelium in the patients who were given corticosteroids (p = 0.014), whereas the group of subjects who were given placebo showed no significant change in GM-CSF staining. There was a correlation between the percentage suppression of GM-CSF staining by inhaled corticosteroids and the percentage increase in FEV1 (r = 0.61, p < 0.05) and percentage decrease in carbachol responsiveness (r = 0.80, p < 0.01). These findings suggest that GM-CSF may play a role in the inflammatory processes of bronchial asthma and that the epithelial cell may be a target cell for drug action.
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PMID:Detection of GM-CSF in asthmatic bronchial epithelium and decrease by inhaled corticosteroids. 850 69

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine whose expression is increased in numerous respiratory diseases, particularly in asthma. However, the role of GM-CSF in the pathogenesis of these conditions in vivo remains unclear. Here, we report the functional activities of GM-CSF highly expressed in rat lung after intrapulmonary transfer of the gene coding for murine GM-CSF by using an adenoviral vector. This high, transient expression of GM-CSF led to the sustained but self-limiting accumulation of eosinophils and macrophages associated with tissue injury in the lung followed by varying degrees of irreversible fibrotic reactions observed in later stages. These results suggest that GM-CSF plays a previously unrealized role in the development of respiratory conditions characterized by eosinophilia, granuloma and/or fibrosis and provide the rationale for targeting this molecule in these diseases.
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PMID:Transfer of granulocyte-macrophage colony-stimulating factor gene to rat lung induces eosinophilia, monocytosis, and fibrotic reactions. 861 34

Using adenoviral-mediated gene transfer techniques, the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene is efficiently targeted to and highly expressed by the respiratory epithelium of rat lung. This lung tissue-directed expression of GM-CSF induces accumulation of both eosinophils and macrophages at early stages and an irreversible fibrotic reaction at later stages. These tissue responses to GM-CSF appear to be distinct from those induced by other proinflammatory cytokines, interleukin (IL)-5, IL-6, macrophage inflammatory protein-2 (MIP-2), or RANTES overexpressed in the lung. These findings clearly demonstrate that GM-CSF is more than a hematopoietic cytokine in the lung and may play a pivotal role in the multiple pathological processes underlying numerous respiratory illnesses, including asthma. In this overview, the differences in tissue responses induced by GM-CSF and other individual cytokines are highlighted. In addition, the mechanisms by which GM-CSF and other individual cytokines are highlighted. In addition, the mechanisms by which GM-CSF contributes to the development of eosinophilia, macrophage granuloma, and fibrosis are discussed in conjunction with the recent findings from us and others.
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PMID:Gene transfer for cytokine functional studies in the lung: the multifunctional role of GM-CSF in pulmonary inflammation. 861 93

Eosinophils and eosinophil granule proteins may play an important role in the pathogenesis of asthma. BALF from 40 patients with symptomatic asthma were analysed for cytokine activity by the eosinophil survival assay. BALF from 15 patients showed increased survival activity. Survival activities in BALF from four of these patients were almost completely blocked by anti-IL-5 MoAb, and the remaining activities were blocked by anti-granulocyte-macrophage colony-stimulating factor (GM-CSF), anti-IL-3 antibody, or both. Surprisingly, BALF samples from the other 25 patients decreased eosinophil viabilities below the levels of medium control. The inhibitory factor in these BALF was of low molecular weight, was heat-stable, was largely overcome by excess exogenously added cytokines, and was positively correlated with the concentrations of lidocaine in the BALF. Lidocaine itself inhibited eosinophil survival at concentrations less than those present in the BALF. These findings indicate that lidocaine is an inhibitor of cytokines in the eosinophil survival assay, and they suggest the need for caution in analyses of BALF containing lidocaine or other local anaesthetics.
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PMID:Lidocaine in bronchoalveolar lavage fluid (BALF) is an inhibitor of eosinophil-active cytokines. 862 28

