Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In asthma, activation and recruitment of eosinophils to the bronchial mucosa amplifies many cellular functions. The blood eosinophil count and the number of hypodense eosinophils increase with asthma severity. Eosinophils produce numerous proinflammatory mediators in response to a variety of agonists, notably the peptido-leukotriene (LT) C4, a potent bronchoconstrictor. In this study, we have evaluated blood eosinophil LTC4 release and its modulation by cytokines in normal individuals and in subjects with asthma of various severities: mild (beta 2-agonist on demand); moderate (inhaled steroids on a regular basis); and severe (inhaled and oral steroids on a regular basis). Eosinophils were isolated using a modified Percoll gradient technique, which recovers both hypodense and normodense eosinophils in a global cell population. Eosinophils released detectable amounts of LTC4 only in the presence of the stimulus (calcium ionophore A23187, 2 microM). The ionophore-induced LTC4 release was greater in moderate asthmatics (mean +/- SEM 5.7 +/- 1.3 pg x 10(3)/250,000 eosinophils) than in normal individuals (1.6 +/- 0.4 pg x 10(3)/250,000 eosinophils), mild asthmatics (1.8 +/- 0.3 pg x 10(3)/250,000 eosinophils) and severe asthmatics (2.0 +/- 0.3 pg x 10(3)/250,000 eosinophils). Granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) amplified the ionophore-induced LTC4 release in the four groups from 1.9 to 2.6 and 1.9 to 2.8 fold, respectively. Interleukin-3 (IL-3) did not increase LTC4 production except by the eosinophils of the severe asthmatics whose ionophore-induced LTC4 production was enhanced by 1.9 fold. These data demonstrate that the asthmatic bronchial inflammatory process may modify blood eosinophil LTC4 release and its modulation by cytokines according to asthma severity and treatment.
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PMID:Blood eosinophil leukotriene C4 production in asthma of different severities. 857 70

Glucocorticosteroids (GCS) are beneficial in allergic asthma. GCS therapy results in reduced mRNA expression of interleukin-4 (IL-4) and IL-5 in cells from bronchoalveolar lavage (BAL) but not of IFN-gamma. In vitro studies with blood-derived T cells, however, show inhibition of all three cytokines by GCS. We studied the effects of GCS on T cells from BAL in vitro, namely Th0-, Th1, and Th2-like clones; and we compared BAL- with blood-derived clones. Dexamethasone (DEX) inhibited the anti-CD3-induced production of IL-4, IL-5 and IFN-gamma in all 20 clones tested. IFN-gamma production was inhibited significantly less than IL-4 and IL-5. DEX enhanced the ratio IFN-gamma/IL-4 (mean +/- SEM: control, 28.7 +/- 17.6; with 10-7 M DEX, 55.0 +/- 27.5, P<0.005). Interestingly, two categories of clones were distinguished based on the effects of GCS on IL-2 production and IL-2R alpha expression and proliferation; 1) In low IL-2 producers DEX blocked IL-2 production and decreased IL-2R alpha expression and proliferation; 2) In high IL-2 producers DEX inhibited IL-2 production partially and enhanced IL-2R alpha expression and proliferation. Anti-IL-2 and anti-IL2R alpha blocked the DEX-induced increase in proliferation. High levels of added IL-2 induced the second type of response. In conclusion, the production of IL-4 and IL-5 by T-cell clones (derived either from BAL or blood) was more sensitive to inhibition by DEX than that of IFN-gamma, which may account for the therapeutic effects of glucocorticosteroids in patients with asthma. The differential effects of DEX on the proliferation of high and low IL-2 producers in vitro may implicate a selective outgrowth of Th1-like T cells in vivo in patients treated with steroids.
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PMID:Glucocorticosteroids affect functions of airway- and blood-derived human T-cell clones, favoring the Th1 profile through two mechanisms. 860 Sep 44

