Polarized secreted IL-17C is a mediator of respiratory epithelial innate immune response

The IL-17 family of cytokines consists of at least six members (IL-17A to -F). IL-17 directly activates epithelial cells leading to the expression of inflammatory mediators and antimicrobial factors. In this study, our aim was to examine the expression and function of IL-17C in respiratory epithelial cells during bacterial infection. In vitro studies showed that common bacterial pathogens, such as Pseudomonas aeruginosa and Haemophilus influenzae, and ligands of Toll-like receptors 3 and 5 (flagellin, polyI:C) induced the expression and release of IL-17C in cultured human bronchial epithelial cells. Differentiated bronchial epithelial cells secreted IL-17C into the basolateral compartment and the secretion of IL-17C was increased in response to basolateral stimulation as compared to apical stimulation with bacterial stimuli. Pharmacological inhibition of intracellular calcium release and calcium chelators inhibited the secretion of IL-17C whereas the release of the inflammatory mediator IL-6 was not affected. IL-17C enhanced inflammatory responses of respiratory epithelial cells infected with P. aeruginosa. These data show that calcium-dependent signaling cascades mediate the polarized secretion of IL-17C and that IL-17C mediates innate immune responses of respiratory epithelial cells.