Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-[beta] Activity
Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral i...
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| description | Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-[Beta] (TGF-[Beta]) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-[Beta]. In the current study, we examine the contribution of TGF-[Beta] activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-[Beta] expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGF[Beta]RI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-[Beta] activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-[Beta]. |
| doi_str_mv | 10.1371/journal.ppat.1006138 |
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The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-[Beta] (TGF-[Beta]) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-[Beta]. In the current study, we examine the contribution of TGF-[Beta] activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-[Beta] expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGF[Beta]RI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-[Beta] activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-[Beta].</description><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1006138</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Asthma ; Care and treatment ; Chronic obstructive pulmonary disease ; Enterovirus ; Glucocorticoids ; Health aspects ; Influenza A virus ; Kinases ; Orthomyxoviridae ; Physiological aspects ; Picornaviridae ; Respiratory syncytial virus ; Risk factors ; Rodents ; Transforming growth factors ; Viral infections</subject><ispartof>PLoS pathogens, 2017-01, Vol.13 (1)</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Xia YC, Radwan A, Keenan CR, Langenbach SY, Li M, Radojicic D, et al. (2017) Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-? Activity. PLoS Pathog 13(1): e1006138. doi:10.1371/journal.ppat.1006138</rights><rights>2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Xia YC, Radwan A, Keenan CR, Langenbach SY, Li M, Radojicic D, et al. (2017) Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-? Activity. 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The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-[Beta] (TGF-[Beta]) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-[Beta]. In the current study, we examine the contribution of TGF-[Beta] activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-[Beta] expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGF[Beta]RI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-[Beta] activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-[Beta].</description><subject>Asthma</subject><subject>Care and treatment</subject><subject>Chronic obstructive pulmonary disease</subject><subject>Enterovirus</subject><subject>Glucocorticoids</subject><subject>Health aspects</subject><subject>Influenza A virus</subject><subject>Kinases</subject><subject>Orthomyxoviridae</subject><subject>Physiological aspects</subject><subject>Picornaviridae</subject><subject>Respiratory syncytial virus</subject><subject>Risk factors</subject><subject>Rodents</subject><subject>Transforming growth factors</subject><subject>Viral infections</subject><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqV0U1rFDEYB_BBFKzVbyAY8KKHWfM2mcxx2bbrQlHQxYvIkMk82aZkkzHJWPfsFzeli1jpRQJJSH7PPySpqpcELwhrybvrMEev3GKaVF4QjAVh8lF1QpqG1S1r-eM_cyGeVs9SusaYE0bESfVr7WYddIjZ6mBHtPEJfLLZ_rD5gKxHX2xUzh3KhgGdYURLG2_UAZ1PNl-Bs8qhFTiX0CahM5jAj-AzCh5to_LJhLi3fofWMdzkK3ShdA6x_jpAVt_QUt8d87x6YpRL8OI4nlbbi_Pt6n19-XG9WS0v6x2lmNSt6ajphNAd1wx3lCtm5NCWvjWMwiiZbuQgOW8UHhWjugE6NB3oQZBGc3ZavbqLnVxI_fHNUk-k6BoqZUeLeHMUMXyfIeV-b5Mut1MewnxLWyq5wJQU-vof-nDgUe2Ug956E3JU-ja0X_KOSSIE7opaPKBKG2FffsWDsWX9XsHbewXFZPiZd2pOqd98_vQf9sPf9jeA0bWh</recordid><startdate>20170103</startdate><enddate>20170103</enddate><creator>Xia, Yuxiu C</creator><creator>Radwan, Asmaa</creator><creator>Keenan, Christine R</creator><creator>Langenbach, Shenna Y</creator><creator>Li, Meina</creator><creator>Radojicic, Danica</creator><creator>Londrigan, Sarah L</creator><creator>Gualano, Rosa C</creator><creator>Stewart, Alastair G</creator><general>Public Library of Science</general><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope></search><sort><creationdate>20170103</creationdate><title>Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-[beta] Activity</title><author>Xia, Yuxiu C ; Radwan, Asmaa ; Keenan, Christine R ; Langenbach, Shenna Y ; Li, Meina ; Radojicic, Danica ; Londrigan, Sarah L ; Gualano, Rosa C ; Stewart, Alastair G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g2201-7f92f966c94c30924a3f8b7a3f7f32ed83c58b8445a0da32c5e2b59ecb615c43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Asthma</topic><topic>Care and treatment</topic><topic>Chronic obstructive pulmonary disease</topic><topic>Enterovirus</topic><topic>Glucocorticoids</topic><topic>Health aspects</topic><topic>Influenza A virus</topic><topic>Kinases</topic><topic>Orthomyxoviridae</topic><topic>Physiological aspects</topic><topic>Picornaviridae</topic><topic>Respiratory syncytial virus</topic><topic>Risk factors</topic><topic>Rodents</topic><topic>Transforming growth factors</topic><topic>Viral infections</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xia, Yuxiu C</creatorcontrib><creatorcontrib>Radwan, Asmaa</creatorcontrib><creatorcontrib>Keenan, Christine R</creatorcontrib><creatorcontrib>Langenbach, Shenna Y</creatorcontrib><creatorcontrib>Li, Meina</creatorcontrib><creatorcontrib>Radojicic, Danica</creatorcontrib><creatorcontrib>Londrigan, Sarah L</creatorcontrib><creatorcontrib>Gualano, Rosa C</creatorcontrib><creatorcontrib>Stewart, Alastair G</creatorcontrib><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xia, Yuxiu C</au><au>Radwan, Asmaa</au><au>Keenan, Christine R</au><au>Langenbach, Shenna Y</au><au>Li, Meina</au><au>Radojicic, Danica</au><au>Londrigan, Sarah L</au><au>Gualano, Rosa C</au><au>Stewart, Alastair G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-[beta] Activity</atitle><jtitle>PLoS pathogens</jtitle><date>2017-01-03</date><risdate>2017</risdate><volume>13</volume><issue>1</issue><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-[Beta] (TGF-[Beta]) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-[Beta]. In the current study, we examine the contribution of TGF-[Beta] activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-[Beta] expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGF[Beta]RI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-[Beta] activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-[Beta].</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><doi>10.1371/journal.ppat.1006138</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Asthma Care and treatment Chronic obstructive pulmonary disease Enterovirus Glucocorticoids Health aspects Influenza A virus Kinases Orthomyxoviridae Physiological aspects Picornaviridae Respiratory syncytial virus Risk factors Rodents Transforming growth factors Viral infections |
| title | Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-[beta] Activity |
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