title: Expression and regulation of interferon-related development regulator-1 in cystic fibrosis neutrophils.
abstract: 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.
authors.affiliation: Children's Hospital, University of Tübingen, Tübingen, Germany. Andreas.Hector@med.uni-tuebingen.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Hector
authors.forename: Michael
authors.initials: M
authors.lastname: Kormann
authors.forename: Julia
authors.initials: J
authors.lastname: Kammermeier
authors.forename: Sofia
authors.initials: S
authors.lastname: Burdi
authors.forename: Veronica
authors.initials: V
authors.lastname: Marcos
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rieber
authors.forename: Lauren
authors.initials: L
authors.lastname: Mays
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: Fabian
authors.initials: F
authors.lastname: Falkenstein
authors.forename: Matthias
authors.initials: M
authors.lastname: Kappler
authors.forename: Joachim
authors.initials: J
authors.lastname: Riethmueller
authors.forename: Ute
authors.initials: U
authors.lastname: Graepler-Mainka
authors.forename: Martin
authors.initials: M
authors.lastname: Stern
authors.forename: Olaf
authors.initials: O
authors.lastname: Eickmeier
authors.forename: Friederike
authors.initials: F
authors.lastname: Serve
authors.forename: Stefan
authors.initials: S
authors.lastname: Zielen
authors.forename: Gerd
authors.initials: G
authors.lastname: Döring
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
mesh_terms: D016022:Case-Control Studies; D054426:Chemokine CXCL2 / Q000378:metabolism; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism*; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000503:physiopathology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C499706:CXCL2 protein, human; C508606:CXCL8 protein, human; D054426:Chemokine CXCL2; C490045:IFRD1 protein, human; D017874:Immediate-Early Proteins; D016209:Interleukin-8; D017382:Reactive Oxygen Species