title: Respiratory syncytial virus represses glucocorticoid receptor-mediated gene activation.
abstract: Respiratory syncytial virus (RSV) is a common cause of bronchiolitis in infants. Although antiinflammatory in nature, glucocorticoids have been shown to be ineffective in the treatment of RSV-induced bronchiolitis and wheezing. In addition, the effectiveness of glucocorticoids at inhibiting RSV-induced proinflammatory cytokine production in cell culture has been questioned. In this study, we have investigated the effect of RSV infection on glucocorticoid-induced gene activation in lung epithelium-derived cells. We show that RSV infection inhibits dexamethasone induction of three glucocorticoid receptor (GR)-regulated genes (glucocorticoid-inducible leucine zipper, FK506 binding protein, and MAPK phosphatase 1) in A549, BEAS-2B cells, and primary small airway epithelial cells. UV irradiation of the virus prevents this repression, suggesting that viral replication is required. RSV is known to activate the nuclear factor κB (NFκB) pathway, which is mutually antagonistic towards the GR pathway. However, specific inhibition of NFκB had no effect on the repression of GR-induced genes by RSV infection, indicating that RSV repression of GR is independent of NFκB. RSV infection of A549 cells does not alter GR protein levels or GR nuclear translocation but does reduce GR binding to the promoters of the glucocorticoid responsive genes analyzed in this study. Repression of GR by RSV infection may account for the apparent clinical ineffectiveness of glucocorticoids in RSV bronchiolitis therapy. In addition, this data adds to our previously published data suggesting that GR may be a general target for infectious agents. Identifying the mechanisms through which this suppression occurs may lead to the development of novel therapeutics.
authors.affiliation: Division of Pulmonary, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Hinzey
authors.forename: Jacob
authors.initials: J
authors.lastname: Alexander
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Corry
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Adams
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Claggett
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Traylor
authors.forename: Ian C
authors.initials: IC
authors.lastname: Davis
authors.forename: Jeanette I
authors.initials: JI
authors.lastname: Webster Marketon
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003907:Dexamethasone / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone