Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eosinophil-mediated diseases, such as allergic asthma, eosinophilic fasciitis, and certain hypersensitivity pulmonary disorders, are characterized by eosinophil infiltration and tissue injury. Mast cells and T cells often colocalize to these areas. Recent data suggest that mast cells can contribute to eosinophil-mediated inflammatory responses. Activation of mast cells can occur by antigen and immunoglobulin E (IgE) via the high-affinity receptor (FcepsilonRI) for IgE. The liberation of proteases, leukotrienes, lipid mediators, and histamine can contribute to tissue inflammation and allow recruitment of eosinophils to tissue. In addition, the synthesis and expression of a plethora of cytokines and chemokines (such as granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin-1 [IL-1], IL-3, IL-5, tumor necrosis factor-alpha [TNF-alpha], and the chemokines IL-8, regulated upon activation normal T cell expressed and secreted [RANTES], monocyte chemotactic protein-1 [MCP-1], and eotaxin) by mast cells can influence eosinophil biology. Stem cell factor (SCF)-c-kit, cytokine-cytokine receptor, and chemokine-chemokine receptor (CCR3) interactions leading to nuclear factor kappaB (NF-kappaB), mitogen-activated protein kinase (MAPK) expression, and other signaling pathways can modulate eosinophil function. Eosinophil hematopoiesis, activation, survival, and elaboration of mediators can all be regulated thus by mast cells in tissue. Moreover, because eosinophils can secrete SCF, eosinophils can regulate mast cell function in a paracrine manner. This two-way interaction between eosinophils and mast cells can pave the way for chronic inflammatory responses in a variety of human diseases. This review summarizes this pivotal interaction between human mast cells and eosinophils.
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PMID:The role of human mast cell-derived cytokines in eosinophil biology. 1515 10

Interleukin-5 (IL-5) plays an important role in the activation of eosinophils in the allergic inflammation in conditions such as asthma, rhinitis, and atopic dermatitis. A newly synthesized compound, YM-90709 (2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo[7,8]indolizino[2,3-b]quinoxaline), was previously reported to inhibit the binding of IL-5 to its receptor (R) on human eosinophils and eosinophilic HL-60 clone 15 cells. However, it did not inhibit the binding of granulocyte-macrophage colony-stimulating factor (GM-CSF) to its receptor on the same cells. In this study, the intravenous injection of YM-90709 resulted in the inhibition of antigen-induced infiltration of eosinophils and lymphocytes, but not neutrophils or monocytes, into the bronchoalveolar lavage fluid (BALF) of Brown-Norway (BN) rats, with ED50 values of 0.32 mg/kg and 0.12 mg/kg, respectively. Two glucocorticoids, dexamethasone and prednisolone, inhibited neutrophil, eosinophil, and lymphocyte infiltration into the BALF. However, both significantly reduced the number of peripheral blood leukocytes and bone marrow leukocytes. In contrast, YM-90709 did not affect the peripheral blood leukocytes or the bone marrow leukocytes. These results indicate that, in this model, YM-90709, which is a novel IL-5 R antagonist, inhibits antigen-induced eosinophil and lymphocyte recruitment into the airway, without any suppressive effects on peripheral blood leukocytes or bone marrow leukocytes, in contrast to the glucocorticoids.
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PMID:Effect of a novel interleukin-5 receptor antagonist, YM-90709 (2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo[7,8]indolizino[2,3-b]quinoxaline), on antigen-induced airway inflammation in BN rats. 1518 27

The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through a receptor (cysLT1-R) which can be targeted in rhinitis and asthma. We investigated the effects of cysLT1-R antagonism in experimental allergic rhinitis, focusing on bone marrow eosinophil progenitor responses. BALB/c mice were sensitized, then given daily intranasal ovalbumin for 2 weeks, with montelukast sodium (5 mg/kg or 2.5 mg/kg) or placebo by gavage. Bone marrow eosinophil/basophil colonies were enumerated, and colony cells were morphologically assessed as indices of eosinophil differentiation and maturation. Montelukast treatment resulted in a significant decrease of eosinophils in the nasal mucosa, and in either bone marrow interleukin (IL)-5-, but not IL-3-, or granulocyte-macrophage colony-stimulating factor-responsive eosinophil/basophil colony-forming units, and IL-5-stimulated eosinophil maturation. These results indicate that cysLT1-R antagonism in vivo limits both IL-5-responsive eosinophilopoiesis, acting at several stages of eosinophil differentiation and maturation. The anti-allergic effects of cysLT1-R antagonists are consistent with the concept that cysLTs and IL-5 act together in the recruitment of eosinophils and eosinophil progenitors from the marrow during upper airway allergic inflammation.
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PMID:Effects of a cysteinyl leukotriene receptor antagonist on eosinophil recruitment in experimental allergic rhinitis. 1537 85

