Double-stranded RNA induces disproportionate expression of thymic stromal lymphopoietin versus interferon-beta in bronchial epithelial cells from donors with asthma.
BACKGROUND
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that strongly activates dendritic cells and can initiate allergic inflammation. Since exposure to rhinovirus or double-stranded (ds) RNA (a surrogate of viral infection) induces TSLP expression in bronchial epithelial cells (BECs), this cytokine may link innate antiviral responses and the type 2 adaptive immune response.


OBJECTIVE
As BECs from donors with asthma have a deficient interferon (IFN) response to rhinovirus infection, a study was undertaken to test the hypothesis that their antiviral response shows a bias towards TSLP production.


METHODS
Primary BECs were grown from subjects with asthma and healthy volunteers. After exposure to dsRNA, interleukin (IL)-8, IFNbeta and TSLP mRNA and protein expression were measured by RT-qPCR and ELISA, respectively.


RESULTS
dsRNA dose-dependently increased IL-8 expression in BECs with no significant difference between the groups. However, BECs from subjects with asthma expressed less IFNbeta and more TSLP mRNA and protein in response to dsRNA than BECs from those without asthma (median (IQR) 57 (38-82) pg/ml vs 106 (57-214) pg/ml for IFNbeta (p<0.05) and 114 (86-143) pg/ml vs 65 (32-119) pg/ml for TSLP (p<0.05) in response to 10 microg/ml dsRNA for 24 h). Induction of TSLP mRNA by dsRNA was blocked by Toll-like receptor 3 or protein kinase inhibitors or by preventing de novo protein synthesis, but not by neutralisation of type I IFN receptors.


CONCLUSIONS
BECs from subjects with asthma are biased towards higher TSLP and lower IFNbeta production in response to dsRNA, suggesting that viral infection in asthma may lead to an altered mediator profile that biases towards a Th2 immune response.
Uller
Lena
L
The Brooke Laboratories, Sir Henry Wellcome Laboratories, South Block, Southampton General Hospital, Southampton SO16 6YD, UK. lena.uller@med.lu.se
Leino
Marina
M
Bedke
Nicole
N
Sammut
David
D
Green
Ben
B
Lau
Laurie
L
Howarth
Peter H
PH
Holgate
Stephen T
ST
Davies
Donna E
DE
D000328:Adult; D001249:Asthma / Q000276:immunology*; D001980:Bronchi / Q000276:immunology*; D001999:Bronchoscopy / Q000379:methods; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D020545:Respiratory Mucosa / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors; D055815:Young Adult; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D000094632:Thymic Stromal Lymphopoietin