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)

TH2-type cytokines, particularly interleukin-5, together with granulocyte-macrophage colony-stimulating factor and interleukin-3, orchestrate the eosinophil response in asthma. Eosinophils are believed to be prime proinflammatory effector cells causing bronchial damage, which in turn, leads to chronic asthma symptoms. Although many cells may secrete cytokines (e.g., mast cells, epithelial cells, macrophages), all of which influence eosinophil differentiation, survival, and function, the TH2-type T cell is seen as having a central role since it is capable of direct antigen recognition. The putative "driving" antigen for asthmatic inflammation may be allergen, although other antigens (e.g., viral, epithelial) are also possible candidates. Although T cells also influence the synthesis of IgE, IgE-mediated mechanisms are seen as playing a secondary role only in atopic subjects, where they may be responsible for acute, short-lived symptoms superimposed on the chronic, on-going cell-mediated inflammatory disease.
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PMID:TH2-type cytokines in asthma. 890 6

T cell-derived cytokines, such as interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) activate eosinophils, whereas other cytokines, such as tumor necrosis factor (TNF)-alpha and IL-13, determine eosinophil recruitment. Interferon-alpha (IFN-alpha), a leukocyte-derived cytokine, has been shown to have beneficial effects in eosinophil-mediated disorders, such as the hypereosinophilic syndrome and a murine model of allergic asthma, where it inhibited eosinophil recruitment. We tested the hypothesis that IFN-alpha acted in eosinophil-mediated disorders by modulating T cell cytokine expression. Peripheral blood mononuclear cells (PBMC) or human ragweed-specific TH1 (2B8) and TH2 (2D2) T cell clones were cultured in the presence of 5 micrograms/ml of phytohemagglutinin (PHA) or 25 micrograms/ml of antigen Amb a 1 (short ragweed allergen), respectively, and lymphoblastoid IFN-alpha (varying from 0 to 10,000 U/ml). We assessed T cell proliferation by [3H]thymidine incorporation and production of IL-5 and GM-CSF by ELISA. Expression of cytokine transcripts was analyzed by the reverse transcription-polymerase chain reaction technique (RT-PCR). IFN-alpha induced a dose-dependent suppression of T cell proliferation of both PBMC (p < 0.001) and the T cell clones (p < 0.001). IFN-alpha inhibited gene expression of IL-5, GM-CSF, TNF-alpha, and IL-13 in PBMC. Furthermore, IFN-alpha significantly inhibited mitogen-induced and antigen-induced production of IL-5 and GM-CSF. IFN-alpha may benefit eosinophil-mediated disorders by inhibiting T cell function and production of cytokines active on human eosinophils.
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PMID:Lymphoblastoid interferon-alpha inhibits T cell proliferation and expression of eosinophil-activating cytokines. 891 Jul 67

Cellular and mediator profiles in bronchoalveolar lavage have not been compared systematically between patients with asthma of different severities, mainly because the patients with more severe asthma have an increased need for antiinflammatory medication. Information is limited to comparisons of allergic and intrinsic asthma, which can be distinguished clinically. When patients from these two groups with similar degrees of bronchial hyperresponsiveness were compared, both groups showed increased numbers of activated T-helper lymphocytes; those in the allergic group expressed the IL-2 receptor (CD25+), whereas in patients with intrinsic asthma there was also an increased number of T-suppressor cells with the activation markers CD25, class II histocompatibility antigen, and very late activation antigen-I, as well as T-helper cells class II histocompatibility antigen and very late activation antigen-I. This pattern is compatible with a more chronic T-cell activation in patients with intrinsic asthma. In patients with allergic asthma the cytokine pattern is compatible with a pure TH2 response (elevated IL-4 and IL-5); however, intrinsic asthma is characterized by elevated IL-5 and IL-2 but not IL-4. Our own findings show similar concentrations of IL-1, IL-8, and granulocyte-macrophage colony-stimulating factor in bronchoalveolar lavage fluid of patients with allergic and intrinsic asthma, whereas IL-6 and interferon-gamma tended to be higher in patients with intrinsic asthma. There are probably fundamental differences in the pathogenesis of allergic and intrinsic asthma. These findings suggest that asthma does not depend on the presence of IgE or IL-4, although both may contribute to the pathogenesis of atopic asthma. The only common pathway in the different presentations of asthma that has been related to clinical symptoms appears to be IL-5-mediated activation of eosinophils; therapies aimed at this mechanism may be promising.
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PMID:Inflammatory determinants of asthma severity: mediator and cellular changes in bronchoalveolar lavage fluid of patients with severe asthma. 893 74