Twice-daily combination therapy of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists (LABA) is now established as a most effective treatment for moderate to severe asthma and is available in a combined single inhaler. The benefits of combination therapy include better day-to-day control and a reduction in exacerbations compared with monotherapy with inhaled corticosteroids at a lower dose. Total control of asthma, defined as no daytime or night-time symptoms, no use of rescue beta2-adrenoceptor agonists (beta2-agonists), no exacerbations and a peak flow rate of >80% predicted, may be achieved with the use of combined salmeterol/fluticasone in up to 41% of patients with moderate to severe asthma, compared with only 28% of patients treated with fluticasone alone. Adjustable maintenance dosing with budesonide/formoterol may provide better control when compared with fixed-dosing combination regimens. Other therapies combining effectively with inhaled corticosteroids include slow-release theophylline and leukotriene inhibitors, montelukast and zafirlukast, but LABA are the most efficacious. Molecular interactions between corticosteroids and beta2-adrenoceptors may underlie the clinical added benefits of combination therapy. Corticosteroids may increase the number of beta2-adrenoceptors and their coupling with Gs proteins, while beta2-agonists may induce glucocorticoid receptor nuclear translocation, activate transcription factor/enhancer binding protein C/EBPalpha together with corticosteroids, or phosphorylate corticosteroid receptors. The combination of corticosteroids and LABA potentiates inhibition of interleukin-8 and eotaxin release from human airway smooth muscle cells and granulocyte-macrophage colony-stimulating factor release from epithelial cells, and also the inhibition of airway smooth muscle cell proliferation. It is important to determine whether there is a potentiating effect of combination therapy compared with corticosteroid treatment alone on airway inflammation and airway wall remodelling. Improvements in combination therapy include a once-daily preparation and possible combination of inhaled corticosteroids with newer drugs such as phosphodiesterase IV inhibitors.
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PMID:Combination therapy of long-acting beta2-adrenoceptor agonists and corticosteroids for asthma. 1560 18

Selective inhibitors of phosphodiesterases (PDEs) have been suggested to have anti-inflammatory effects on bronchial asthma through the inhibition of chemotaxis, adhesion, degranulation, the respiratory burst, and survival prolongation of eosinophils. However, the mechanisms by which these agents inhibit eosinophil survival remain unclear. We therefore investigated the possible mechanisms of inhibitory effects of selective inhibitors of PDE 3 (cilostazol) and PDE 4 (rolipram) on granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated eosinophil survival. Purified blood eosinophils were cultured with medium alone or GM-CSF (0.01 ng/ml) in the presence or absence of the agents for up to 6 d. DNA was extracted from freshly isolated eosinophils and eosinophils cultured for 2 d with medium alone, GM-CSF, or GM-CSF in the presence of the agents, and analyzed using agarose gel electrophoresis. The presence of rolipram (10(-4), 10(-5), 10(-6) M), but not cilostazol, significantly inhibited eosinophil survival at days 2, 4, and 6. A laddering pattern was observed in the DNA of eosinophils cultured with medium alone and with GM-CSF in the presence of rolipram. The results reveal that selective PDE 4 inhibitors inhibit GM-CSF-mediated eosinophil survival through the induction of apoptosis.
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PMID:Inhibition of eosinophil survival by a selective inhibitor of phosphodiesterase 4 via the induction of apoptosis. 1574 80

The infiltration, accumulation and degranulation of eosinophils in the lung represents a hallmark of active asthma. In vivo or in vitro eosinophil activation triggers the secretion of the antiapoptotic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). We now identify Pin1, a cis-trans isomerase, as an essential component of the ribonucleoprotein complex responsible for GM-CSF mRNA stabilization, cytokine secretion and the survival of activated eosinophils. Pin1 regulated the association of the AU-rich element-binding proteins AUF1 and hnRNP C with GM-CSF mRNA, accelerating or slowing decay, respectively. These data indicate Pin1 is a key mediator of GM-CSF production.
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PMID:The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils. 1636 62

Decreased allergen-induced histamine release from peripheral blood basophils in allergic rhinitis patients treated with specific immunotherapy (SIT) correlates with clinical outcomes of SIT. The aim of this study was to investigate if decreased histamine release is a permanent effect of SIT. Fifty-one patients (mean age, 35.3 years) with allergic rhinitis, diagnosed based on clinical history and positive skin-prick test results to common aeroallergens, were studied. Twenty-three patients had never received SIT (group A), and 28 patients had been treated with inhalant allergen extracts (group B). Eleven patients from group A participated in a prospective part of this study. Basophil histamine release in these patients was evaluated before (TO) and after-1 year (TI) of SIT. Histamine release from peripheral blood with and without interleukin (IL)-3 pretreatment was performed using the glass-fiber-based histamine release test. Brief pretreatment of whole blood basophils with one of the four concentrations (0.01, 0.1, 1, or 10 ng/mL) of recombinant human IL(rhIL)-3, rhIL-5, or rh-granulocyte-macrophage colony-stimulating factor resulted in a significant amplification of allergen-induced basophil histamine release. The amplification using cytokines at the optimal concentrations was the greatest with rhIL-3 and the lowest with rhIL-5; therefore, for further studies rhIL-3 was used. Prospective analysis showed no significant difference in allergen-induced basophil histamine release on rhIL-3 pretreatment after 1 year of SIT (192.7 +/- 75.3 ng and 176.1 +/- 76.4 ng for T0 and T1, respectively; p = 0.18). Short-term SIT does not decrease rhIL-3-mediated amplification of allergen-induced histamine release from peripheral blood basophils.
Allergy Asthma Proc
PMID:Effect of allergen-specific immunotherapy on recombinant human interleukin 3-mediated amplification of allergen-induced basophil histamine release. 1654 69

