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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳俊任(Chun-Jen Chen) | |
dc.contributor.author | Chiu-Ying Lu | en |
dc.contributor.author | 呂秋瑩 | zh_TW |
dc.date.accessioned | 2021-06-16T23:23:00Z | - |
dc.date.available | 2017-08-01 | |
dc.date.copyright | 2012-08-01 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-07-31 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65085 | - |
dc.description.abstract | IL-1β 是一個關鍵的促發炎反應細胞激素,同時可調控先天與後天免疫反應,而IL-1β 的產生受到發炎體的嚴密管控。發炎體是一類多蛋白複合體,主要負責 caspase-1 的活化,而使得 caspase-1 對 pro-IL-1β 進行酵素作用而成為具有功能性的 IL-1β ,才能分泌至胞外。本篇研究探討靈芝免疫調節蛋白(fungal immunomodulatory proteins, FIPs) LZ-8 和 GMI 刺激小鼠巨噬細胞後,對於發炎體的活化及 IL-1β 分泌的影響。結果發現 LZ-8 和 GMI 可使經 LPS 刺激的巨噬細胞之 caspase-1 活化,導致 IL-1β 的分泌量上升。進一步發現,於細胞培養中添加高濃度氯化鉀、使用P2X7 受體或 pannexin-1 的抑制劑皆能顯著降低 FIP 所引起的 IL-1β 分泌量,顯示 FIPs 所引發的發炎體活化需要透過鉀離子由離子通道外流的途徑。此外,抑制活性氧自由基 (ROS) 的產生也可以有效降低 IL-1β 的分泌量,代表 ROS 也可能參與其中的活化路徑。此外, LZ-8 以腹腔注射方式打入小鼠體內後,可引發嗜中性球聚集至腹腔中,而對於後續李斯特菌的感染具有保護的效果,上述的保護現象在 IL-1 受體缺陷 (IL-1R-/-) 小鼠中則顯著下降,顯示 IL-1β-IL-1R 訊息在 LZ-8 誘發的先天免疫反應中具有重要的角色。相反地,經初步實驗結果發現, IL-1β-IL-1R 訊息在 LZ-8 的佐劑活性中較不具影響力。總結而言,本研究證實 FIPs 是可活化發炎體的蛋白質,故在使用 FIPs 作為免疫調節物時,須同時考慮其活化發炎體的特性。 | zh_TW |
dc.description.abstract | IL-1β is a key proinflammatory cytokine regulating both innate and adaptive immune responses, and its production is controlled by the inflammasome. Inflammasomes are multiprotein platforms responsible for caspase-1 activation and subsequent processing and secretion of mature IL-1β. Here we studied the stimulatory effect of fungal immunomodulatory proteins (FIPs) LZ-8 and GMI on inflammasome activation and IL-1β production in murine macrophages. FIP stimulation resulted in caspase-1 activation and robust IL-1β production in LPS-primed macrophages. FIP-induced IL-1β production was inhibited in the presence of high extracellular KCl or inhibitors targeting the membrane pores P2X7 and pannexin-1, indicating that FIP-induced inflammasome activation requires potassium efflux through ion channels. In addition, inhibition of reactive oxygen species (ROS) production also reduced FIP-induced IL-1β production, indicating that ROS generation is also involved in the process. Intraperitoneal administration of LZ-8 in mice elicited a robust influx of neutrophils and protected mice against subsequent L. monocytogenes infection, which were both attenuated in IL-1R-/- mice, indicating that the IL-1β-IL-1R signal plays a significant role in the innate immune response triggered by LZ-8. In contrast, our preliminary results indicate that the adjuvant function of LZ-8 is less dependent on the IL-1β-IL-1R signal. Overall, our findings provide evidence that FIPs are a new type of protein ligand for inflammasome activation, and this activity should be taken into consideration when using FIPs as an immunomodulatory agent. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T23:23:00Z (GMT). No. of bitstreams: 1 ntu-101-R99b22014-1.pdf: 2591315 bytes, checksum: 703bb4403e177247ffafe4cb62b505a1 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 口試委員審定書 ........................................................................................................... I
謝誌 ..............................................................................................................................II 中文摘要 .................................................................................................................... III Abstract ...................................................................................................................... IV Abbreviation ............................................................................................................... VI 目錄 ............................................................................................................................. X 圖表目錄 ................................................................................................................. XIII 第一章 緒論 ....................................................................................................... 1 1.1 靈芝屬真菌具生物活性之成份 ................................................................. 1 1.1.1 多醣體 (polysaccharides) ................................................................. 1 1.1.2 三萜類 (triterpenoids) ....................................................................... 2 1.1.3 小分子蛋白 (proteins) ...................................................................... 2 1.2 靈芝屬免疫調節蛋白................................................................................. 3 1.2.1 Ling Zhi-8 (LZ-8) .............................................................................. 3 1.2.2 Ganoderma microsporum immunomodulatory protein (GMI) ............ 4 1.3 Interleukin-1β (IL-1β) 與免疫系統 ............................................................ 5 1.3.1 IL-1β 於先天免疫系統的角色 ......................................................... 5 1.3.2 IL-1β 對後天免疫系統的影響 ......................................................... 5 1.3.3 IL-1β 的生成與其下游訊號 ............................................................. 6 1.4 發炎體 (inflammasome) ............................................................................ 