Cytokine-mediated immune responses to Mycobacterium tuberculosis infection are important determinants of M. tuberculosis disease development and pathology. However, the distinction between changes in cytokine profile attributable to M. tuberculosis infection and those associated with active pulmonary tuberculosis is unclear. We have compared T cells and their subsets, macrophages, and cytokine messenger RNA (mRNA) profile in the bronchoalveolar lavage (BAL) of patients with active pulmonary tuberculosis with inactive tuberculosis subjects. Ten patients with microbiologically confirmed active pulmonary tuberculosis and 25 subjects with inactive tuberculosis were recruited. Bronchoscopy with BAL was undertaken in all cases and BAL cytospins were examined using the techniques of immunocytochemistry and in situ hybridization. There was a significant increase in the percentage of BAL cells that were CD8+ T cells in active tuberculosis compared with inactive tuberculosis (mean +/- SEM: 7.2 +/- 0.9 versus 2.1 +/- 0.4, p < 0.001), but not CD3+ or CD4+ T cells nor macrophages. There were significant increases in the percentage of BAL cells expressing mRNA for interferon-gamma (IFN-gamma) and interleukin-12 (IL-12) in active versus inactive pulmonary tuberculosis subjects (8.0 +/- 0.6 versus 3.7 +/- 0.4 and 28.4 +/- 2.3 versus 10.2 +/- 1.0, p < 0.001, respectively). There were no significant differences between the active and inactive groups in the number of cells expressing mRNA for IL-2, tumor necrosis factor-alpha (TNF-alpha), IL-4, and IL-5. In conclusion, active pulmonary tuberculosis is associated with increased numbers of CD8+ cells and marked increases in the expression of IL-12 and IFN-gamma mRNA in the BAL, both of which may be useful markers of disease activity.
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PMID:IFN-gamma and IL-12 are increased in active compared with inactive tuberculosis. 911 99

We have compared an immunocytochemical and a flow cytofluorimetric method to detect intracellular IFN-gamma, IL-4 and IL-5 in T-cell clones, peripheral blood mononuclear cells (PBMC) and bronchoalveolar lavage fluid (BALF) cells. Intracellular bound cytokine-specific antibodies were visualized either with amino-ethyl carbazole (for immunocytochemistry), or with fluorescent antibodies (for flow cytofluorimetry). The staining was inhibited with recombinant cytokines and corresponded qualitatively and quantitatively to cytokine levels in the supernatants of T-helper-0 (Th0), Th1 and Th2 clones. In analysing in vitro stimulated cells, sufficient signal in the fluorimetric assay was only obtained after the addition of monensin to the cultures. We then observed a good correlation between immunocytochemical (with no monensin added) and the flow cytofluorimetric staining for all three cytokines (PBMC, IFN-gamma and IL-4, rho = 0.9, no IL-5 detectable; clones, IL-5, rho = 0.81, all three p < 0.05). However, compared to flow cytometry, a greater percentage of positively stained cells was frequently observed using immunocytochemistry. In BALF cells, the immunocytochemical method was able to detect significant percentages of positive cells without in vitro stimulation of the cells, in contrast to the flow cytofluorimetric method. In BALF cells from sarcoidosis patients, T-cells were mainly IFN-gamma-positive (immunocytochemically assessed), both with (mean +/- SEM, 39.7 +/- 9.8%), and without (3.5 +/- 1.3%) in vitro stimulation. In BALF cells from allergic subjects, the immunocytochemical method showed lymphocytes positive for IFN-gamma (40.3 +/- 8.3%), IL-4 (19.1 +/- 0.49) and IL-5 (6.1 +/- 3.1). We conclude that both methods can be used to assess the production of IFN-gamma, IL-4 or IL-5 at the single-cell level in T-cell clones, PBMC and cells from the BALF. The high sensitivity and the low number of cells required for the immunocytochemical method indicate that this method can provide detailed information on cytokine production of airway-derived cells in diseases with airway inflammation such as sarcoidosis and asthma.
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PMID:Immunocytochemical and flow cytofluorimetric detection of intracellular IL-4, IL-5 and IFN-gamma: applications using blood- and airway-derived cells. 913 33

Here we show that the supernatant from activated lung mast cells induced the release of eosinophil cationic protein (ECP) from eosinophils. Lung mast cells were purified using affinity magnetic selection with monoclonal antibody (mAb) YB5.B8 to achieve a final mast cell purity of 93-99%. Eosinophils were purified by immunomagnetic negative selection (>98.0% pure). The supernatant was obtained from lung mast cells activated for 24 h with 1 microg/ml anti-IgE and 50 ng/ml stem cell factor (SCF). Human eosinophils were incubated with various concentrations of the supernatants for 4 h and ECP released was measured by RIA. Using 4 different donors' supernatant from mast cells, each donor's supernatant caused a dose-dependent release of ECP from eosinophils. The dilutant of 1:2 (v/v) of the supernatant induced 657.5 +/- 55.6 ng/10(6) eosinophils of ECP which is statistically significant (p = 0.008, n = 4) compared with the culture medium alone. Anti-interleukin (IL-5 neutralizing mAb, 10 microg/ml, and anti-tumor necrosis factor-alpha (TNF alpha) neutralizing mAb, 10 microg/ml, significantly inhibited the supernatant-induced ECP release in 79.3 +/- 9.4 and 68.2 +/- 14.1% (mean +/- SEM, n = 6, p < 0.005), respectively. Anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) neutralizing mAb, 50 microg/ml, caused 68.0 +/- 6.1% of inhibition (p = 0.002). The isotype negative control had no measurable inhibitory or stimulatory effect for the stimuli. We confirmed that mast cells produce IL-5, GM-CSF and TNF alpha in response to IgE-dependent stimulation by using RT-PCR, in situ hybridization, ELISA and immunocytochemistry. A million of lung mast cells generated 41.4 pg (7.0-273.6) (median with range) of TNF alpha, 252.6 pg (158.7-3,652) of GM-CSF and 735 pg (< 10-2,750) of IL-5 24 h after activation with SCF and anti-IgE. These findings indicate that the human mast cells may contribute to the chronicity of tissue inflammation.
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PMID:Activation of eosinophils with cytokines produced by lung mast cells. 936 32