Asthma rates have been increasing worldwide, and exposure to diesel exhaust particles (DEP) may be implicated in this increase. DEP may also play a role in the increased morbidity and mortality associated with ambient airborne particulate matter (PM) exposure. Two types of nasal responses have been reported for human subjects nasally instilled with one type of DEP: alterations in cytokines responses, and an increase in immunoglobulin E (IgE) production. Since DEP composition can vary depending on several factors, including fuel composition and engine load, the ability of another DEP particle and ozone-treated DEP to alter nasal IgE and cytokine production was examined. Nonasthmatic and asthmatic subjects were intranasally instilled with 300 microg NIST 1650 DEP per nostril, NIST 1650 DEP previously exposed to ozone (ozDEP; 300 microg/nostril), or vehicle. Subjects underwent nasal lavage before DEP exposure, and 4 and 96 h after exposure. Nasal cell populations and soluble mediators in the nasal lavage fluid were characterized. Total cell number, cell types, cell viability, concentrations of soluble mediators (including interleukin [IL]-8, IL-6, IgE, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) were not altered by either DEP or ozDEP exposure. NO levels were not altered by either particle exposure. These findings suggest that DEP can be relatively noninflammatory and nontoxic, and that the physicochemical characteristics of DEP need to be considered when assessing the health effects of exposure to diesel exhaust.
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PMID:Nasal responses in asthmatic and nonasthmatic subjects following exposure to diesel exhaust particles. 1686 50

Toluene diisocyanate (TDI) is known as one of causes of occupational asthma and hypersensitivity pneumonitis. To investigate the stimulatory effect on bronchial epithelial cells in response to TDI, the authors examined production of cytokines by the bronchial epithelial cell line BEAS-2B and intercellular signal transduction stimulated by TDI-human serum albumin (HSA) conjugate. The production of interleukin (IL)-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and regulated on activation normal T cell expressed and secreted (RANTES) from the bronchial epithelial cells were augmented by the TDI-HSA conjugate. Extracellular signal-regulated kinase (Erk) 1/2 and p38 mitogen-activated protein kinase (MAPK) were phosphorylated by the TDI-HSA conjugate. AG1478, SB203580, and dexamethasone prevented augmentation of these cytokine production. TDI-HSA conjugate did not augment release of epidermal growth factor (EGF) ligands from BEAS-2B. These results suggest that TDI directly induces production of proinflammatory cytokines and chemokines through p38 MAPK and EGF receptor (EGFR)-Erk pathway without an autocrine mechanism. Thus, TDI was shown to have a stimulatory effect on bronchial epithelial cells, suggesting the potent role of bronchial epithelial cells in TDI-induced asthma.
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PMID:Toluene diisocyanate (TDI) induces production of inflammatory cytokines and chemokines by bronchial epithelial cells via the epidermal growth factor receptor and p38 mitogen-activated protein kinase pathways. 1690 50

Mycoplasma pneumoniae is a leading cause of pneumonia and is associated with asthma. Evidence links M. pneumoniae respiratory disease severity with interleukin-12 (IL-12) concentration in respiratory secretions. We evaluated the microbiologic, inflammatory, and pulmonary function indices of M. pneumoniae pneumonia in IL-12 (p35) knockout (KO) mice and wild-type (WT) mice to determine the role of IL-12 in M. pneumoniae respiratory disease. Eight-week-old wild-type BALB/c mice and 8-week-old IL-12 (p35) KO BALB/c mice were inoculated once intranasally with 10(7) CFU of M. pneumoniae. Mice were evaluated at days 2, 4, and 7 after inoculation. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniae culture, lung histopathologic scores (HPS), BAL cytokine concentrations determined by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-alpha], gamma interferon [IFN-gamma], IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor) and plethysmography, before and after methacholine, to assess airway obstruction (AO) and airway hyperreactivity (AHR). IL-12 (p35) KO mice infected with M. pneumoniae were found to have significantly lower BAL M. pneumoniae concentrations compared with M. pneumoniae-infected WT mice. Lung HPS and the parenchymal pneumonia subscores (neutrophilic alveolar infiltrate), as well as AO, were significantly lower in infected KO mice. No difference was found for AHR. Infected KO mice had significantly lower BAL concentrations of IFN-gamma than WT mice; a trend toward lower BAL concentrations was observed for IL-10 (P = 0.065) and TNF-alpha (P = 0.078). No differences were found for IL-1beta, IL-2, IL-4, IL-5, or IL-6. The lack of IL-12 in experimental M. pneumoniae pneumonia was associated with less severe pulmonary disease and more rapid microbiologic and histologic resolution.
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PMID:Respiratory tract infection with Mycoplasma pneumoniae in interleukin-12 knockout mice results in improved bacterial clearance and reduced pulmonary inflammation. 1707 51


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