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 (H(2)O(2)) is an important mediator of airway epithelial injury. In this context, we hypothesized that H(2)O(2) would increase the expression of cell surface Fas in human airway epithelial cells. To test this hypothesis, the modulation of Fas expression with H(2)O(2) 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 H(2)O(2)-treated cells in proportion to the level of surface Fas expression on those cells. Inhibitors of poly(ADP-ribose) polymerase abrogated the H(2)O(2)-induced Fas translocation to the plasma membrane and p53 activation. Expression of dominant-negative p53 also inhibited the Fas translocation induced by H(2)O(2) in A549 cells. These results indicate that H(2)O(2) 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) polymerase-p53 pathway may be involved in this mechanism.
Fujita
Tadashi
T
The First Department of Internal Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Japan.
Maruyama
Muneharu
M
Araya
Jun
J
Sassa
Kazuhiko
K
Kawagishi
Yukio
Y
Hayashi
Ryuji
R
Matsui
Shoko
S
Kashii
Tatsuhiko
T
Yamashita
Naohiro
N
Sugiyama
Eiji
E
Kobayashi
Masashi
M
D017209:Apoptosis / Q000187:drug effects; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases