title: Molecular mechanisms of decreased steroid responsiveness induced by latent adenoviral infection in allergic lung inflammation.
abstract: BACKGROUND
  We recently reported that allergic lung inflammation in guinea pigs became steroid resistant in the presence of latent adenoviral infection.
  
  
  OBJECTIVE
  We sought to investigate the molecular mechanisms that underlie steroid resistance in adenoviral infection.
  
  
  METHODS
  Guinea pigs with a latent adenoviral infection were sensitized and challenged with ovalbumin (OVA) and given daily injections of budesonide (20 mg/kg administered intraperitoneally). Sham-infected animals received either saline challenge without budesonide injection or OVA challenge with or without budesonide. The inflammatory response in the lung was measured by means of quantitative histology. Eotaxin, monocyte chemoattractant protein 1 (MCP-1), and RANTES expression in the lung were analyzed by means of Northern blotting, and the binding activity of activator protein 1 (AP-1) and nuclear factor kappaB in nuclear extracts from the lung was analyzed with electrophoretic mobility shift assays.
  
  
  RESULTS
  OVA challenge increased eosinophil infiltration and eotaxin and MCP-1 mRNA expression in the lungs, and glucocorticoids reduced these increases in the sham-infected, but not the adenovirus-infected, animals. Changes in binding activity of AP-1, but not nuclear factor kappaB, paralleled changes in eotaxin and MCP-1 mRNA.
  
  
  CONCLUSIONS
  We conclude that latent adenoviral infection inhibits the anti-inflammatory effects of glucocorticoids on allergen-induced eotaxin and MCP-1 expression through AP-1, leading to steroid-resistant allergic lung inflammation.
authors.affiliation: UBC McDonald Research Laboratory/ The iCAPTURE Centre, St Paul's Hospital, Vancouver, Canada.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yamada
authors.forename: W Mark
authors.initials: WM
authors.lastname: Elliott
authors.forename: Ralph
authors.initials: R
authors.lastname: Brattsand
authors.forename: Anders
authors.initials: A
authors.lastname: Valeur
authors.forename: James C
authors.initials: JC
authors.lastname: Hogg
authors.forename: Shizu
authors.initials: S
authors.lastname: Hayashi
mesh_terms: D000257:Adenoviridae Infections / Q000276:immunology*; D000818:Animals; D018925:Chemokines / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D006168:Guinea Pigs; D006967:Hypersensitivity / Q000188:drug therapy*; D016328:NF-kappa B / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000188:drug therapy*; D012333:RNA, Messenger / Q000032:analysis; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D018925:Chemokines; D005938:Glucocorticoids; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D010047:Ovalbumin; D004247:DNA