title: Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells.
abstract: Allergic asthma is characterized by persistent chronic airway inflammation, which leads to mucus hypersecretion and airway hyperresponsiveness. Nuclear receptor Nur77 plays a pivotal role in distinct immune and inflammatory cells and is expressed in eosinophils and lung epithelium. However, the role of Nur77 in allergic airway inflammation has not been studied so far. In the present study, we determined the role of Nur77 in airway inflammation using a murine model of OVA-induced allergic airway inflammation. We found that OVA-challenged Nur77 knockout (KO) mice show significantly enhanced infiltration of inflammatory cells, including eosinophils and lymphocytes, and aggravated mucus production. The infiltration of macrophages is limited in this model and was similar in wild-type and Nur77 KO mice. Higher levels of Th2 cytokines were found in bronchoalveolar lavage fluid and draining lymph node cells of Nur77-KO mice, as well as increased serum IgG1 and IgG2a levels. Knockdown of Nur77 in human lung epithelial cells resulted in a marked increase in IκBα phosphorylation, corresponding with elevated NF-κB activity, whereas Nur77 overexpression decreased NF-κB activity. Consistently, Nur77 significantly decreased mRNA levels of inflammatory cytokines and Muc5ac expression and also attenuated mucus production in lung epithelial cells. To further corroborate these findings, we searched for association of single nucleotide polymorphisms in Nur77 gene with asthma and with the severity of bronchial hyperresponsiveness. We identified three Nur77 single nucleotide polymorphisms showing association with severity of bronchial hyperresponsiveness in asthma patients. Collectively, these findings support a protective role of Nur77 in OVA-induced airway inflammation and identify Nur77 as a novel therapeutic target for airway inflammation.
authors.affiliation: Department of Medical Biochemistry, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Kondababu
authors.initials: K
authors.lastname: Kurakula
authors.affiliation: Department of Medical Biochemistry, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Mariska
authors.initials: M
authors.lastname: Vos
authors.affiliation: Department of Experimental Immunology, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Adrian
authors.initials: A
authors.lastname: Logiantara
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Joris J
authors.initials: JJ
authors.lastname: Roelofs
authors.affiliation: Department of Pulmonology, University Medical Center Groningen, University of Groningen, and Groningen Research Institute for Asthma and COPD, 9700 RB Groningen, the Netherlands; and.
authors.forename: Maartje A
authors.initials: MA
authors.lastname: Nieuwenhuis
authors.affiliation: Department of Pediatric Pulmonology, University Medical Center Groningen, University of Groningen, and Beatrix Children's Hospital, Groningen Research Institute for Asthma and COPD, 9700 RB Groningen, the Netherlands.
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koppelman
authors.affiliation: Department of Pulmonology, University Medical Center Groningen, University of Groningen, and Groningen Research Institute for Asthma and COPD, 9700 RB Groningen, the Netherlands; and.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Department of Experimental Immunology, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Leonie S
authors.initials: LS
authors.lastname: van Rijt
authors.affiliation: Department of Medical Biochemistry, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; c.j.devries@amc.uva.nl.
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
mesh_terms: D000483:Alleles; D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004804:Eosinophils / Q000473:pathology; D015870:Gene Expression; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007958:Leukocyte Count; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D016328:NF-kappa B; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1