Late Breaking Abstract - IL-36 receptor agonists contribute to a pro-inflammatory milieu in smokers with and without COPD

Background: The IL-36 cytokine family is a group of pro-inflammatory cytokines produced by structural and myeloid-derived cells in vitro , and in in vivo experimental models, such as psoriasis and pneumonia. Objective: We examined whether IL-36 signaling is enhanced in long-term smokers with and without COPD and whether IL-36 receptor agonists contribute to a pro-inflammatory milieu in the lung. Methods: Bronchoalveolar lavage (BAL) fluid and plasma from a cohort of nonsmokers (n = 8), healthy smokers (n = 10), and smokers with COPD/CB (n = 5) were sonicated. Primary mouse lung macrophages, fibroblasts, and alveolar epithelial cells (AEC) were stimulated with either heat-killed K. pneumoniae (Kp) or recombinant IL-36α or –γ. We quantified mRNA (qRT-PCR) from murine primary cells, as well as proteins (ELISA) in BAL fluid and plasma. Results: Lung macrophages, fibroblasts, and AEC express IL-36α and –γ in response to Kp. Treatment of macrophages with IL-36α or –γ triggered induction of CXC and CC chemokines, and TNFα in a dose-dependent fashion. IL-36α and -γ protein levels were enhanced in BAL fluid from smokers with and without COPD, whereas IL-36β, IL-36RA, and IL-38 were undetectable. Plasma levels of IL-36α but not –γ protein were elevated in smokers with and without COPD. The BAL levels of IL-36α protein correlate negatively with FEV1 and FEV1/FVC. Conclusion: IL-36α and -γ are produced by lung cells in vitro and are increased in smokers with and without COPD in vivo, correlating with a decline in lung function and induction of pro-inflammatory chemokines. This suggests that IL-36 agonists may play a pro-inflammatory role in the lungs of long-term smokers.