Circadian changes in granulocyte-macrophage colony-stimulating factor message in circulating eosinophils
ABSTRACT Granulocyte-macrophage colony-stimulating factor (GM-CSF), which stimulates eosinophil recruitment, activation, and survival, is expressed by activated eosinophils. Although eosinophil recruitment and enhanced survival have been associated with nocturnal asthma (NA), the contribution of GM-CSF to NA is unknown.
To determine whether circulating eosinophil GM-CSF expression correlates with the symptoms of NA.
The GM-CSF messenger RNA (mRNA) expression at 4 PM and 4 AM was determined by reverse-transcriptase polymerase chain reaction with Southern blot analysis in subjects with and without NA and in controls.
A total of 142 asthma subjects were screened for nocturnal asthma with 1-week home peak expiratory flow rate (PEFR) monitoring. Eleven subjects had NA (>20% diurnal variation in PEFR on 4 of 7 days), and 6 met the criteria for non-NA (<10% diurnal variation in PEFR on 7 of 7 days); 8 controls were studied. In subjects with NA, GM-CSF mRNA expression in circulating eosinophils increased 3-fold at 4 AM compared with 4 PM. Diurnal changes in GM-CSF mRNA expression were not detected in the non-NA and control groups.
Day-night variation in eosinophil GM-CSF expression is associated with circadian variation in airway function in asthma, a key manifestation of asthma severity.
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ABSTRACT: Differentiation and activation of CD4(+) T cells is controlled by various cytokines produced by innate immune cells. We have shown that eosinophils (EOS) have the potential to influence Th1 and Th2 cytokine generation by CD4(+) cells, but their influence on IL-17A (IL-17) has not been established. The purpose of this study is to determine the effect of EOS on IL-17 production by lymphocytes. Pre-activated CD4(+) T cells were cultured in the presence of either autologous EOS or EOS culture supernatants. Expression of IL-17 was determined by real-time quantitative PCR (qPCR) after 5 h and protein level was measured after 48 h. To determine the effect of allergen-induced airway EOS on IL-17, subjects with mild allergic asthma underwent bronchoscopic segmental bronchoprovocation with allergen (SBP-Ag) after a treatment with an anti-IL-5 neutralizing antibody (mepolizumab) to reduce airway eosinophilia. IL-17 mRNA was measured in bronchoalveolar lavage (BAL) cells by qPCR. In vitro, EOS significantly increased IL-17 production by CD4(+) T cells. Addition of exogenous IL-1ß increased expression of IL-17 mRNA by CD4(+) T cells. EOS expressed and released IL-1ß. Furthermore, levels of IL-1ß in EOS supernatants highly correlated with their ability to increase IL-17 expression by CD4(+) T cells, and neutralizing antibody to IL-1ß reduced expression of IL-17 mRNA. In vivo, reduction of EOS in the airway using mepolizumab was associated with diminished IL-17 expression after SBP-Ag. Our data demonstrate that EOS can promote IL-17 production through the release of IL-1ß. Enhanced IL-17 cytokine production is another mechanism by which EOS may participate in pathogenesis of allergic airway inflammation in asthma.Clinical & Experimental Allergy 12/2012; 42(12):1756-64. DOI:10.1111/j.1365-2222.2012.04060.x · 4.77 Impact Factor