Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons
File(s)
Published version
Author(s)
Type
Journal Article
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.
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.
Date Issued
2015-07-01
Date Acceptance
2014-11-12
Citation
Journal of Allergy and Clinical Immunology, 2015, 136 (1), pp.177-188e.11
ISSN
1097-6825
Publisher
Elsevier
Start Page
177
End Page
188e.11
Journal / Book Title
Journal of Allergy and Clinical Immunology
Volume
136
Issue
1
Copyright Statement
Crown Copyright © 2014 Published by Elsevier Inc. on behalf of the American Academy
of Allergy, Asthma & Immunology. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/3.0/).
of Allergy, Asthma & Immunology. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/3.0/).
License URL
Sponsor
Medical Research Council (MRC)
Medical Research Council (MRC)
Asthma UK
Medical Research Council (MRC)
Asthma UK
Asthma UK
Medical Research Council (MRC)
Commission of the European Communities
Commission of the European Communities
Asthma UK
Identifier
https://www.sciencedirect.com/science/article/pii/S0091674914036677?via%3Dihub
Grant Number
G1100238
G0601236
RF07/04
G1000758
CH11SJ
CH11SJ
G1000758
260895
233015
10/058
Subjects
Science & Technology
Life Sciences & Biomedicine
Allergy
Immunology
Rhinovirus
asthma
asthma exacerbation
atopy
interferon
innate immunity
cytokine
T(H)2 inflammation
suppressor of cytokine signaling
BLOOD MONONUCLEAR-CELLS
PLASMACYTOID DENDRITIC CELLS
PLACEBO-CONTROLLED TRIAL
IMMUNE-RESPONSES
I INTERFERON
ANTIVIRAL RESPONSES
ALLERGIC RESPONSES
DOUBLE-BLIND
IFN-ALPHA
EXPRESSION
Publication Status
Published
Date Publish Online
2015-01-25