Myofibroblasts have been previously described beneath the bronchial epithelium and were found to increase in number proportional to the accumulation of extracellular matrix in the bronchial lamina reticularis in asthma. The aim of this study was to assess further the contribution of these structural cells to allergic inflammation in the bronchial mucosa through their cytokine expression. Cell cultures were established from the lamina reticularis of human bronchial biopsies from asthmatic and non-asthmatic subjects. Cytokine secretion was measured by ELISA in supernatants of cultures with or without tumour necrosis factor-alpha (TNF-alpha). The mRNA levels for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the cultures were examined by ribonuclease protection assays (RPAs). Bronchial myofibroblasts grown from bronchial biopsies were capable of producing GM-CSF, interleukin-6 (IL-6), interleukin-8 (IL-8), and stem cell factor (SCF) constitutively. The GM-CSF production by myofibroblasts was significantly increased in response to TNF-alpha simulation with a corresponding increase in GM-CSF mRNA expression. The enhancement of GM-CSF production by TNF-alpha in myofibroblasts was blocked by the inhibition of RNA synthesis. Prednisolone abolished the GM-CSF production. This study provides evidence for the role of bronchial myofibroblasts in the regulation of inflammatory cell recruitment and activation by interaction in the cytokine network in the bronchial mucosa.
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PMID:Cytokine production by cell cultures from bronchial subepithelial myofibroblasts. 894 23

Atopic dermatitis (AD), a chronic inflammatory skin disease, is frequently seen in patients with a personal or family history of asthma and allergic rhinitis. Population studies suggest an increasing prevalence of AD in children since World War II, with 10-15% of the population being affected by AD at some time during childhood. In patients with moderate to severe AD, involvement can be life-long, causing significant interference with school, work and social interactions. The term atopic dermatitis was introduced to reflect the close association between AD and respiratory allergy. During the past decade, extraordinary progress has been made in our understanding of the immunopathogenesis of allergic diseases. In particular, this constellation of inherited illnesses has now been demonstrated to be associated with activation of a specific group of cytokine genes encompassing IL-3, IL-4, IL-5, IL-13 and granulocyte-macrophage colony-stimulating factor (GM-CSF). The molecular basis for selective activation of this cytokine gene cluster and the immunological consequences are now being pursued actively by many laboratories. However, it is clear that allergic diseases result from a polygenic inheritance pattern which involves not only cytokine gene activation but also activation of other less well defined gene products. Furthermore, the clinical expression of allergic diseases is highly dependent on a complex interaction between the host and its environment, e.g. allergen exposure. The genetic predisposition to develop allergic responses may be similar in patients with AD and other allergic diseases, such as asthma. However, targeting of the allergic immune response may relate to the organ in which allergen sensitization first occurs; the capacity of immune effector cells, e.g. T lymphocytes, to home preferentially to the skin versus the respiratory mucosa; and the programmed response of resident cells, e.g. epithelial cells, to injury and inflammation. This review examines the cellular and immunological mechanisms that are thought to play an important role in the pathogenesis of chronic AD. An understanding of the immunological basis of AD is likely to have important clinical implications in our approach to the management of this common illness, and the development of immunomodulators for its treatment.
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PMID:Atopic dermatitis: immunobiology and treatment with immune modulators. 902 Sep 32

Bronchial antigen challenge of sensitized atopic patients with asthma results in an early fall in FEV1, followed in a proportion of patients by a late (4 to 24 hours) fall. The late response is accompanied by an increase in bronchial reactivity, which is widely believed to reflect local influx and degranulation of inflammatory cells, particularly eosinophils, in association with elevated local secretion of cytokines. We hypothesized that the development of a late-phase bronchoconstrictor response and airway eosinophilia after allergen challenge of sensitized atopic patients with asthma is associated with elevated induced sputum concentrations of the eosinophil-active cytokines IL-5 and granulocyte-macrophage colony-stimulating factor and the proinflammatory cytokine tumor necrosis factor-alpha. We counted inflammatory leukocytes and measured cytokine concentrations in induced sputum at baseline and 24 hours after inhalational allergen challenge of 15 atopic patients with asthma who had previously demonstrated a late response. We observed significant increases in the numbers of eosinophils and the concentrations of their granule products, eosinophil cationic protein and eosinophil peroxidase. In contrast, the numbers of neutrophils and concentrations of two of their products, myeloperoxidase and human neutrophil lipocalin, did not significantly change. The numbers of sputum eosinophils correlated with the maximal late-phase fall in FEV1. Concentrations of IL-5 and tumor necrosis factor-alpha, but not granulocyte-macrophage colony-stimulating factor, were significantly elevated after allergen challenge. We conclude that the relatively noninvasive technique of induced sputum production can be used to monitor the effect of bronchial provocation on cytokine concentrations in asthma.
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PMID:Late response to allergen is associated with increased concentrations of tumor necrosis factor-alpha and IL-5 in induced sputum. 956 18

