Article

Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells.

Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2605, USA.
Infection and immunity (impact factor: 4.21). 07/2011; 79(7):2535-43. DOI:10.1128/IAI.01370-10 pp.2535-43
Source: PubMed

ABSTRACT Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach and contributes to the development of peptic ulcer disease and gastric cancer. The secreted pore-forming toxin VacA is one of the major virulence factors of H. pylori. In the current study, we show that AZ-521 human gastric epithelial cells are highly susceptible to VacA-induced cell death. Wild-type VacA causes death of these cells, whereas mutant VacA proteins defective in membrane channel formation do not. Incubation of AZ-521 cells with wild-type VacA results in cell swelling, poly(ADP-ribose) polymerase (PARP) activation, decreased intracellular ATP concentration, and lactate dehydrogenase (LDH) release. VacA-induced death of these cells is a caspase-independent process that results in cellular release of histone-binding protein high mobility group box 1 (HMGB1), a proinflammatory protein. These features are consistent with the occurrence of cell death through a programmed necrosis pathway and suggest that VacA can be included among the growing number of bacterial pore-forming toxins that induce cell death through programmed necrosis. We propose that VacA augments H. pylori-induced mucosal inflammation in the human stomach by causing programmed necrosis of gastric epithelial cells and subsequent release of proinflammatory proteins and may thereby contribute to the pathogenesis of gastric cancer and peptic ulceration.

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Keywords

AZ-521 human gastric epithelial cells
 
caspase-independent process
 
cell death
 
cellular release
 
gastric cancer
 
gastric epithelial cells
 
growing number
 
H. pylori
 
Helicobacter pylori
 
histone-binding protein
 
induce cell death
 
membrane channel formation
 
mutant VacA proteins defective
 
peptic ulcer disease
 
peptic ulceration
 
proinflammatory protein
 
subsequent release
 
VacA-induced cell death
 
VacA-induced death
 
Wild-type VacA causes death