Abstract
Helicobacter pylori (H. pylori) infection is associated with chronic gastritis, peptic ulcer and gastric cancer. Apoptosis induced by microbial infections is implicated in the pathogenesis of H. pylori infection. Here we show that human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death receptor signaling. Human gastric epithelial cells are intrinsically resistant to TRAIL-mediated apoptosis. The induction of TRAIL sensitivity by H. pylori is dependent on the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex (DISC) through downregulation of cellular FLICE-inhibitory protein (FLIP). Overexpression of FLIP abolished the H. pylori-induced TRAIL sensitivity in human gastric epithelial cells. Our study thus demonstrates that H. pylori induces sensitivity to TRAIL apoptosis by regulation of FLIP and assembly of DISC, which initiates caspase activation, resulting in the breakdown of resistance to apoptosis, and provides insight into the pathogenesis of gastric damage in Helicobacter infection. Modulation of host apoptosis signaling by bacterial interaction adds a new dimension to the pathogenesis of Helicobacter.
Highlights
tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a novel TNF superfamily member with a strong homology to FasL, is capable of inducing apoptosis in a variety of transformed cell lines in vitro[11,12] but usually not in normal primary cells
In the absence of TRAIL, H. pylori induced only mild apoptosis in AGS cells; apoptosis was markedly induced after adding TRAIL, and induction of TRAILmediated apoptosis by H. pylori was blocked by adding soluble TRAIL receptor, death receptor 4 (DR4)-Fc, indicating that cell death resulted from the interaction between TRAIL and the TRAIL receptor on the cell surface (Figure 1a)
When we investigated the assembly of the TRAIL death-inducing signaling complex (DISC) after TRAIL engagement in the presence or absence of H. pylori via co-immunoprecipitation experiments, the results (Figure 5b) demonstrate that, in the absence of H. pylori, TRAIL induced the assembly of DR5 (TRAIL-R2), FADD (MORT1), FLICE-inhibitory protein (FLIP), and a small amount of caspase-8 in the DISC
Summary
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand; called Apo2L), a novel TNF superfamily member with a strong homology to FasL, is capable of inducing apoptosis in a variety of transformed cell lines in vitro[11,12] but usually not in normal primary cells. Recent studies indicate that TRAIL-induced apoptosis occurs through a caspase signaling cascade and that resistance to TRAIL is controlled by intracellular regulators of apoptosis. Crosslinking of the TRAIL receptors leads to the formation of a death-inducing signaling complex (DISC).[16] The death adaptor protein FADD (MORT1) and the proteolytic enzymes caspase-8 and -10 are recruited to the TRAIL DISC.[17,18,19,20,21] Procaspase-8 is proteolytically cleaved and activated at the DISC. H. pylori induces TRAIL apoptosis signaling by downregulation of FLICE-inhibitory protein (FLIP), which enhances the assembly of TRAIL DISC, induces caspase-8 activation, and conveys the death signal to mitochondria, resulting in a breakdown of apoptosis resistance
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