Apoptotic Signaling Pathway Activated by Helicobacter pylori Infection and Increase of Apoptosis-Inducing Activity under Serum-Starved Conditions

Abstract

The enhanced gastric epithelial cell apoptosis observed during infection with Helicobacter pylori has been suggested to be of significance in the etiology of gastritis, peptic ulcers, and neoplasia. To investigate the cell death signaling induced by H. pylori infection, human gastric epithelial cells were incubated with H. pylori for up to 72 h. H. pylori infection induced the activation of caspase -8, -9, and -3 and the expression of the proapoptotic Bcl-2 family proteins Bad and Bid. The peak of the activity of the caspases occurred at 24 h. At this time, the inhibition of caspase-8 or -9 almost completely suppressed H. pylori-induced apoptosis. Inhibition of caspase-8 suppressed the expression of Bad and Bid and the subsequent activation of caspase-9 and -3. These observations indicate that H. pylori induces apoptosis through a pathway involving the sequential induction of apical caspase-8 activity, the proapoptotic proteins Bad and Bid, caspase-9 activity, and effector caspase-3 activity. Activation of the pathway was independent of CagA or vacuolating toxin. A membrane fraction of H. pylori was sufficient to activate this pathway, and treatment with proteinase K eliminated the activity. Apoptotic activity of the membrane fraction was significantly increased by incubating the bacteria under serum-starved conditions for 24 h. These observations suggest that environmental conditions in the human stomach could induce H. pylori-mediated pathogenesis, leading to a variety of clinical outcomes.

Helicobacter pyloriInfection Induces Oxidative Stress and Programmed Cell Death in Human Gastric Epithelial Cells

“…Increased numbers of apoptotic cells are found in the gastric epithelium of infected patients (36,45,50,58), suggesting that induction of apoptosis may be a common method of cell growth regulation for H. pylori (24). In agreement with these findings, we and others have demonstrated that H. pylori induces programmed cell death in cultured gastric epithelial cells, as do proinflammatory cytokines that are released during infection (3,4,26,44,68,76). Proliferative (13,43) and apoptotic rates (24,36,50) have both been shown to return to control levels after eradication of infection.…”

Effect ofHelicobacter pyloriinfection on expressions of Bcl-2 family members in gastric adenocarcinoma

“…Activation of Caspase-8 could result in the cleavage of cytosolic Bid to truncate tBID, which could translocate to mitochondria and initiate apoptosis [48] . Shibayama et al [31] found that H pylori infection induced the activation of Caspase-8 and the expression of Bid in human gastric epithelial cells, and inhibition of Caspase-8 suppressed the expression of Bid. In the present study, we found that H pylori infection upregulated expression of Bid mRNA in both gastric adenocarcinoma and resection margin tissues.…”

“…The role of H pylori infection in the gastric carcinogenesis is not clear. It might be involved in imbalance between apoptosis and proliferation [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] . Bcl-2 family members have been closely related to apoptosis, which could either promote cell survival (Bcl-2, Bcl-x L , A1, Mcl-1, and Bcl-w) or promote cell death (Bax, Bak, Bcl-x S , Bad, Bid, Bik, Bim, Hrk, Bok) [34][35][36] .…”

Nuclear Factor κB Protects against Host Cell Apoptosis during Rickettsia rickettsii Infection by Inhibiting Activation of Apical and Effector Caspases and Maintaining Mitochondrial Integrity

“…Several pathogenic bacteria and secreted toxins, e.g. Helicobacter pylori and staphylococcal alpha toxin, trigger apoptosis of host cells in vitro and in vivo via caspase-8 and caspase-9, followed by cleavage and activation of caspase-3 (2,4,30). Conversely, the ability of intracellular pathogens to establish strategies for the inhibition of host cell apoptosis mechanisms have also been recognized.…”