UNIPROT:P04141 - FACTA Search

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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)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine which can stimulate the proliferation and functions of eosinophils and neutrophils. We have studied whether peripheral blood mononuclear cells (PBMC), obtained from children with stable asthma, can produce GM-CSF through stimulation with crude Dermatophagoides farinae (Df) antigen in vitro. The patients had strongly positive RAST results for house dust mite Df. Levels of GM-CSF in PBMC culture supernatant were assayed by an enzyme immunoassay. When stimulated with Df antigen, patient's PBMC released significantly increased levels of GM-CSF compared with unstimulated ones. PBMC of non-allergic controls, however, did not. The addition of polymyxin B, an inactivator of endotoxin, did not suppress the Df-antigen-induced production of GM-CSF. Levels of GM-CSF produced by PBMC stimulated with Df antigens were significantly higher in the patients than in the controls. These results indicate that PBMC of children with Df-allergic asthma, unlike those of non-allergic children, can produce elevated levels of GM-CSF by stimulation with Df antigens.
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PMID:[Elevated production of GM-CSF by peripheral blood mononuclear cells stimulated with mite antigens in children with bronchial asthma]. 129 Apr 8

We have attempted to determine whether interleukin-5 (IL-5), a cytokine that selectively affects eosinophil (as opposed to neutrophil) differentiation and activation, also modulates eosinophil migrational responses. Using a modified Boyden chemotaxis assay, IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) gave a weak locomotory response for eosinophils from normal nonatopic subjects (optimal at 10(-11), 10(-8), and 10(-9) mol/L, respectively), but not for eosinophils from subjects with an eosinophilia associated with asthma and/or allergic rhinitis. In contrast, IL-5 and IL-3 had no effect on neutrophils, while GM-CSF was chemotactic for neutrophils over a limited concentration range, optimal at 10(-8) mol/L. When eosinophils from normal subjects were incubated with IL-5 (10(-9) mol/L), the locomotory response to platelet-activating factor (PAF; 10(-8) mol/L, P less than .05), leukotriene B4 (LTB4; 10(-6) mol/L, P less than .01), and N-formyl-methionyl-leucyl-phenylalanine (FMLP; 10(-8) mol/L, P less than .01) was significantly enhanced. The percentage enhancement of eosinophil locomotion by IL-5 was greater for eosinophils from normal as compared with subjects with an eosinophilia associated with asthma (P less than .05 for PAF and LTB4; P less than .01 for FMLP). Preincubation of eosinophils from normal subjects with IL-5 (10(-9) mol/L) attenuated the subsequent locomotory response to IL-5 (10(-12) and 10(-11) mol/L, P less than .05). Therefore, the observed refractoriness of eosinophils from eosinophilic subjects to both directional migratory and priming effects of IL-5 in vitro, may reflect a deactivation process resulting from prior exposure in vivo. The selective priming of eosinophil but not neutrophil locomotion by IL-5 suggests that this cytokine may play a significant role in the preferential accumulation of eosinophils at sites of allergic inflammation.
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PMID:Interleukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not eosinophilic subjects. 131 89

Cultured human bronchial epithelial cells constitutively produce granulocyte-macrophage colony-stimulating factor (GM-CSF). The synthesis and release of GM-CSF is upregulated in bronchial epithelium of patients with symptomatic asthma and this may contribute to the local activation of inflammatory cells in their bronchial mucosa. The cause of this upregulation of GM-CSF expression is unknown, but an increased release of interleukin-1 (IL1) from other airway resident cells might be involved, as an increase in GM-CSF production can be induced in vitro in normal bronchial epithelial cells by IL1 and the airway secretions of asthmatics contain high amounts of this cytokine. In the present study, we have evaluated the effect of the anti-inflammatory and antiasthmatic drug, nedocromil sodium, on the spontaneous and IL1-induced expression of GM-CSF in cultured bronchial epithelial cells. This compound, at the concentration of 10(-5) M, reduced the IL1-induced increase in GM-CSF release from epithelial cells by more than 40%, but it did not affect the constitutive production of GM-CSF.
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PMID:Protective effect of nedocromil sodium on the IL1-induced release of GM-CSF from cultured human bronchial epithelial cells. 131 31

