title: Interleukin-24 inhibits influenza A virus replication in vitro through induction of toll-like receptor 3 dependent apoptosis.
abstract: New anti-viral agents and strategies are urgently needed to fight rapidly mutating viruses, as vaccine programs cannot react fast enough to prevent pandemics. Recently, we have shown that interleukin-24 (IL-24) sensitizes tumor cells to toll-like receptor 3 (TLR3) mediated apoptosis. As influenza A virus stimulates the TLR3 receptor, we hypothesized that IL-24 might also exert an anti-viral effect. This study demonstrates that IL-24 reduces the titer of different influenza A virus subtypes independently of type I interferon in an apoptosis dependent manner. The anti-viral effect of IL-24 correlated with caspase-3 activation and could be blocked by a pan-caspase inhibitor and by small interfering RNA (siRNA) directed towards TLR3. Surprisingly, caspase-3 activation in influenza A virus/IL-24-stimulated cells correlated with the down-regulation of the B-cell lymphoma 2 (Bcl-2) family member myeloid cell leukemia 1 (Mcl-1). Correspondingly, knockdown of Mcl-1 by siRNA enhanced caspase activation in influenza A virus infected cells and was furthermore linked to a reduction of viral titers. We conclude that IL-24 exerts an anti-viral role selectively purging virally infected cells by leading to a down-regulation of Mcl-1. Our findings might therefore represent the first step towards a new rational concept in the development of anti-viral strategies based on the induction of apoptosis.
authors.affiliation: Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: René
authors.initials: R
authors.lastname: Weiss
authors.affiliation: Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Laengle
authors.affiliation: Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Sachet
authors.affiliation: Research Institute of Influenza, Ministry of Health and Social Development of the Russian Federation, Prof. Popov Street, 15/17, 197376 Saint-Petersburg, Russia.
authors.forename: Anna-Polina
authors.initials: AP
authors.lastname: Shurygina
authors.affiliation: Research Institute of Influenza, Ministry of Health and Social Development of the Russian Federation, Prof. Popov Street, 15/17, 197376 Saint-Petersburg, Russia.
authors.forename: Oleg
authors.initials: O
authors.lastname: Kiselev
authors.affiliation: Research Institute of Influenza, Ministry of Health and Social Development of the Russian Federation, Prof. Popov Street, 15/17, 197376 Saint-Petersburg, Russia.
authors.forename: Andrej
authors.initials: A
authors.lastname: Egorov
authors.affiliation: Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Electronic address: michael.bergmann@meduniwien.ac.at.
authors.forename: Michael
authors.initials: M
authors.lastname: Bergmann
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D006801:Humans; D009980:Influenza A virus / Q000276:immunology* / Q000502:physiology*; D007378:Interleukins / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D014779:Virus Replication; D000099180:Interleukin-24
chemical_list: D007378:Interleukins; D051196:Toll-Like Receptor 3; D000099180:Interleukin-24
keywords: Apoptosis; Caspase-3; Influenza A virus; Interleukin-24; Myeloid cell leukemia 1; Toll-like receptor 3