title: Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons.
abstract: BACKGROUND
  Rhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown.
  
  
  OBJECTIVE
  We sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients.
  
  
  METHODS
  We assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes.
  
  
  RESULTS
  We report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation-related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients.
  
  
  CONCLUSIONS
  We describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Centre for Respiratory Infection, Imperial College London, London, United Kingdom.
authors: Vera
authors: V
authors: Gielen
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Centre for Respiratory Infection, Imperial College London, London, United Kingdom; Imperial College Healthcare National Health Service Trust, London, United Kingdom.
authors: Annemarie
authors: A
authors: Sykes
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Centre for Respiratory Infection, Imperial College London, London, United Kingdom.
authors: Jie
authors: J
authors: Zhu
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Brian
authors: B
authors: Chan
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Centre for Respiratory Infection, Imperial College London, London, United Kingdom; Imperial College Healthcare National Health Service Trust, London, United Kingdom.
authors: Jonathan
authors: J
authors: Macintyre
authors: Pediatric Medicine, University of Bern, Bern, Switzerland.
authors: Nicolas
authors: N
authors: Regamey
authors: Pediatric Medicine, University of Bern, Bern, Switzerland.
authors: Elisabeth
authors: E
authors: Kieninger
authors: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Respiratory Pediatrics, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Atul
authors: A
authors: Gupta
authors: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Respiratory Pediatrics, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Amelia
authors: A
authors: Shoemark
authors: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Respiratory Pediatrics, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Cara
authors: C
authors: Bossley
authors: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Respiratory Pediatrics, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Jane
authors: J
authors: Davies
authors: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Respiratory Pediatrics, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Sejal
authors: S
authors: Saglani
authors: Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Heidelberg, Germany.
authors: Patrick
authors: P
authors: Walker
authors: Walter & Eliza Hall Institute, Parkville, Australia; Department of Medical Biology of the University of Melbourne, Parkville, Australia.
authors: Sandra E
authors: SE
authors: Nicholson
authors: Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Heidelberg, Germany.
authors: Alexander H
authors: AH
authors: Dalpke
authors: Imperial College Healthcare National Health Service Trust, London, United Kingdom.
authors: Onn-Min
authors: OM
authors: Kon
authors: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Respiratory Pediatrics, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Andrew
authors: A
authors: Bush
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Centre for Respiratory Infection, Imperial College London, London, United Kingdom; Imperial College Healthcare National Health Service Trust, London, United Kingdom.
authors: Sebastian L
authors: SL
authors: Johnston
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Centre for Respiratory Infection, Imperial College London, London, United Kingdom. Electronic address: michael.edwards@imperial.ac.uk.
authors: Michael R
authors: MR
authors: Edwards
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001249:Asthma / Q000150:complications / Q000276:immunology* / Q000821:virology; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010850:Picornaviridae Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D021381:Protein Transport; D020545:Respiratory Mucosa / Q000276:immunology* / Q000821:virology; D012229:Rhinovirus / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D014779:Virus Replication; D055815:Young Adult
chemical_list: C108944:SOCS1 protein, human; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma
keywords: Rhinovirus; T(H)2 inflammation; asthma; asthma exacerbation; atopy; cytokine; innate immunity; interferon; suppressor of cytokine signaling
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