title: Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells.
abstract: BACKGROUND
  Asthma and other Th2 inflammatory conditions have been associated with increased susceptibility to viral infections. The mechanisms by which Th2 cytokines can influence immune responses to infections are largely unknown.
  
  
  METHODS
  We measured the effects of Th2 cytokines (IL-4 and IL-13) on bronchial epithelial cell innate immune antiviral responses by assessing interferon (IFN-β and IFN-λ1) induction following rhinovirus (RV)-16 infection. We also investigated the modulatory effects of Th2 cytokines on Toll-like receptor 3 (TLR3), interferon-responsive factor 3 (IRF3) and nuclear factor (NF)-kB, that is key molecules and transcription factors involved in the rhinovirus-induced interferon production and inflammatory cascade. Pharmacological and redox modulation of these pathways was also assessed.
  
  
  RESULTS
  Th2 cytokines impaired RV-16-induced interferon production, increased rhinovirus replication and impaired TLR3 expression in bronchial epithelial cells. These results were replicated in vivo: we found increased IL-4 mRNA levels in nasal epithelial cells from nasal brushing of atopic rhinitis patients and a parallel reduction in TLR3 expression and increased RV-16 replication compared to nonatopic subjects. Mechanistically, Th2 cytokines impaired RV-16-induced activation of IRF3, but had no effects on RV-16-induced NF-kB activation in bronchial epithelial cell cultures. N-acetylcysteine and phosphoinositide 3-kinase (PI3K) inhibitor restored the inhibitory effects of Th2 cytokines over RV-16-induced activation of IRF3.
  
  
  CONCLUSIONS
  IL-4 and IL-13, through inhibition of TLR3 expression and signalling (IRF3), impair immune response to RV-16 infection. These data suggest that Th2 conditions increase susceptibility to infections and identify pharmacological approaches with potential to restore impaired immune response in these conditions.
authors: Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
authors: M
authors: M
authors: Contoli
authors: Airway Disease, National Heath and Lung Institute, Imperial College, London, UK.
authors: K
authors: K
authors: Ito
authors: Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
authors: A
authors: A
authors: Padovani
authors: ENT Unit, Department of Biomedical and Surgical Sciences, University of Ferrara, Ferrara, Italy.
authors: D
authors: D
authors: Poletti
authors: Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
authors: B
authors: B
authors: Marku
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College and MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
authors: M R
authors: MR
authors: Edwards
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College and MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
authors: L A
authors: LA
authors: Stanciu
authors: Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
authors: G
authors: G
authors: Gnesini
authors: ENT Unit, Department of Biomedical and Surgical Sciences, University of Ferrara, Ferrara, Italy.
authors: A
authors: A
authors: Pastore
authors: University of Insubria and Fondazione Maugeri, Varese, Italy.
authors: A
authors: A
authors: Spanevello
authors: Cros NT, Verona, Italy.
authors: P
authors: P
authors: Morelli
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College and MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
authors: S L
authors: SL
authors: Johnston
authors: Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
authors: G
authors: G
authors: Caramori
authors: Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
authors: A
authors: A
authors: Papi
mesh_terms: D001249:Asthma / Q000276:immunology / Q000378:metabolism; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004198:Disease Susceptibility; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism; D012229:Rhinovirus / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018793:Interleukin-13; D016328:NF-kappa B; D051196:Toll-Like Receptor 3; D015847:Interleukin-4
keywords: Th2 inflammation; asthma; innate immunity; interferon; virus