Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
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.
Date Issued
2015-04-24
Date Acceptance
2015-04-01
Citation
Allergy, 2015, 70 (8), pp.910-920
ISSN
0105-4538
Publisher
Wiley
Start Page
910
End Page
920
Journal / Book Title
Allergy
Volume
70
Issue
8
Copyright Statement
This is the peer reviewed version of the following article: Contoli M, Ito K, Padovani A, Poletti D, Marku B, Edwards MR, Stanciu LA, Gnesini G, Pastore A, Spanevello A, Morelli P, Johnston SL, Caramori G, Papi A. Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells. Allergy 2015; 70: 910–920, which has been published in final form at https://dx.doi.org/10.1111/all.12627. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
Sponsor
Asthma UK
Grant Number
RF07/04
Subjects
Science & Technology
Life Sciences & Biomedicine
Allergy
Immunology
asthma
innate immunity
interferon
Th2 inflammation
virus
TOLL-LIKE RECEPTOR-3
ALLERGIC AIRWAY INFLAMMATION
ADHESION MOLECULE-1 ICAM-1
GENE-EXPRESSION
ASTHMA
INFECTION
INHIBITION
INTERFERON
ACTIVATION
MODEL
Publication Status
Published