Tnf Alpha And Il-17 Alkalinize Airway Surface Liquid Through Cftr And Pendrin

The pH of airway surface liquid (ASL) is a key factor that determines respiratory host defense; ASL acidification impairs and alkalinization enhances key defense mechanisms. Under healthy conditions. airway epithelia secrete base (HCO3-) and acid (H+) to control ASL pH (pH(ASL)). Neutrophil-predominant inflammation is a hallmark of several airway diseases, and TNF alpha and IL-17 are key drivers. However, how these cytokines perturb pH(ASL) regulation is uncertain. In primary cultures of differentiated human airway epithelia, TNFa decreased and IL-17 did not change pH(ASL). However, the combination (TNF alpha+EL-17) markedly increased pH(ASL) by increasing HCO3- secretion. TNF alpha+IL-17 increased expression and function of two apical HCO3- transporters, CI-1R anion channels and pendrin Cl-/HCO3- exchangers. Both were required for maximal alkalinization. TNF alpha+IL-17 induced pendrin expression primarily in secretory cells where it was coexpressed with CFTR. Interestingly, significant pendrin expression was not detected in CFTR-rich ionocytes. These results indicate that TNF alpha +IL-17 stimulate HCO3 secretion via CFTR and pendrin to alkalinize ASL, which may represent an important defense mechanism in inflamed airways.