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Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection

BACKGROUND: Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the...

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Autores principales: Foronjy, Robert F, Dabo, Abdoulaye J, Cummins, Neville, Geraghty, Patrick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4189665/
https://www.ncbi.nlm.nih.gov/pubmed/25277705
http://dx.doi.org/10.1186/s12865-014-0041-4
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author Foronjy, Robert F
Dabo, Abdoulaye J
Cummins, Neville
Geraghty, Patrick
author_facet Foronjy, Robert F
Dabo, Abdoulaye J
Cummins, Neville
Geraghty, Patrick
author_sort Foronjy, Robert F
collection PubMed
description BACKGROUND: Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study. METHODS: A549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-β (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR. Neutralizing anti-leukemia inhibitory factor (LIF) IgG or control IgG was administered to a group of wild-type animals prior to RSV infection. RESULTS AND DISCUSSION: RSV-infected A549 and SAE cells release a network of cytokines, including newly identified RSV-inducible cytokines LIF, migration inhibitory factor (MIF), stem cell factor (SCF), CCL27, CXCL12 and stem cell growth factor beta (SCGF-β). These RSV-inducible cytokines were also observed in the airways of mice during an infection. To identify the regulation of RSV inducible cytokines, Mavs and Trif deficient animals were infected with RSV. In vivo induction of airway IL-1β, IL-4, IL-5, IL-6, IL-12(p40), IFN-γ, CCL2, CCL5, CCL3, CXCL1, IP-10/CXCL10, IL-22, MIG/CXCL9 and MIF were dependent on Mavs expression in mice. Loss of Trif expression in mice altered the RSV induction of IL-1β, IL-5, CXCL12, MIF, LIF, CXCL12 and IFN-γ. Silencing of retinoic acid–inducible gene-1 (RIG-I) expression in A549 cells had a greater impact on RSV-inducible cytokines than melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and Trif expression. To evaluate the role of LIF in the airways during RSV infection, animals were treated with neutralizing anti-LIF IgG, which enhanced RSV pathology observed with increased airspace protein content, apoptosis and airway hyperresponsiveness compared to control IgG treatment. CONCLUSIONS: RSV infection in the epithelium induces a network of immune factors to counter infection, primarily in a RIG-I dependent manner. Expression of LIF protects the lung from lung injury and enhanced pathology during RSV infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12865-014-0041-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-41896652014-10-09 Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection Foronjy, Robert F Dabo, Abdoulaye J Cummins, Neville Geraghty, Patrick BMC Immunol Research Article BACKGROUND: Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study. METHODS: A549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-β (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR. Neutralizing anti-leukemia inhibitory factor (LIF) IgG or control IgG was administered to a group of wild-type animals prior to RSV infection. RESULTS AND DISCUSSION: RSV-infected A549 and SAE cells release a network of cytokines, including newly identified RSV-inducible cytokines LIF, migration inhibitory factor (MIF), stem cell factor (SCF), CCL27, CXCL12 and stem cell growth factor beta (SCGF-β). These RSV-inducible cytokines were also observed in the airways of mice during an infection. To identify the regulation of RSV inducible cytokines, Mavs and Trif deficient animals were infected with RSV. In vivo induction of airway IL-1β, IL-4, IL-5, IL-6, IL-12(p40), IFN-γ, CCL2, CCL5, CCL3, CXCL1, IP-10/CXCL10, IL-22, MIG/CXCL9 and MIF were dependent on Mavs expression in mice. Loss of Trif expression in mice altered the RSV induction of IL-1β, IL-5, CXCL12, MIF, LIF, CXCL12 and IFN-γ. Silencing of retinoic acid–inducible gene-1 (RIG-I) expression in A549 cells had a greater impact on RSV-inducible cytokines than melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and Trif expression. To evaluate the role of LIF in the airways during RSV infection, animals were treated with neutralizing anti-LIF IgG, which enhanced RSV pathology observed with increased airspace protein content, apoptosis and airway hyperresponsiveness compared to control IgG treatment. CONCLUSIONS: RSV infection in the epithelium induces a network of immune factors to counter infection, primarily in a RIG-I dependent manner. Expression of LIF protects the lung from lung injury and enhanced pathology during RSV infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12865-014-0041-4) contains supplementary material, which is available to authorized users. BioMed Central 2014-10-03 /pmc/articles/PMC4189665/ /pubmed/25277705 http://dx.doi.org/10.1186/s12865-014-0041-4 Text en © Foronjy et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Foronjy, Robert F
Dabo, Abdoulaye J
Cummins, Neville
Geraghty, Patrick
Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection
title Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection
title_full Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection
title_fullStr Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection
title_full_unstemmed Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection
title_short Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection
title_sort leukemia inhibitory factor protects the lung during respiratory syncytial viral infection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4189665/
https://www.ncbi.nlm.nih.gov/pubmed/25277705
http://dx.doi.org/10.1186/s12865-014-0041-4
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