In asthma, a beta-adrenoceptor dysfunction may be the consequence of an active disease state rather than a fundamental abnormality. In the present study the possible involvement of T lymphocytes in beta-adrenergic impairment was investigated by studying the effects of lymphocyte-derived mediators of beta-adrenoceptor function of human peripheral blood mononuclear cells (PBMCs) and guinea pig trachea. Supernatants of phytohemagglutinin- or concanavalin A-activated PBMCs from either persons with asthma or healthy persons inhibited isoprenaline stimulated cyclic adenosine 3',5'-monophosphate (cAMP) production of PBMCs after 20 hours of preincubation. These supernatants also inhibited beta-adrenoceptor function of PBMCs from patients with asthma to the same extent. The isoprenaline stimulated cAMP production of PBMCs was not altered after a 2-hour preincubation period with human interleukin-1 (IL-1), IL-2, IL-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN-gamma). In contrast, after 20 hours of preincubation, stimulated cAMP production of PBMCs was significantly diminished, with 63% by IL-1 (40 U/ml, p less than 0.01), with 36% by IL-2 (100 U/ml, p less than 0.05), with 37% by IFN-gamma (1000 U/ml, p less than 0.05), and with 21% by GM-CSF (100 U/ml, p less than 0.05). Preincubation of guinea pig tracheal segments with IL-1, IL-2, IL-4, or GM-CSF during 1 or 3 days did not affect the EC50 values or the maximal relaxation of isoprenaline dose response curves.
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PMID:Effects of cytokines on beta-adrenoceptor function of human peripheral blood mononuclear cells and guinea pig trachea. 132 72

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) are hematopoietic growth factors that have been shown to induce proliferation and activation of inflammatory cells, and may play a role in allergic reactions. Since little is known about the involvement of cytokines in allergic inflammation in the lung, the levels of GM-CSF and IL-3 were measured in bronchoalveolar lavage (BAL) fluids obtained in the late phase after segmental lung antigen (Ag) challenge in 14 allergic rhinitis subjects with or without bronchial asthma. BAL fluids either after Ag (ragweed, dust mite, or timothy) or saline control challenge were recovered 19 h later. In 6 of the 14 patients, BAL fluids were concentration-dialyzed (20x) and assayed for cytokine activity. Cytokine assays were performed using the human megakaryocytic leukemic cell line M-07e, which is responsive to either GM-CSF or IL-3. The level of GM-CSF-equivalents was approximately 25 times higher in Ag-challenged sites (49.9 +/- 12.7 pg/ml; mean +/- SEM), compared to saline challenge sites (2.2 +/- 1.0, p < 0.01, n = 9). Neutralization experiments using a polyclonal specific antibody (Ab) against GM-CSF and IL-3 revealed that the bulk of the activity was GM-CSF. BAL fluids from Ag- and saline-challenged sites in one nonatopic subject contained no significant GM-CSF activity. Furthermore, the level of GM-CSF in Ag-challenged BAL fluid and the percentage of eosinophils in BAL from each subject correlated significantly (r = 0.73, p < 0.005, n = 14).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Production of granulocyte/macrophage colony-stimulating factor in human airways during allergen-induced late-phase reactions in atopic subjects. 147 81

We have tested the hypothesis that the bronchial epithelium has the capacity to generate and release cytokines that could contribute to inflammatory events associated with inflammatory lung diseases. Messenger RNA (mRNA) for interleukin-6 (IL-6), IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) was identified in human bronchial epithelial cell primary cultures, characterized on the basis of staining for cytokeratin, using both in situ hybridization and Northern blotting. Using in situ hybridization we have shown that the majority of the cells expressed mRNA for IL-6 and IL-8, whereas fewer than 20% of cells expressed message for GM-CSF. The numbers of cells expressing message were increased by culture with tumour necrosis factor-alpha (TNF-alpha) (20 ng/ml, 24 hr). These observations were substantiated by Northern blotting, which showed that both TNF-alpha and IL-1 beta were able to induce a dose-dependent increase in IL-8-specific mRNA. Immunoreactive IL-6 and GM-CSF were detected and quantified in the culture supernatants by ELISA, and IL-8 by radioimmunoassay. The levels of immunoreactivity were increased by incubation of epithelial cells with either IL-1 beta or TNF-alpha for 24 hr. A transformed tracheal epithelial cell line (9HTEo-) expressed mRNA for IL-6, IL-8 and GM-CSF but, whereas levels of immunoreactive IL-6 in culture supernatants were comparable with those in primary cell cultures, levels of IL-8 were low and GM-CSF trivial. These observations indicate that the bronchial epithelium has the potential to be a major source of IL-8 and a number of other cytokines, and that production can be amplified substantially by IL-1 beta and TNF-alpha. The bronchial epithelium is ideally situated to modulate inflammatory and immunological events in and around the airways, and these observations suggest that it could contribute to promote and sustain inflammatory and immunological processes in inflammatory lung diseases such asthma.
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PMID:Expression and generation of interleukin-8, IL-6 and granulocyte-macrophage colony-stimulating factor by bronchial epithelial cells and enhancement by IL-1 beta and tumour necrosis factor-alpha. 147 79

