| Summary: | 碩士 === 國立臺灣大學 === 免疫學研究所 === 102 === Helicobacter pylori (HP), a common human pathogen which infects about 50% of the world’s population, is associated with duodenal ulcer, peptic ulcer diseases, gastric cancer and Mucosa-associated lymphoid tissue lymphoma (MALToma). Gastric cells apoptosis induced by HP were reported to be involved in the pathogenesis of peptic ulcer. Our previous studies have demonstrated that T lymphocytes from gastric tissue of HP patients expressed TRAIL, which could induce apoptosis. Furthermore, HP regulates TRAIL apoptosis signaling in human gastric epithelial cells by down-regulation of cellular short form of FLICE-inhibitory protein (FLIPs), which leads to enhanced assembly of the TRAIL death-inducing signaling complex (DISC) and caspase-8 activation and eventually apoptosis.
In this thesis, we further study the HP factors which regulated the apoptosis signaling in host cells, HP mutants with gene deficiency in the cytotoxin-associated gene pathogenicity island (CagPAI) were screened to identify the key factors in inducing apoptosis. Our data revealed that the induction of apoptosis signaling is dependent on the type IV secretory system of HP. We found that mutant strains with deficient type IV secretion system lost the ability to induce TRAIL sensitivity. Furthermore, these mutant strains were unable to down-regulate FLIPs and caspase-8 activation upon TRAIL treatment in human gastric epithelial cells. In contrast, CagA mutation showed no effect on HP-induced FLIPs down-regulation and TRAIL sensitivity. These results indicated that type IV secretion system of HP, but not CagA, is critical. In addition, in host cells aspect, we also explore the signaling pathway that HP may disturb to down-regulate FLIPs expression. Our results indicated that HP suppressed Akt (protein kinase B) activation, and there is a correlation between Akt activity and FLIPs expression in human gastric epithelial cell line. FLIPs expression was down- or up-regulated respectively by inhibiting Akt activity or over-expressing Akt. We further investigate whether HP disturbed Akt signaling pathway to induce TRAIL sensitivity by using Akt-overexpressing gastric epithelial cells. Over-expression of Akt mitigated HP-induced apoptosis, so these results indicated that HP modulated FLIPs expression to enhance TRAIL-mediated apoptosis partially by disturbing Akt signaling pathway. This study helps us to understand the mechanisms in inducing apoptosis by HP, and thereby to identify key factors which may help to design treatment of HP-associated diseases.
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