Repeated low-dose allergen challenge increases airway hyperresponsiveness in atopic asthmatics. However, it is not known whether low-dose allergen challenge increases airway inflammation. Eight atopic asthmatics were enrolled in a controlled, cross-over study to evaluate the effect and time course of repeated low-dose allergen challenge on airway inflammation and hyperresponsiveness. The dose of allergen to reduce forced expiratory volume in one second (FEV1) by approximately 5% was selected in a screening allergen challenge. The subjects then were challenged for five consecutive days with either diluent or the selected low-dose of allergen. Methacholine airway hyperresponsiveness (PC20,meth) was measured and sputum induced on days 1, 3 and 5 of the repeated challenge, and then 1 day and 3 days after the last challenge. Repeated low-dose allergen challenge caused small reductions in FEV1, but increased airway eosinophils and interleukin (IL)-5, airway hyperresponsiveness, asthma symptoms and beta2-agonist use, all of which peaked on days 3 or 5 of the challenge. The mean (SEM) percentage sputum eosinophils was 21.2 (0.7)% after allergen versus 3.9 (0.1)% after diluent (p<0.001); percentage EG2+ cells were 13.4 (03)% after allergen versus 1.1 (0.04)% after diluent (p<0.01) and geometric mean (GSEM) eosinophil cationic protein (ECP) was 1061.8 (1.6) microg x L(-1) after allergen versus 447.03 (1.2) microg x L(-1) after diluent (p<0.05). Geometric mean (GSEM) IL-5 was 71.4 (1.4) pg x mL(-1) after allergen versus 18.4 (1.04) pg x mL(-1) after diluent (p<0.01). All the changes had resolved by 3 days after the last challenges. The study demonstrated that repeated inhalation of a low-dose of allergen causes airway eosinophilia and increases in interleukin-5, associated with airway hyperresponsiveness, and mild worsening of asthma control, without the development of marked acute bronchoconstriction or the development of late responses.
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PMID:Increases in airway eosinophils and interleukin-5 with minimal bronchoconstriction during repeated low-dose allergen challenge in atopic asthmatics. 962 78

Macrophage migration inhibitory factor (MIF) is a potent proinflammatory mediator that has been shown to potentiate lethal endotoxemia and to play a potentially important regulatory role in human acute respiratory distress syndrome (ARDS). We have investigated whether eosinophils are an important source of MIF and whether MIF may be involved in the pathophysiology of asthma. Unstimulated human circulating eosinophils were found to contain preformed MIF. Stimulation of human eosinophils with phorbol myristate acetate in vitro yielded significant release of MIF protein. For example, eosinophils stimulated with phorbol myristate acetate (100 nM, 8 h, 37 degreesC) released 1,539+/-435 pg/10(6) cells of MIF, whereas unstimulated cells released barely detectable levels (< 142 pg/10(6) cells, mean+/-SEM, n = 8). This stimulated release was shown to be (a) concentration- and time-dependent, (b) partially blocked by the protein synthesis inhibitor cycloheximide, and (c) significantly inhibited by the protein kinase C inhibitor Ro-31,8220. In addition, we show that the physiological stimuli C5a and IL-5 also cause significant MIF release. Furthermore, bronchoalveolar lavage fluid obtained from asthmatic patients contains significantly elevated levels of MIF as compared to nonatopic normal volunteers (asthmatic, 797.5+/-92 pg/ml; controls, 274+/-91 pg/ml). These results highlight the potential importance of MIF in asthma and other eosinophil-dependent inflammatory disorders.
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PMID:Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma. 963 21