In order to test the hypothesis that ozone (O3)-induced changes in lung function and respiratory tract injury/inflammation are greater in subjects with asthma than in normal subjects, we exposed 18 asthmatic subjects, on separate days, to O3 (0.2 ppm) and filtered air for 4 h during exercise. Symptom questionnaires were administered before and after exposure, and pulmonary function tests (FEV1, FVC, and specific airway resistance [SRaw]) were performed before, during, and immediately after each exposure. Fiberoptic bronchoscopy, with proximal airway lavage (PAL) of the isolated left main bronchus and bronchoalveolar lavage (BAL; bronchial fraction, the first 10 ml of fluid recovered) of the right middle lobe, was performed 18 h after each exposure. The PAL, bronchial fraction, and BAL fluids were analyzed for the following endpoints: total and differential cell counts; total protein, lactate dehydrogenase (LDH), fibronectin, interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), myeloperoxidase (MPO), and transforming growth factor-beta (TGF beta 2) concentrations. We found a significant O3 effect on FEV1, FVC, SRaw (p < 0.04) and lower respiratory symptoms (p < 0.001) for the asthmatic subjects. Ozone exposure also significantly increased the percent neutrophils in PAL (p < 0.01); percent neutrophils, total protein, and IL-8 in the bronchial fraction (p < 0.001, p < 0.05, and p < 0.01, respectively); and the percent neutrophils, total protein, LDH, fibronectin, IL-8, GM-CSF, and MPO in BAL (p < 0.001, p < 0.01, p < 0.01, p < 0.001, p < 0.05, p < 0.01, and p < 0.001, respectively) for the asthmatic subjects. There were no significant differences in the lung function responses of the asthmatic subjects in comparison with a group of normal subjects (n = 81) previously studied using an identical protocol, although there was a trend toward a greater O3-induced increase in SRaw in the asthmatic subjects (p < 0.13). In contrast, the asthmatic subjects showed significantly greater (p < 0.05) O3-induced increases in several inflammatory endpoints (percent neutrophils and total protein concentration) in BAL as compared with normal subjects who underwent bronchoscopy (n = 20). Our results indicate that asthmatic persons may be at risk of developing more severe O3-induced respiratory tract injury/inflammation than normal persons, and may help explain the increased asthma morbidity associated with O3 pollution episodes observed in epidemiologic studies.
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PMID:Greater ozone-induced inflammatory responses in subjects with asthma. 868 Jun 87

Mechanisms of eosinophil accumulation and activation in the bronchial mucosa are crucial for the pathogenesis of asthma. The location of specialized fibroblasts, myofibroblasts, beneath the bronchial basement membrane and their proximity to infiltrating eosinophils potentially enable the myofibroblasts to modulate eosinophil survival and function in asthma. The aim of this study was to investigate the effects of bronchial myofibroblasts on eosinophil survival in vitro. Eosinophils from human peripheral blood were exposed to cell cultures from bronchial myofibroblasts and to myofibroblast-conditioned media. Eosinophil viability was assessed and granulocyte/macrophage colony-stimulating factor (GM-CSF) production was examined in co-culture supernatants and as messenger ribonucleic acid (mRNA) in myofibroblasts. Eosinophil survival was significantly increased and eosinophil apoptosis was inhibited by co-culture with myofibroblasts. Conditioned medium from tumour necrosis factor-alpha (TNF-alpha)-stimulated myofibroblasts also prolonged eosinophil survival. This effect could be blocked by GM-CSF antibody. GM-CSF mRNA and secretion from myofibroblasts were increased in co-cultures and by eosinophil-conditioned medium. Addition of antibodies to TNF-alpha and interleukin-1 alpha (IL-1 alpha) to co-cultures resulted in significant reduction both in eosinophil survival and GM-CSF levels. Blocking of fibronectin in the co-cultures did not affect the eosinophil survival enhancing activity. Prednisolone inhibited the eosinophil survival enhancing activity of the co-cultures by suppression of GM-CSF production. Soluble eosinophil-derived cytokines are involved in the interaction of eosinophils with myofibroblasts, which results in a tumour necrosis factor-alpha/interleukin-1 alpha mediated release of granulocyte/macrophage colony-stimulating factor from myofibroblasts. Bronchial myofibroblasts can, thereby, contribute to allergic inflammation by granulocyte/macrophage colony-stimulating factor-mediated inhibition of eosinophil apoptosis.
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PMID:Cell cultures from bronchial subepithelial myofibroblasts enhance eosinophil survival in vitro. 888 Jan


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