Dual Oxidase 2 (Duox2) Regulates Pannexin 1-mediated ATP Release in Primary Human Airway Epithelial Cells via Changes in Intracellular pH and Not H2O2 Production

摘要: Human airway epithelial cells express pannexin 1 (Panx1) channels to release ATP, which regulates mucociliary clearance. Airway inflammation causes dysfunction. Exposure of primary human cell cultures IFN-γ for 48 h did not alter Panx1 protein expression but significantly decreased ATP in response hypotonic stress. The IFN-γ-induced functional down-regulation was due the up-regulation dual oxidase 2 (Duox2). Duox2 suppression by siRNA led an increase control and restoration treated with IFN-γ. Both effects were reduced inhibitor probenecid. stoichiometrically increases H2O2 proton production. inhibited function temporarily formation disulfide bonds at thiol group its terminal cysteine. Long-term exposure H2O2, however, had no inhibitory effect. To assess role cellular acidification upon treatment, fully differentiated exposed ammonium chloride alkalinize cytosol. This a 2-fold that also knockdown partially corrected IFN-γ-mediated acidification. direct correlation between intracellular pH open probability shown oocytes. Therefore, less stress inflammatory environment (IFN-γ exposure). Decreased is mediated Duox2, representing novel mechanism dysfunction diseases.