Cystic fibrosis pathogens activate Ca2+-dependent mitogen-activated protein kinase signaling pathways in airway epithelial cells

Much of the pulmonary disease in cystic fibrosis is associated with polymor phonuclear leukocyte-dominated airway inflammation caused by bacterial infe ction. Respiratory epithelial cells express the polymorphonuclear chemokine interleukin-8 (IL-8) in response to ligation of asialylated glycolipid rec eptors, which are increased on damaged or regenerating cells and those with cystic fibrosis transmembrane conductance regulator mutations. Because bot h Pseudomonas aeruginosa and Staphylococcus aureus, the most common pathoge ns in cystic fibrosis, bind asialylated glycolipid receptors such as asialo GM1, we postulated that diverse bacteria can activate a common epithelial s ignaling pathway to elicit IL-8 expression. P, aeruginosa PAO1 but not pil mutants and S. aureus RN6390 but not the agr mutant RN6911 stimulated incre ases in [Ca2+](i) in 1HAEo- airway epithelial cells. This response stimulat ed p38 and ERK1/2 mitogen-activated protein kinase (MAPK) signaling cascade s resulting in NF-KB activation and IL-8 expression. Ligation of the asialo GM1 receptor or thapsigargin-elicited Ca2+ release activated this pathway, whereas P. aeruginosa lipopolysaccharide did not. The rapid kinetics of epi thelial activation precluded bacterial invasion of the epithelium, Recognit ion of asialylated glycolipid receptors on airway epithelial cells provides a common pathway for Gram-positive and Gram-negative organisms to initiate an epithelial inflammatory response.