Atopic dermatitis (AD) is associated with increased IL-4, IL-5, and IL-13 but decreased IFN-gamma production. This cytokine profile may account for the atopic features of this illness, including IgE upregulation. Recent studies have demonstrated that tumor necrosis factor (TNF)-beta is produced by Th1-like cells, but the cytokine modulation by TNF-beta and the clinical significance of this cytokine in AD is not known. Therefore, this study was carried out to determine the potential role of TNF-beta in AD. In this study, we cultured peripheral blood mononuclear cells from patients with AD and normal subjects with anti-CD3 monoclonal antibodies and investigated the production of TNF-beta by ELISA. The mean +/- SEM of TNF-beta production in AD was significantly lower than normal subjects (p = 0.03). The effect of TNF-beta on cytokine production was investigated by culturing peripheral blood mononuclear cells with anti-CD3 monoclonal antibodies in the presence or absence of TNF-beta. Compared with medium control, TNF-beta significantly decreased IL-5 (p = 0.0004) and IL-13 (p = 0.008) but increased IFN-gamma (p = 0.001) production. The effect of TNF-beta on IgE production was determined by culturing peripheral blood mononuclear cells in the IL-4- and anti-CD40-induced IgE production system. Interestingly, TNF-beta significantly decreased IgE (p = 0.02), but not IgG production compared with medium control. Our study demonstrates that TNF-beta production is downregulated in AD. This cytokine increases IFN-gamma production but decreases IL-5, IL-13, as well as IgE production. These findings suggest a potential role for TNF-beta in the pathogenesis of AD.
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PMID:The modulation of cytokine and IgE production by tumor necrosis factor-beta in atopic dermatitis. 1062 Jan 39

Theophylline, a known phosphodiesterase inhibitor, has been widely used as an additional bronchodilator in asthmatic patients who are not adequately controlled on high-doses of inhaled steroids. However, there is growing evidence that theophylline may also have anti-inflammatory or immunomodulatory effects in asthma. This study investigated whether theophylline administration has an impact on serum levels of interleukin (IL)-4 and IL-5 in asthmatic patients. Eight asymptomatic patients aged 30+/-1.5 yrs (mean +/- SEM) with mild atopic asthma were given a single daily dose of theophylline 150 mg or placebo in an on (theophylline)-off (placebo)-on (theophylline)-off (placebo) protocol with a 3-week duration of each on- or off- interval. Determination of serum IL-4 and IL-5 was done at baseline for all subjects and on the last day of each 3-week interval for the patients under study. Serum IL-4 levels were: 35+/-6 (baseline), 19+/-3 (on-1 interval), 29.5+/-4 (off-2), 15+/-2 (on-3) and 26+/-4 pg x mL(-1) (off-4), while IL-5 levels were 27+/-5, 18+/-4, 28+/-5, 17+/-4 and 28+/-5 pg x mL(-1), respectively. Spirometry was unchanged during the study and serum theophylline levels at the end of the two on-periods were 4.5+/-0.05 and 4.2+/-0.07 microg x mL(-1), while all patients remained asymptomatic. In conclusion, the administration of a low, single, daily dose of oral theophylline in asymptomatic patients with mild atopic asthma seems to reduce circulating interleukin-4 and interleukin-5.
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PMID:Theophylline induces a reduction in circulating interleukin-4 and interleukin-5 in atopic asthmatics. 1083 23

The blockade of alpha4 integrins with a monoclonal antibody (TA-2) decreases late airway responses (LR) in ovalbumin (OVA)-sensitized and challenged rats. In this study, we used a model of CD4+ cell-driven LR to test the hypothesis that alpha4-integrin blockade involves interference with T-cell activation in the inhibition of LR. Purified CD4+ cells from OVA-sensitized rats were transferred to unsensitized recipients, which received either TA-2 or a control antibody (cAb), and were OVA-challenged. A sham-challenged group was also studied. LR, calculated from pulmonary resistance after challenge, were reduced in the TA-2 group compared with the cAb group (p = 0.015). Total cell counts, macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage (BAL), and CD3+ cells in airway sections, were unaffected. The cAb group had higher numbers of cells expressing interleukin-5 (IL-5) mRNA (55.2 +/- 3.39 cells/1,000, mean +/- SEM) and major basic protein (MBP) (6.2 +/- 0.4/100 cells) in bronchoalveolar lavage (BAL), than the TA-2 group (25.37 +/- 2.41 IL-5+ and 2.7 +/- 0.2 MBP+) and the sham group (12.37 +/- 0.96 IL-5+, 1.7 +/- 0.1 MBP+). Interferon gamma (IFN-gamma) mRNA+ cells were downregulated in both OVA-challenged groups, compared with the sham group. Our results suggest that the attenuation of LR and eosinophilia by alpha4-integrin blockade may involve interference with CD4+ cell activation and IL-5 expression.
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PMID:Effect of alpha4-integrin blockade on CD4+ cell-driven late airway responses in the rat. 1120 33


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