241 : Increased IL-17C production by the TLR3 ligand poly (I:C) in primary cystic fibrosis airway epithelial cells

Abstract

Cystic fibrosis is characterized by chronic inflammation that ultimately lead to death from respiratory failure. Overproduction of IL-8, a key chemokine that is crucial for an induction of neutrophil-dominated inflammation, has been considered as one of the important hallmarks of CF airway. Thus, identification of novel pathways underlying IL-8 induction could provide novel drug targets for prevention and treatment of CF. Importantly, recent studies suggest that airway epithelial cells produce IL-17C, an IL-17 member that is produced by epithelial but not Th17 cells, which contributes to production of proinflammatory cytokines such as IL-8 in an autocrine manner. However, the regulatory mechanism responsible for IL-17C expression in both non-CF and CF airway epithelial cells is still largely unexplored. The present study sought to determine how IL-17C expression is regulated during pathogenic infection in CF airway. Among the tested ligands of toll-like receptors (TLRs) that mimic infection signaling, poly (I:C), a synthetic analog of viral double-stranded RNA that works as a ligand for TLR3, strongly induced IL-17C gene expression and secretion in primary airway epithelial cells derived from non-CF (NHBE) and CF (DHBE-CF) subjects. Maximum induction of IL-17C gene expression and secretion was observed at 24 h post-treatment in both cells, and the induction was mainly through NF-kB and partially through MAPKs (ERK, JNK, p38). Importantly, the poly (I:C)-induced IL-17C up-regulation was strongly enhanced in DHBE-CF cells. Moreover, TLR3 expression and poly (I:C)-induced up-regulation of IL-8 and IFNb were also higher in DHBE-CF cells, suggesting that the enhancement of poly (I:C)-dependent IL-17C induction appears to be the result of increased TLR3 expression in CF airway epithelial cells. Thus, these findings firstly provide the idea that poly (I:C) signal is a critical pathway in accelerating IL-17C expression in CF airway, which may imply that the TLR3-IL-17C axis is crucial for exacerbating viral infection-associated inflammation in CF lung disease.