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Azithromycin augments rhinovirus-induced IFNβ via cytosolic MDA5 in experimental models of asthma exacerbation.
Oncotarget 2017; 8(19):31601-31611O

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 stimulus-induced asthma exacerbations. Azithromycin dose-dependently augmented viral-induced 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, anti-viral, 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.

Authors+Show Affiliations

Respiratory Immunopharmacology, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.Respiratory Immunopharmacology, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, 22184 Lund, Sweden.Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, 22184 Lund, Sweden.Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, 22184 Lund, Sweden.Respiratory Immunopharmacology, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28415826

Citation

Menzel, Mandy, et al. "Azithromycin Augments Rhinovirus-induced IFNβ Via Cytosolic MDA5 in Experimental Models of Asthma Exacerbation." Oncotarget, vol. 8, no. 19, 2017, pp. 31601-31611.
Menzel M, Akbarshahi H, Tufvesson E, et al. Azithromycin augments rhinovirus-induced IFNβ via cytosolic MDA5 in experimental models of asthma exacerbation. Oncotarget. 2017;8(19):31601-31611.
Menzel, M., Akbarshahi, H., Tufvesson, E., Persson, C., Bjermer, L., & Uller, L. (2017). Azithromycin augments rhinovirus-induced IFNβ via cytosolic MDA5 in experimental models of asthma exacerbation. Oncotarget, 8(19), pp. 31601-31611. doi:10.18632/oncotarget.16364.
Menzel M, et al. Azithromycin Augments Rhinovirus-induced IFNβ Via Cytosolic MDA5 in Experimental Models of Asthma Exacerbation. Oncotarget. 2017 May 9;8(19):31601-31611. PubMed PMID: 28415826.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Azithromycin augments rhinovirus-induced IFNβ via cytosolic MDA5 in experimental models of asthma exacerbation. AU - Menzel,Mandy, AU - Akbarshahi,Hamid, AU - Tufvesson,Ellen, AU - Persson,Carl, AU - Bjermer,Leif, AU - Uller,Lena, PY - 2017/02/08/received PY - 2017/03/12/accepted PY - 2017/4/19/pubmed PY - 2018/3/27/medline PY - 2017/4/19/entrez KW - IFNβ KW - MDA5 KW - asthma KW - azithromycin KW - rhinovirus SP - 31601 EP - 31611 JF - Oncotarget JO - Oncotarget VL - 8 IS - 19 N2 - 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 stimulus-induced asthma exacerbations. Azithromycin dose-dependently augmented viral-induced 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, anti-viral, 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/28415826/Azithromycin_augments_rhinovirus_induced_IFNβ_via_cytosolic_MDA5_in_experimental_models_of_asthma_exacerbation_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=16364 DB - PRIME DP - Unbound Medicine ER -