Role of mitochondria activation in Helicobacter pylori-sensitized TRAIL-mediated apoptosis in human gastric epithelial cells
Date Issued
2004
Date
2004
Author(s)
Wu, Yung-Hsuan
DOI
en-US
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various transformed cell lines but not in most primary cells. The sensitivity to TRAIL is under regulation and the resistance to TRAIL in some tumor cells lines have been demonstrated to be controlled by intracellular regulators. Previous studies in our laboratory have demonstrated that human gastric epithelial cells were sensitized to Helicobacter pylori (H. pylori), conferring susceptibility to TRAIL-mediated apodosis. The enhanced TRAIL sensitivity by H. pylori is via altering intracellular signaling pathway in human gastric epithelial cells.
In order to investigate signaling pathway of TRAIL-mediated apoptosis in gastric epithelial cell during H. pylori infection, we used an in vitro co-culture system to study the gastric epithelial cell apoptosis after interaction with H. pylori. Our previous study had shown that H. pylori-induced TRAIL-mediated apoptosis in gastric epithelial cells could be blocked by caspase-3, -8 or -9 inhibitors. In this study, our results demonstrated that caspase-8 was activated induced by TRAIL in human gastric epithelial cells either in the absence or presence of H. pylori. In contrast, activation of caspase-3 and -9 in gastric epithelial cells were induced by TRAIL only in the presence of H. pylori. These results indicate that H. pylori induces TRAIL-mediated apoptosis in gastric epithelial cells through a pathway involving the sequential induction of apical caspase-8 activity, effector-cascade and effector caspase-3 activity. The alteration of TRAIL signal transduction by H. pylori seems to be regulated at the level of caspase-8 downstream, and caspase-9 upstream pathway. Besides, we also examined the cytochrome c release and activation of regulatory molecules, Bid, in mitochondria activation. Our results showed that in the presence of H. pylori, TRAIL induces cytochrome c release and Bid cleavage in gastric epithelial cells. We further generated Bcl-2-overexpressing cell line and in which the H. pylori-induced TRAIL sensitivity could be reversed by overexpression of Bcl-2. Moreover, Bid cleavage after TRAIL engagement was observed only in the presence of H. pylori and expression of exogenous DN-Bid in AGS cells partially inhibit H. pylori-sensitized TRAIL-mediated apoptosis. These results indicated that mitochondria activation is required for H. pylori-sensitized TRAIL-mediated apoptosis and the regulation of TRAIL apoptosis signaling is at the level of Bid activation.
Subjects
細胞凋亡
胃幽門螺旋桿菌
粒線體
apoptosis
Helicobacter pylori
mitochondria
Type
other
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