Molecular mechanisms of decreased steroid responsiveness induced by latent adenoviral infection in allergic lung inflammation.
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.
Yamada
Katsuhiko
K
UBC McDonald Research Laboratory/ The iCAPTURE Centre, St Paul's Hospital, Vancouver, Canada.
Elliott
W Mark
WM
Brattsand
Ralph
R
Valeur
Anders
A
Hogg
James C
JC
Hayashi
Shizu
S
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
D018925:Chemokines; D005938:Glucocorticoids; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D010047:Ovalbumin; D004247:DNA