Hydrogen peroxide induces upregulation of Fas in human airway epithelial cells via the activation of PARP-p53 pathway

Fas mediates apoptosis following binding with Fas ligand. Fas is expressed in human airway epithelial cells and has a critical role in the pathophysiology of various pulmonary disorders. Hydrogen peroxide (H2O2) is an important mediator of airway epithelial injury. In this context, we hypothesized that H2O2 would increase the expression of cell surface Fas in human airway epithelial cells. To test this hypothesis, the modulation of Fas expression with H2O2 was assessed in normal human bronchial epithelial cells and A549 cells. The majority of Fas was cytoplasmic in both cell types without any stimulation. Hydrogen peroxide significantly increased Fas in the plasma membrane fraction, while decreasing Fas in the cytoplasmic fraction. Incubation with an agonistic antibody for Fas induced apoptosis in H2O2-treated cells in proportion to the level of surface Fas expression on those cells. Inhibitors of poly(ADPribose) polymerise abrogated the H2O2-induced Fas translocation to the plasma membrane and p53 activation. Expression of dominant-negative p53 also inhibited the Fas translocation induced by H2O2 in A549 cells. These results indicate that H2O2 induces Fas upregulation by promoting cytoplasmic transport of Fas to the cell surface in human airway epithelial cells, and that the activation of the poly(ADP-ribose) polymerise-p53 pathway may be involved in this mechanism.