LSC Abstract – Role For IL-1alpha in viral-induced inflammatory responses in an epithelial-fibroblast co-culture model of the airway mucosa

Bronchial epithelial cells (BECs) and fibroblasts (FB) form an epithelial mesenchymal trophic unit (EMTU) that drives responses to disruptions in homeostasis such as viral infection. Evidence suggests that viral infection of BECs releases mediators which activate FBs. We hypothesised that epithelial virus exposure activates the EMTU. The EMTU was modelled using polarised BECs (16HBE14o-) and FBs (MRC5) maintained on the apical and basolateral surface of a nanoporous membrane respectively. Cytokine responses to dsRNA (a viral mimetic) were determined by ELISA. A primary EMTU model was established using primary BECs differentiated at an air-liquid interface, co-cultured with FBs and challenged with rhinovirus (RV16). dsRNA activation of the EMTU model induced significant IL-6, IL-8, GM-CSF and IP-10 release which was synergistically enhanced basolaterally compared to BEC or FB monocultures. dsRNA dependent IL-1αrelease was also detected in the EMTU model and BECs.IL-1 receptor (IL-1R) antagonist abrogated dsRNA-dependent basolateral IL-6, IL-8 and GM-CSF responses.However, only FBs were responsive to stimulation with exogenous IL-α. In the primary EMTU model, RV16 induced IL-1α,IL-6, IL-8 and IP-10 release and following IL-1R antagonism there was a significant reduction in RV16-dependent IL-6 and IL-8. In the EMTU cross-talk between BECs and FBs led to synergistic enhancement in viral-induced responses. Viral-induced basolateral inflammatory responses were mediated by BEC-derived IL-1αacting on FBs.IL-1α may therefore have important consequences in promoting inflammation in viral exacerbations of chronic lung diseases such as asthma.