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Azithromycin augments rhinovirus-induced IFNβ via cytosolic MDA5 in experimental models of asthma exacerbation

Menzel, Mandy LU ; Akbarshahi, Hamid LU ; Tufvesson, Ellen LU ; Persson, Carl LU ; Bjermer, Leif LU and Uller, Lena LU (2017) In Oncotarget 8(19). p.31601-31611
Abstract

Deficient production of anti-viral interferons (IFNs) may be involved in causing viral-induced asthma exacerbations. Hence, drugs inducing lung IFN production would be warranted. Azithromycin may reduce asthma exacerbations but its modus operandi is unknown. Here, we investigated if azithromycin induces IFNβ expression in vitro in rhinovirus-infected bronchial epithelial cells from asthmatic donors and in vivo in our allergic inflammation-based mouse model of viral stimulusinduced asthma exacerbations. Azithromycin dose-dependently augmented viralinduced IFNβ expression in asthmatic, but not in healthy bronchial epithelial cells. The effect negatively correlated with viral load. Knockdown of MDA5 and RIG-I by siRNA showed involvement of... (More)

Deficient production of anti-viral interferons (IFNs) may be involved in causing viral-induced asthma exacerbations. Hence, drugs inducing lung IFN production would be warranted. Azithromycin may reduce asthma exacerbations but its modus operandi is unknown. Here, we investigated if azithromycin induces IFNβ expression in vitro in rhinovirus-infected bronchial epithelial cells from asthmatic donors and in vivo in our allergic inflammation-based mouse model of viral stimulusinduced asthma exacerbations. Azithromycin dose-dependently augmented viralinduced IFNβ expression in asthmatic, but not in healthy bronchial epithelial cells. The effect negatively correlated with viral load. Knockdown of MDA5 and RIG-I by siRNA showed involvement of MDA5 but not RIG-I in azithromycin's IFN-inducing effects in vitro. In vivo azithromycin induced IFNβ protein, restoring a reduced lung IFN response exclusively in allergic exacerbating mice. This was associated with induction of interferon-stimulated genes and MDA5, but not RIG-I. We suggest that clinically relevant concentrations of azithromycin produce MDA5-dependent, antiviral, IFN-inducing effects in bronchial epithelium distinctly from asthmatic donors. Similarly, azithromycin induced MDA5-associated IFN in virally stimulated lungs in vivo exclusively in allergic mice. Effects of azithromycin and MDA5-active drugs on viral-induced exacerbations deserve further research.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Asthma, Azithromycin, IFNβ, MDA5, Rhinovirus
in
Oncotarget
volume
8
issue
19
pages
11 pages
publisher
Impact Journals, LLC
external identifiers
  • scopus:85019159861
  • wos:000401003200079
ISSN
1949-2553
DOI
10.18632/oncotarget.16364
language
English
LU publication?
yes
id
97b3ee74-5f8a-48d5-b6cd-ddd2f62ade20
date added to LUP
2017-06-01 10:48:08
date last changed
2018-01-07 12:05:53
@article{97b3ee74-5f8a-48d5-b6cd-ddd2f62ade20,
  abstract     = {<p>Deficient production of anti-viral interferons (IFNs) may be involved in causing viral-induced asthma exacerbations. Hence, drugs inducing lung IFN production would be warranted. Azithromycin may reduce asthma exacerbations but its modus operandi is unknown. Here, we investigated if azithromycin induces IFNβ expression in vitro in rhinovirus-infected bronchial epithelial cells from asthmatic donors and in vivo in our allergic inflammation-based mouse model of viral stimulusinduced asthma exacerbations. Azithromycin dose-dependently augmented viralinduced IFNβ expression in asthmatic, but not in healthy bronchial epithelial cells. The effect negatively correlated with viral load. Knockdown of MDA5 and RIG-I by siRNA showed involvement of MDA5 but not RIG-I in azithromycin's IFN-inducing effects in vitro. In vivo azithromycin induced IFNβ protein, restoring a reduced lung IFN response exclusively in allergic exacerbating mice. This was associated with induction of interferon-stimulated genes and MDA5, but not RIG-I. We suggest that clinically relevant concentrations of azithromycin produce MDA5-dependent, antiviral, IFN-inducing effects in bronchial epithelium distinctly from asthmatic donors. Similarly, azithromycin induced MDA5-associated IFN in virally stimulated lungs in vivo exclusively in allergic mice. Effects of azithromycin and MDA5-active drugs on viral-induced exacerbations deserve further research.</p>},
  author       = {Menzel, Mandy and Akbarshahi, Hamid and Tufvesson, Ellen and Persson, Carl and Bjermer, Leif and Uller, Lena},
  issn         = {1949-2553},
  keyword      = {Asthma,Azithromycin,IFNβ,MDA5,Rhinovirus},
  language     = {eng},
  number       = {19},
  pages        = {31601--31611},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {Azithromycin augments rhinovirus-induced IFNβ via cytosolic MDA5 in experimental models of asthma exacerbation},
  url          = {http://dx.doi.org/10.18632/oncotarget.16364},
  volume       = {8},
  year         = {2017},
}