胃幽門螺旋桿菌引起發炎體活化之研究

Abstract

The Gram-negative bacterium Helicobacter pylori causes gastritis, gastric ulceration, and gastric cancer in humans. The key pathophysiological event in H. pylori infection is initiation of an inflammatory response, including polymorphonuclear and mononuclear cell infiltration, such as macrophages, and proinflammatory cytokine production in gastric mucosa. One of the most important mediators of inflammation is Interleukin (IL)-1β. It is reported that the inflammasome, which comprises nucleotide and oligomerization domain-like receptor (NLR), apoptosis-associated speck-like protein containing a CARD (ASC) and procaspase-1, is a molecular platform which triggers caspase-1 activation and pro-IL-1β processing. Moreover, recent studies demonstrate that certain pathogens such as Salmonella typhimurium, Listeria monocytogenes and Staphylococus aureus are potent activators of the inflammasome. However, whether the inflammasome could be activated in response to H. pylori is still unknown. In order to examine whether H. pylori could induce IL-1β production, we first detected IL-1β in the culture medium of H. pylori-cocultured THP-1 cells or murine macrophages by IL-1β ELISA. To further confirm H. pylori-induced IL-1β release was through caspase-1, we detected the activation of caspase-1 by Western blot. Our results demonstrated that H. pylori could induce caspase-1 activation and IL-1β release, indicating H. pylori could activate the inflammaseome. In addition, different H. pylori strains revealed different ability to IL-1β production and these clinical isolates could induce IL-1β production. The clinical strains isolated from gastric ulcer are with lower IL-1β inducing activity and the clinical isolated strain from gastric cancer is with the higher IL-1β inducing activity compared to other strains. Since H. pylori is a potent activator of the inflammasome, the question of which constituents sensed by the inflammasome arises. Thus, we investigated which component of H. pylori is involved in the activation of inflammasome by screening H. pylori mutants. Most of H. pylori strains contain the virulence factor, Cag (cytotoxin-associated genes) A. Our results revealed that the production of IL-1β is reduced via mutants with cagA deletion, indicating H. pylori CagA protein involves in inflammasome activation and IL-1β production. Activation of inflammasome may play a role in inflammatory response induced by H. pylori, and the virulent factor CagA is critical in H. pylori-induced inflammasome activation.