The innate antiviral response upregulates IL-13 receptor α2 in bronchial fibroblasts.
BACKGROUND
IL-13 is key mediator of allergic inflammation in asthmatic patients. We have previously shown that the decoy receptor IL-13 receptor (IL-13R) α2 attenuates responses of fibroblasts to IL-13. Because the expression of IL-13Rα2 can be regulated by IFN-γ, a type II interferon, we hypothesized that innate antiviral responses characterized by type I interferon expression can also induce IL-13Rα2 expression.


OBJECTIVE
We sought to induce an innate antiviral response in primary fibroblasts using exposure to double-stranded RNA (dsRNA) and to examine the expression and function of IL-13Rα2.


METHODS
Primary human fibroblasts were cultured from endobronchial biopsy specimens obtained from healthy or asthmatic volunteers and challenged with dsRNA. Upregulation of IL-13Rα2 mRNA was measured by using real-time quantitative PCR, and cell-surface IL-13Rα2 protein expression was measured by using fluorescence-activated cell sorting. Eotaxin release was determined by means of ELISA.


RESULTS
Direct treatment with IFN-β led to an upregulation of IL-13Rα2. Exposure to dsRNA rapidly induced IFN-β mRNA in fibroblasts, and this was followed by significant induction of IL-13Rα2 mRNA and cell-surface protein expression, which was dependent on de novo protein synthesis. A neutralizing antibody to the IFN-α/β receptor blocked cell-surface expression of IL-13Rα2 in the presence of dsRNA. Pretreatment of fibroblasts with dsRNA led to attenuation of IL-13-stimulated eotaxin production. However, the presence of an IL-13Rα2 neutralizing antibody restored IL-13-stimulated eotaxin production in dsRNA-treated cells.


CONCLUSIONS
IFN-β induces IL-13Rα2 expression, leading to a consequential suppression of responsiveness to IL-13. These data suggest cross-talk between TH1 and TH2 pathways and point to an immunomodulatory role for IL-13Rα2 in human bronchial fibroblasts during viral infection.
Academic Unit of Clinical and Experimental Sciences and the Southampton NIHR Respiratory Biomedical Research Unit, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton, United Kingdom.
Gemma
G
Campbell-Harding
Hannah
H
Sawkins
Nicole
N
Bedke
Stephen T
ST
Holgate
Donna E
DE
Davies
Allison-Lynn
AL
Andrews
D001249:Asthma / Q000276:immunology; D001980:Bronchi / Q000166:cytology; D005347:Fibroblasts / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000494:pharmacology; D018793:Interleukin-13 / Q000276:immunology; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics / Q000276:immunology*; D012330:RNA, Double-Stranded / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology*
D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D016899:Interferon-beta