RT Journal Article
SR Electronic
T1 Inhibitors of apoptosis proteins in asthmatic airway inflammation
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P579
VO 42
IS Suppl 57
A1 James Reihill
A1 Catriona Kelly
A1 Shaomeng Wang
A1 Shields Michael
A1 Schock Bettina
A1 Bettina Schock
YR 2013
UL http://erj.ersjournals.com/content/42/Suppl_57/P579.abstract
AB Background: In atopic asthma aero-allergens and infections cause chronic airway inflammation, even when ‘well’. Transcription factor NF-kB is central in the response, but its regulation is compromised in asthma leading to constitutive activation. Inhibitors of Apoptosis (IAPs) may regulate NF-kB inflammation via TRAF6 activation. Endogenous IAP antagonist (Smac) regulates IAPs and pharmacological depletion by Smac-mimetics inhibits NF-kB and inflammation. IAPs may significantly contribute to the innate immune response in asthma.Methods: Adult Primary Nasal Epithelial cells (PNECs, atopic asthma, non-asthmatic controls, n=3) were stimulated with LPS (P.aeruginosa, 100ng/ml) or PolyI:C (50μg/ml). Protein and mRNA expression of IAPs/Smac and NF-kB p65 mRNA were determined. Cells were pre-incubated with smac-mimetic SM164 and IL-8 analysed.Results: Basal IAP1/2 and p65 mRNA are increased in atopic-asthmatics (all p<0.05), Smac is significantly lower. LPS had little effect on IAPs/Smac, but PolyI:C caused a time-dependent increase in cIAP2 mRNA (p<0.01), which was higher in controls (p<0.001). p65 mRNA was significantly higher in atopic-asthmatics. IAP proteins were only detectable after immunoprecipitation: PolyI:C induced cIAP2 in controls and significantly less in atopic-asthmatics. IL-8 release after PolyI:C was higher in controls and was significantly reduced by SM164.Conclusion: Although atopic asthmatics have increased basal levels of IAPs, they show a blunted cIAP2 response to PolyI:C. Degradation of IAP1/2 only reduces the inflammatory response in controls, suggest a beneficial role for increased cIAP2 in airway epithelium. The role of the natural inhibitor Smac in atopic asthma needs further investigation.