Early studies of patients dying from status asthmaticus revealed marked inflammation of the bronchial tree. Subsequent histological studies of the airways and examination of bronchoalveolar lavage fluid of subjects with mild asthma have confirmed the presence of airway inflammation in life. There is epithelial edema and desquamation, subepithelial deposition of collagen and fibronectin, and an inflammatory cell infiltrate in the mucosa. There are increased numbers of activated eosinophils, CD25-positive T lymphocytes, and immature macrophages with the phenotypic characteristics of blood monocytes. An increased expression of HLA class II is present on epithelium, macrophages, and other infiltrating cells. The severity of clinical asthma correlates with several measurements of the severity of the inflammatory response, suggesting a crucial role for airway inflammation in the pathophysiology of the disease. There is considerable interest and research into the mechanisms underlying the pathogenesis and maintenance of the inflammatory response in asthma. The development and maintenance of the inflammatory response in asthma is likely to be a consequence of a complicated interaction between various cells and the mediators they generate. The characterization of an ever-increasing number of cytokines is of particular interest. Interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor are hematopoietic growth factors that increase the survival of eosinophils in culture and enhance certain eosinophil functions, such as mediator generation and toxicity. Alveolar macrophages derived from asthmatic subjects produce twofold to threefold more GM-CSF than do those from normal control subjects. Using in situ hybridization, the presence of IL-5 mRNA has been demonstrated in bronchial biopsies from asthmatic subjects. Thus IL-3, IL-5, and GM-CSF influence eosinophil function and survival, and may be generated by T lymphocytes and/or alveolar macrophages within the airways in asthma. In addition to these three cytokines, IL-4 and interferon-gamma may be crucial to the regulation of IgE biosynthesis. TNF-alpha and IL-1 are potentially important in the up-regulation of endothelial adhesion molecules. An important step in the recruitment of leukocytes to an inflammatory focus is margination to the vascular endothelium. Our understanding of the molecular events involved in migration of leukocytes to an inflammatory focus has been advanced by the discovery and characterization of a variety of cell adhesion molecules. The potential role of ELAM-1 and ICAM-1 in allergic inflammation is suggested by their up-regulation on vascular endothelium in association with late cutaneous responses to allergen and by their role in certain primate models of asthma.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The pathobiology of bronchial asthma. 150 77

Recent studies have indicated that airway inflammation in atopic asthma is characterized by T-cell activation and local eosinophilia, but it is unknown whether this also applies to nonatopic asthma. In this study, the cytokine mRNA profile and activation status of inflammatory cells in bronchoalveolar lavage fluid (BALF) of eight nonallergic patients with symptomatic asthma and eight nonallergic healthy controls were compared using the message amplification phenotyping (MAPPing) with the polymerase chain reaction (PCR) procedure and immunocytochemical evaluation. Asthmatics had an increasing number of inflammatory cells in BALF, including activated eosinophils (EG2-positive) (p less than 0.001) and activated T cells (CD25-positive) (p less than 0.001). Activated T cells from five of the eight asthmatic patients and from one control subject expressed high levels of interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF). All the asthmatic patients had increased numbers of monocytes in their BALF (p less than 0.002) and those cells invariably showed increased expression of interleukin 1 beta (IL1 beta) transcripts. In five patients they also expressed appreciable levels of IL-6 and GM-CSF mRNA. IL-5 and GM-CSF can induce local activation of eosinophils, and IL-1 beta and IL-6 are known to promote T-cell activation and proliferation. Thus, there is an increased production of cytokines with inflammatory properties in the airways of patients with nonatopic symptomatic asthma, which may contribute to the persistence of inflammation, and monocytes and activated T cells are important sources of these cytokines.
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PMID:Cytokine mRNA profile and cell activation in bronchoalveolar lavage fluid from nonatopic patients with symptomatic asthma. 151 85

