Expression and regulation of interferon-related development regulator-1 in cystic fibrosis neutrophils
| Autor: | Gerd Döring, Matthias Griese, Julia Kammermeier, Thomas Illig, Veronica Marcos, Fabian Falkenstein, Stefan Zielen, Norman Klopp, Nikolaus Rieber, Dominik Hartl, Michael S. D. Kormann, Matthias Kappler, Andreas Hector, Martin Stern, Lauren Mays, Ute Graepler-Mainka, Friederike Serve, Joachim Riethmueller, Sofia Burdi, Olaf Eickmeier |
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| Rok vydání: | 2012 |
| Předmět: |
Pulmonary and Respiratory Medicine
Cystic Fibrosis Neutrophils Clinical Biochemistry Chemokine CXCL2 Inflammation Single-nucleotide polymorphism Biology Cystic fibrosis Polymorphism Single Nucleotide Immediate-Early Proteins Cohort Studies IFRD1 Interferon medicine Humans Molecular Biology Lung Innate immune system Interleukin-8 Case-control study Cell Biology medicine.disease Ifrd1 Innate Immunity Immunity Innate Case-Control Studies Immunology medicine.symptom Reactive Oxygen Species Ex vivo medicine.drug |
| Zdroj: | Am. J. Respir. Cell Mol. Biol. 48, 71-77 (2013) |
| ISSN: | 1535-4989 |
| Popis: | A genome-wide association study identified interferon-related development regulator-1 (IFRD1), a protein expressed by neutrophils, as a key modifier gene in cystic fibrosis (CF) lung disease. Here, we investigated the expression and regulation of IFRD1 in CF neutrophils. IFRD1 expression was quantified in peripheral blood and airway neutrophils from patients with CF, patients with non-CF lung disease, and healthy control subjects. The regulation of IFRD1 expression was analyzed using isolated neutrophils and ex vivo stimulation assays with CF airway fluids. IFRD1 single-nucleotide polymorphisms (SNPs) were analyzed in a CF cohort (n = 572) and correlated with longitudinal lung function and IFRD1 expression. Patients with CF expressed higher protein levels of IFRD1 in peripheral blood neutrophils compared with healthy or non-CF disease control subjects. Within patients with CF, IFRD1 protein expression levels in neutrophils were lower in airway fluids compared with peripheral blood. High IFRD1 expression was positively associated with the production of reactive oxygen species (ROS) in CF neutrophils. In vitro regulation studies showed that CF airway fluid and the CF-characteristic chemokines CXCL8 and CXCL2 down-regulated IFRD1 expression in neutrophils, an effect that was mediated through CXCR2. Genetic analyses showed that three IFRD1 SNPs were associated with longitudinal declines in lung function, and modulated IFRD1 expression. These studies demonstrate that IFRD1 expression is systemically up-regulated in human CF neutrophils, is linked to the production of ROS, and is modulated by chemokines in CF airway fluids, depending on the IFRD1 genotype. Understanding the regulation of IFRD1 may pave the way for novel therapeutic approaches to target neutrophilic inflammation in CF. |
| Databáze: | OpenAIRE |
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