| Summary: | 碩士 === 高雄醫學大學 === 醫學研究所 === 99 === Helicobacter pylori is a spiral-shaped gram-negative bacterium which infecting approximately 50% of the world’s population. Approximately 90% of the population who infected H. pylori were asymptomatic and 10% of this population were inducted gastric or duodenal ulcers disease, only 1% of this population will get gastric cancer. It is known that persistent chronic inflammation and severe disease will be induced when human body can’t eliminate bacterium following H. pylori infection. DC is not only an antigen presenting cell but also an important linking cell between the innate immune response and acquired immune responses. It is believed that the maturation of DC is the key point for deciding the reaction of innate immune response and acquired immune responses.
This study investigated whether H. pylori affect DC maturation, cytokine expression and T cell immune responses. In addition , the difference of immune responses between gastric cancer patient and healthy individuals after H. pylori infection was compared. Otherwise, whether H. pylori virulence factor CagA, VacA affect DC maturation and cytokine expression was evaluated.
Recent showed that increased TNF-α and IL-10 expression from MDDC was via actuation of NF-κB and through p38 pathway after H. pylori infection.IL-10 expression was regulated through TLR2,TLR4 and DC-SIGN. On the other hand, TNF-α expression was regulated through TLR2 and TLR4. Additionally, MDDC increased IL-10 expression from MDDC after H. pylori infection is regulated by histone acetylation and methylation. TNF-α expression increased by acetylation or methylation of acetylation-H3 in the + TNF4 region, tri-methylated H3K36 in + TNF1417 region and tri-methylated H3K79 in + TNF4 and + TNF720 region. Otherwise, IL-10 expression will be increased by histone H3-acetylation. Histone H3K9 tri-methylated will result in TNF-α, IL-10 gene expression decreased. Only IL-10 expression was affected when acetylation and methylation inhibitor was added. Co-culture H. pylori pulsed MDDC with CD4+ T cell will induce IL-17 expression from T cells.
We found that the expression of IL-10 in gastric cancer patients were lower than normal controls when compared the expression of TNF-α and IL-10 from MDDC between gastric cancer patients and healthy controls. Besides, the expression of CD40,CD80,CD86 and MHCⅡ, especially CD40 on MDDC from the patients was lower than normal controls. Expression of IL-17 from MDDC in gastric cancer was lower than normal controls. Virulence factors VacA and CagA of H. pylori were associated with TNF-α expression in MDDC after H. pylori infection.
In this study, we found that H. pylori can activate MDDC through TLR2, TLR4 and DC-SIGN receptor and activate NF-κB through p38 signaling pathway to induce the expression of TNF-α and IL-10. In addition, the expression of IL-10 was regulated by histone acetylation and methylation, and we also found that H. pylori could activate T cell and increased IL-17 expression. TNF-α secreted by MDDC is regulated by virulence factors VacA and CagA of H. pylori. According to our results, we thought that due to lower maturation of MDDC in gastric cancer patient after H. pylori infection, unmaturated MDDC can not activate T cell and initiate affective immune response to eradicate pathogen and finally leads to chronic gastric inflammation and gastric disease.
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