| Summary: | 博士 === 國立臺灣大學 === 免疫學研究所 === 99 === Infection with the gastric pathogen H. pylori infection has been associated with the development of chronic gastritis and peptic ulcer diseases, moreover, gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. H. pylori infection leads to pathogenesis of gastric diseases mainly by two different mechanisms : direct toxicity of H. pylori virulent factors and induction of inflammatory responses. The role of H. pylori in association with disease development has been demonstrated, however, the mechanisms underlying pathogenesis are still unclear.
First, in order to investigate the mechanisms underlying H. pylori induces the tumourgenesis, we examine the role of H. pylori CagA in the development of MALT lymphoma. Previous studies reveal that H. pylori attaches to the epithelial cells, and translocates CagA proteins into cells. Intracellular CagA deregulates intracellular sighaling pathway and causes the pathogenic effects. This in turn raised the possibility that H. pylori is associated with the development of MALT lymphomas during persistent infection by direct interaction with B lymphocytes. We demonstrated that H. pylori directly translocates CagA into human B cell line and primary B cells. Furthermore, injected CagA undergoes tyrosine phosphorylation and interacts with SHP-2. Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase were activated upon CagA translocation. The cell survival factors, such as Bcl-2 and Bcl-XL were upregulated through the translocated CagA, moreover, prevents apoptosis. These results provide evidence that CagA is directly delivered into B cells by H. pylori and acts as a bacterium-derived oncoprotein in human B cells to cause the development of MALT lymphoma.
Second, to study the role of host factors in regulating H. pylori-induced gastric diseases, we investigated the role of TNF related-apoptosis inducing ligand (TRAIL) in the induction of apoptosis during H. pylori infection. In our previous study, we provided the evidences that H. pylori can sensitize human gastric epithelial cells to TRAIL-mediated apoptosis. Further, we demonstrated that H. pylori could sensitize gastric epithelial cells to TRAIL, resulting in caspase-8, caspase-3 and mitochondrial pathway activation and induce apoptosis. H. pylori could enhance the death inducing signaling complex (DISC) assembly and induce sufficient amount of caspase-8 activation to break apoptosis resistance, inducing the TRAIL sensitivity via downregulation of the c-FLIPS in gastric epithelial cells. Overexpression of c-FLIPS could block apoptosis induced by TRAIL in the presence of H. pylori. Moreover, silencing c-FLIPS expression by siRNA increased TRAIL-induced apoptosis in human gastric epithelial cells. In summary, our data suggest that H. pylori could downregulate the expression level of c-FLIPS, resulting in enhanced DISC assembly and caspase-8 activation to modulate TRAIL-mediated apoptosis in gastric epithelial cells.
Taken together, pathogen and host factors are critical in the development of H. pylori-associated diseases, the interplay between H. pylori and immune cells as well as gastric epithelial cells play important roles in the pathogenesis of H. pylori-mediated gastric disease.
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