7 1.4.1 發炎體的構造及種類 ....................................................................... 7 1.4.2 發炎體的可能活化途徑 .................................................................... 8 1.4.3 發炎體於免疫系統的重要性 ............................................................ 9 1.5 李斯特菌 (Listeria monocytogenes) 感染引發之免疫反應 .................... 10 1.6 佐劑 (adjuvant) ........................................................................................ 11 1.7 研究動機與目的 ...................................................................................... 12 第二章 材料與方法 ......................................................................................... 13 2.1 LZ-8 及 GMI .......................................................................................... 13 2.1.1 LZ-8 及 GMI 之樣品純度檢驗 .................................................... 13 2.1.2 製備經蛋白質酶處理之 LZ-8 樣品 .............................................. 13 2.2 實驗動物 .................................................................................................. 13 2.3 探討 LZ-8 與 GMI 對發炎體的活化作用 ............................................ 14 2.3.1 培養與刺激巨噬細胞 ..................................................................... 14 2.3.2 細胞激素濃度之測定 ..................................................................... 15 2.3.3 細胞存活率檢定 ............................................................................. 15 2.3.4 蛋白質電泳與西方墨點法 .............................................................. 16 2.3.5 抑制劑詴驗 ..................................................................................... 17 2.4 IL-1β-IL-1R 對於 LZ-8 誘發小鼠發炎反應之影響 .............................. 17 2.4.1 LZ-8 免疫小鼠模式 ....................................................................... 17 2.4.2 嗜中性球及單核球聚集現象分析 .................................................. 18 2.4.3 腹腔沖洗液細胞激素及趨化因子分析........................................... 18 2.5 IL-1β-IL-1R 對於 LZ-8 之抗微生物感染活性之影響 .......................... 19 2.5.1 李斯特菌 (Listeria monocytogenes) 之培養 .................................. 19 2.5.2 小鼠免疫模式 ................................................................................. 19 2.5.3 脾臟及肝臟菌數評估 ..................................................................... 19 2.6 IL-1β-IL-1R 對於 LZ-8 之佐劑活性之影響.......................................... 20 2.6.1 小鼠免疫模式 ................................................................................. 20 2.6.2 去除 OVA 抗原中之內毒素 .......................................................... 21 2.6.3 血清中之具 OVA 專一性抗體測定 .............................................. 21 2.6.4 小鼠初代脾臟細胞培養與刺激 ...................................................... 21 2.6.5 細胞激素濃度之測定 ..................................................................... 22 2.6.6 脾臟細胞增生詴驗 ......................................................................... 22 2.6.7 細胞毒殺作用測詴 ......................................................................... 22 2.7 統計與繪圖軟體之分析 ........................................................................... 23 第三章 實驗結果 ............................................................................................. 24 3.1 LZ-8 及 GMI 可活化巨噬細胞中之發炎體 .......................................... 24 3.1.1 LZ-8 及 GMI 可刺激巨噬細胞產生 IL-1β .................................. 24 3.1.2 LZ-8 及 GMI 刺激細胞產生 IL-1β 是透過 caspase-1 ............... 24 3.2 LZ-8 及 GMI 活化發炎體的可能途徑 .................................................. 25 3.2.1 FIPs 活化發炎體透過 P2X7R / pannexin-1 / K + efflux 途徑 ........ 25 3.2.2 FIPs 活化發炎體並非透過產生 ATP 而得................................... 26 3.2.3 FIPs 活化發炎體途徑需要 ROS 的參與 ...................................... 26 3.3 IL-1β-IL-1R 訊息對於 LZ-8 刺激小鼠所引發之發炎反應的影響 ....... 27 3.4 IL-1β-IL-1R 在 LZ-8 保護小鼠不受李斯特菌感染中扮演之角色 ....... 27 3.5 IL-1β-IL-1R 對 LZ-8 的佐劑活性影響之評估 ...................................... 28 3.5.1 對於產生具抗原專一性之 IgG1 及 IgG2a 的影響 ..................... 28 3.5.2 對於活化 T 細胞產生細胞激素的影響 .......................................... 28 3.5.3 對於具抗原專一性淋巴球活化增生的影響 ................................... 29 3.5.4 對於 CD8 T 細胞之毒殺作用的影響 ............................................ 29 第四章 討論與結論 ......................................................................................... 30 圖表 ............................................................................................................................ 35 參考文獻 .................................................................................................................... 54 | |
dc.language.iso | zh-TW | |
dc.title | 靈芝免疫調節蛋白 LZ-8 和 GMI 對發炎體活化之作用 | zh_TW |
dc.title | Activation of the inflammasome by fungal immunomodulatory proteins LZ-8 and GMI | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 徐立中,朱清良 | |
dc.subject.keyword | 真菌免疫調節蛋白,LZ-8,GMI,發炎體,介白素-1β,李斯特菌感染,佐劑, | zh_TW |
dc.subject.keyword | fungal immunomodulatory protein (FIP),Ganoderma lucidium immunomodulatory protein, LZ-8,Ganoderma microsporum immunomodulatory protein, GMI,inflammasome,interleukin-1β,Listeria monocytogenes infection,adjuvant, | en |
dc.relation.page | 65 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-08-01 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科技學系 | zh_TW |
顯示於系所單位: | 生化科技學系 |
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