Inflammasome-Mediated IL-1β Production in Humans with Cystic Fibrosis

Background: Inflammation and infection are major determinants of disease severity and consequently, the quality of life and outcome for patients with cystic fibrosis (CF). Interleukin-1 beta (IL-1 beta) is a key inflammatory mediator. Secretion of biologically active IL-1 beta involves inflammasome-mediated processing. Little is known about the contribution of IL-1 beta and the inflammasomes in CF inflammatory disease. This study examines inflammasome-mediated IL-1 beta production in CF bronchial epithelial cell lines and human patients with CF. Results: Bronchial epithelial cell lines were found to produce negligible amounts of basal or stimulated IL-1 beta compared to hematopoeitic cells and they did not significantly upregulate caspase-1 activity upon inflammasome stimulation. In contrast, peripheral blood mononuclear cells (PBMCs) from both CF and healthy control subjects produced large amounts of IL-1 beta and strongly upregulated caspase-1 activity upon inflammasome stimulation. PBMCs from CF patients and controls displayed similar levels of caspase-1 activation and IL-1 beta production when stimulated with inflammasome activators. This IL-1 beta production was dependent on NF-kappa B activity and could be enhanced by priming with LPS. Finally, chemical inhibition of CFTR activity in control PBMCs and THP-1 cells did not significantly alter IL-1 beta or IL-8 production in response to P. aeruginosa. Conclusion: Hematopoeitic cells appear to be the predominant source of inflammasome-induced pro-inflammatory IL-1 beta in CF. PBMCs derived from CF subjects display preserved inflammasome activation and IL-1 beta secretion in response to the major CF pathogen Pseudomonas aeruginosa. However, our data do not support the hypothesis that increased IL-1 beta production in CF subjects is due to an intrinsic increase in NF-kappa B activity through loss of CFTR function.