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

Recent studies from our laboratory indicate that local and (particularly) systemic steroids can modulate the traffic of dendritic cells (DC) through resting and inflamed airway epithelial tissues. The present report focuses upon the T-cell activating properties of DC, which are controlled by granulocyte-macrophage colony-stimulating factor (GM-CSF) signals, and in particular the question of whether the DC-stimulating effects of GM-CSF are susceptible to regulation by steroids. We present evidence that while dexamethasone inhibited GM-CSF-dependent uptake and/or processing of exogenous antigen by DC, it was ineffective in blocking the presentation of preprocessed self antigen to alloreactive T cells in a one-way mixed lymphocyte reaction (MLR). Associated GM-CSF-induced up-regulation of major histocompatability complex (MHC) class II and CTLA4 ligand expression by DC were also unaffected by dexamethasone phosphate (DX), reinforcing the view that the inhibitory effects of steroids on the T-cell activating functions of DC are restricted to steps upstream from presentation of processed antigen to the T-cell receptor (TCR). These findings have potentially important implications in relation to the use of topical steroids in the treatment of atopic asthma, a disease in which local T-cell activation in airway tissue is a key pathogenic factor, and which furthermore is characterized by intense production of GM-CSF within the airway epithelium.
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PMID:Steroids inhibit uptake and/or processing but not presentation of antigen by airway dendritic cells. 920 78

Increased numbers of eosinophils and mast cells in the bronchial mucosa are characteristic features in subjects with aspirin-sensitive asthma. Interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are involved in the activation, maturation, and perpetuation of survival of eosinophils. Immunohistochemical techniques were therefore used to study the expression of IL-5 and GM-CSF on frozen bronchial biopsies from 13 aspirin-sensitive asthmatic (ASA) and 8 non-ASA (NASA) subjects. Aspirin sensitivity was diagnosed by lysine-aspirin inhalation provocation. ASA airways demonstrated a significant 2-fold increase in the total number of submucosal inflammatory cells expressing IL-5 (p = 0.03) and approximate 4- and 2-fold increases in the numbers of mast cells expressing IL-5 and GM-CSF (p = 0.02 and p = 0.04, respectively). There was also a 4-fold increase in the number of eosinophils expressing IL-5 (p = 0.004). These results suggest a central role for the mast cell and eosinophil in regulation of the inflammatory cell infiltrate of ASA airways by secretion of the hemopoietic cytokines IL-5 and GM-CSF.
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PMID:Expression of interleukin-5 and granulocyte-macrophage colony-stimulating factor in aspirin-sensitive and non-aspirin-sensitive asthmatic airways. 937 49

There is evidence that eosinophils have an important role in the pathogenesis of allergy and asthma. These cells are regulated by two classes of polypeptides, the colony-stimulating factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), and the chemokines, such as RANTES and eotaxin. GM-CSF is involved in the production, survival, and functional activation of eosinophils. RANTES and eotaxin regulate the migration of eosinophils to inflammatory sites, but any effect of these chemokines on eosinophil survival is not known. In this study we demonstrate that although GM-CSF promoted eosinophil survival, the specific GM-CSF analogue E21R induced apoptosis of eosinophils. Apoptosis was observed with unstimulated as well as with chemokine (RANTES and eotaxin)-activated eosinophils. Neither RANTES nor eotaxin supported eosinophil survival, and a RANTES antagonist did not affect either cell survival or apoptosis. E21R also induced apoptosis of eosinophils from asthmatic patients. These findings suggest that the GM-CSF receptor may actively control the death as well as the survival of eosinophils, and thus precisely regulate their numbers and activities. Our data also indicate that chemokines are not involved in regulating the lifespan of eosinophils. The introduction of the GM-CSF analogue E21R may offer a novel therapy in inflammatory diseases associated with eosinophil infiltration of different etiologies.
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PMID:The GM-CSF analogue E21R induces apoptosis of normal and activated eosinophils. 937 86


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