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Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons.
J Allergy Clin Immunol 2015; 136(1):177-188.e11JA

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.

CONCLUSION

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+Show Affiliations

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.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.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.Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.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.Pediatric Medicine, University of Bern, Bern, Switzerland.Pediatric Medicine, University of Bern, Bern, Switzerland.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.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.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.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.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.Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Heidelberg, Germany.Walter & Eliza Hall Institute, Parkville, Australia; Department of Medical Biology of the University of Melbourne, Parkville, Australia.Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Heidelberg, Germany.Imperial College Healthcare National Health Service Trust, London, United Kingdom.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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25630941

Citation

Gielen, Vera, et al. "Increased Nuclear Suppressor of Cytokine Signaling 1 in Asthmatic Bronchial Epithelium Suppresses Rhinovirus Induction of Innate Interferons." The Journal of Allergy and Clinical Immunology, vol. 136, no. 1, 2015, pp. 177-188.e11.
Gielen V, Sykes A, Zhu J, et al. Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons. J Allergy Clin Immunol. 2015;136(1):177-188.e11.
Gielen, V., Sykes, A., Zhu, J., Chan, B., Macintyre, J., Regamey, N., ... Edwards, M. R. (2015). Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons. The Journal of Allergy and Clinical Immunology, 136(1), pp. 177-188.e11. doi:10.1016/j.jaci.2014.11.039.
Gielen V, et al. Increased Nuclear Suppressor of Cytokine Signaling 1 in Asthmatic Bronchial Epithelium Suppresses Rhinovirus Induction of Innate Interferons. J Allergy Clin Immunol. 2015;136(1):177-188.e11. PubMed PMID: 25630941.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons. AU - Gielen,Vera, AU - Sykes,Annemarie, AU - Zhu,Jie, AU - Chan,Brian, AU - Macintyre,Jonathan, AU - Regamey,Nicolas, AU - Kieninger,Elisabeth, AU - Gupta,Atul, AU - Shoemark,Amelia, AU - Bossley,Cara, AU - Davies,Jane, AU - Saglani,Sejal, AU - Walker,Patrick, AU - Nicholson,Sandra E, AU - Dalpke,Alexander H, AU - Kon,Onn-Min, AU - Bush,Andrew, AU - Johnston,Sebastian L, AU - Edwards,Michael R, Y1 - 2015/01/25/ PY - 2014/04/27/received PY - 2014/10/27/revised PY - 2014/11/12/accepted PY - 2015/1/30/entrez PY - 2015/1/30/pubmed PY - 2015/10/6/medline KW - Rhinovirus KW - T(H)2 inflammation KW - asthma KW - asthma exacerbation KW - atopy KW - cytokine KW - innate immunity KW - interferon KW - suppressor of cytokine signaling SP - 177 EP - 188.e11 JF - The Journal of allergy and clinical immunology JO - J. Allergy Clin. Immunol. VL - 136 IS - 1 N2 - 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. CONCLUSION: 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. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/25630941/Increased_nuclear_suppressor_of_cytokine_signaling_1_in_asthmatic_bronchial_epithelium_suppresses_rhinovirus_induction_of_innate_interferons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(14)03667-7 DB - PRIME DP - Unbound Medicine ER -