Eosinophils are known to adhere to cytokine-activated endothelium. Whereas transendothelial migration for neutrophils is an inevitable consequence of this endothelial-dependent adherence, this has not yet been shown for eosinophils. By means of human umbilical vein endothelial cells (HUVE) grown to confluence on microporous filters as an in vitro model of leukocytic migration across postcapillary venules, we have characterized the conditions leading to endothelium-driven transmigration of blood eosinophils from normals and from patients with allergic asthma. Freshly isolated eosinophils from nonallergic donors adhered to interleukin-1 (IL-1) and tumor necrosis factor-activated HUVE, but did not penetrate these monolayers. In contrast, eosinophils from allergic asthma patients showed an increased adherence and transmigration capacity. This increased functional competence was not caused by a difference in density phenotype, because the eosinophils from both groups showed a comparable density distribution over discontinuous Percoll gradients. Moreover, no difference existed within one group among eosinophils harvested from the Percoll density bands 1.080, 1.085, and 1.090 g/mL in terms of transendothelial migration. In vitro cultivation of freshly isolated eosinophils from nonallergic individuals in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3 induced a stepwise decrease of the density distribution over such gradients. In contrast, eosinophils from patients with allergic asthma directly shifted to a final density of 1.075 g/mL within 24 hours of culture. Notwithstanding the kinetics of density changes, eosinophils from nonallergic donors already expressed the capacity to transmigrate IL-1-activated HUVE monolayers 20 hours after cultivation with different combinations of GM-CSF, IL-3, and IL-5. Inhibition studies with monoclonal antibodies showed that endothelium-driven transmigration of eosinophils predominantly implicates CD11/CD18 structures on the eosinophil surface, whereas no significant inhibition was found with the anti-VLA-4 monoclonal antibody HP2/1. From cytofluorometric studies, we conclude that spontaneous transmigration of eosinophils from allergic asthma patients is not accompanied by quantitative upregulation of these antigens. Taken together, these results allow the conclusion that blood eosinophils from allergic asthma patients have undergone in vivo priming, mimicked in vitro by cytokines such as GM-CSF, IL-3, and IL-5, leading to induction of the capacity to migrate across cytokine-activated HUVE monolayers.
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PMID:Migration of primed human eosinophils across cytokine-activated endothelial cell monolayers. 158 39

We have examined the in vitro interaction between bronchial epithelial cells and eosinophils derived from five asthmatics by determining the effect of epithelial cell-conditioned medium on the survival and activation of peripheral blood eosinophils. The supernatants of epithelial cells from six normal donors were used as control. The asthmatic epithelial cell-conditioned medium significantly increased the survival of eosinophils cultured for 3 (P less than 0.025) and 6 (P less than 0.05) days. The incubation of eosinophils with the supernatants of asthmatic epithelial cells for 1 h also increased the generation of superoxide anion and the release of leukotriene C4, triggered by phorbol myristate acetate and calcium ionophore, by more than twofold. The preincubation of asthmatic epithelial cell-conditioned media with saturating concentrations of a mono-specific antiserum against granulocyte-macrophage colony-stimulating factor (GM-CSF) completely abolished their activity, whereas the addition of recombinant human GM-CSF restored it. The supernatants of asthmatic epithelial cells contained 0.88 +/- 0.09 (SD) ng/5 X 10(5) cells immunoreactive GM-CSF, and this amount was significantly greater than that measured in the supernatants of normal epithelial cells (0.21 +/- 0.105, P less than 0.025). Bronchial epithelial cells from asthmatics also expressed increased levels of GM-CSF mRNA when compared with normal epithelial cells. Thus both the synthesis and release of GM-CSF by bronchial epithelial cells are upregulated in asthma, and this may contribute to the persistence of eosinophil infiltration and activation in asthmatic airways.
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PMID:A bronchial epithelial cell-derived factor in asthma that promotes eosinophil activation and survival as GM-CSF. 164 80

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