Double-stranded RNA induces disproportionate expression of thymic stromal lymphopoietin versus interferon-  in bronchial epithelial cells from donors with asthma

Abstract

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, IFNb 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 IFNb and more TSLP mRNA and protein in response to dsRNA than BECs from those without asthma (median (IQR) 57 (38e82) pg/ml vs 106 (57e214) pg/ml for IFNb (p<0.05) and 114 (86e143) pg/ml vs 65 (32e119) pg/ml for TSLP (p<0.05) in response to 10 mg/ml dsRNA for 24 h).

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

“…2012b; Uller et al. 2010) and COPD tissues (Mallia et al. 2010), and IFN‐ β has been recently trialed in a Phase I/II study for efficacy on naturally occurring asthma exacerbations (Djukanovic et al.…”

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…Several studies with PBECs from non-asthmatic and asthmatic individuals have highlighted differences in the cellular response after exposure to environmental agents with the potential to cause epithelial damage. For example, it has been shown that monolayer cultures of PBECs derived from moderate-to-severe asthmatic individuals have a deficient innate immune response to rhinovirus infection by producing less interferon (IFN)-β (Wark et al, 2005), and this is paralleled by higher levels of the Th2-promoting chemokine, thymic stromal lymphopoietin (TSLP) (Uller et al, 2010). Based on the observation that exogenous IFN-β restores the anti-viral response and suppresses viral replication (Cakebread et al, 2011), clinical trials using inhaled IFN-β as a new treatment for virus-induced exacerbations have reported a beneficial effect in a subgroup of patients with severe asthma (Djukanović et al, 2014).…”

Bronchial epithelium in children: a key player in asthma

“…TSLP is a cytokine secreted by the airway epithelium in response to respiratory viruses and is known to promote allergic Th2 responses in asthma. Bronchial epithelium from asthmatic adults produces more TSLP compared with healthy controls when stimulated by double-stranded RNA [68]. However, there is no data in children except for a clinical study that showed increased TSLP in nasal secretions during rhinovirus-induced asthma exacerbations [69].…”