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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 呂紹俊(Shao-Chun Lu) | |
| dc.contributor.author | Yuan-Yi Chou | en |
| dc.contributor.author | 周苑怡 | zh_TW |
| dc.date.accessioned | 2021-06-13T06:35:15Z | - |
| dc.date.available | 2016-10-05 | |
| dc.date.copyright | 2011-10-05 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-07-25 | |
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Zschiedrich, I., Hardeland, U., Krones-Herzig, A., Berriel Diaz, M., Vegiopoulos, A., Muggenburg, J., Sombroek, D., Hofmann, T.G., Zawatzky, R., Yu, X., et al. (2008). Coactivator function of RIP140 for NFkappaB/RelA-dependent cytokine gene expression. Blood 112, 264-276. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34829 | - |
| dc.description.abstract | 這篇研究論文探討哺乳動物雷帕霉素靶蛋白的抑制劑雷帕霉素對巨噬細胞可誘導型一氧化氮合成酶及粒細胞集落刺激因子表現的影響，包含兩個部份。第一部份是關於雷帕霉素對於脂多糖誘導巨噬細胞表現可誘導型一氧化氮合成酶及粒細胞集落刺激因子的抑制作用及其潛在機制。這個研究是源自觀察對小鼠巨噬細胞株RAW264.7預先處理雷帕霉素或是轉染顯性無效抑制因子哺乳動物雷帕霉素靶蛋白的表現質體會抑制脂多糖透過隸屬於哺乳動物雷帕霉素靶蛋白的路徑誘導的八核苷酸結合因子-2的蛋白量增加。因為可誘導型一氧化氮合成酶及粒細胞集落刺激因子都可能是八核苷酸結合因子-2的目標基因，我們測試雷帕霉素對於它們表現的作用並發現它會減少脂多糖誘導增加可誘導型一氧化氮合成酶及粒細胞集落刺激因子的訊息核糖核酸量及蛋白量、一氧化氮的生成和粒細胞集落刺激因子啟動子的活性。使用顯性無效抑制因子哺乳動物雷帕霉素靶蛋白的表現質體阻斷哺乳動物雷帕霉素靶蛋白的訊息傳遞會導致脂多糖誘導增加可誘導型一氧化氮合成酶及粒細胞集落刺激因子的蛋白量和一氧化氮的生成被抑制，證實了哺乳動物雷帕霉素靶蛋白不可或缺的角色。八核苷酸結合因子-2參與脂多糖誘導可誘導型一氧化氮合成酶及粒細胞集落刺激因子表現更進一步由下列發現證實：使用pCG-Oct-2質體大量表現八核苷酸結合因子-2能克服雷帕霉素對於脂多糖誘導增加可誘導型一氧化氮合成酶及粒細胞集落刺激因子的訊息核糖核酸量的抑制作用。染色質免疫沉澱分析顯示脂多糖增加八核苷酸結合因子-2和可誘導型一氧化氮合成酶及粒細胞集落刺激因子的啟動子的結合而預先處理雷帕霉素會抑制這個作用。此外，對八核苷酸結合因子-2的表現進行核糖核酸干擾基因抑制會降低脂多糖處理的細胞中可誘導型一氧化氮合成酶及粒細胞集落刺激因子的表現。雷帕霉素對於脂多糖誘導增加八核苷酸結合因子-2的蛋白量、可誘導型一氧化氮合成酶及粒細胞集落刺激因子的訊息核糖核酸量的抑制效果也在人類THP-1單核球分化而成的巨噬細胞株中發現。這個研究顯示雷帕霉素在轉錄的層次上減少脂多糖處理的巨噬細胞中可誘導型一氧化氮合成酶及粒細胞集落刺激因子的表現是透過抑制八核苷酸結合因子-2的表現。第二部份是研究雷帕霉素對於脂磷壁酸誘導巨噬細胞表現粒細胞集落刺激因子的作用及其潛在機制。我們的結果顯示對小鼠巨噬細胞株RAW264.7或是骨髓細胞分化而成的巨噬細胞處理脂磷壁酸會誘導粒細胞集落刺激因子的表現，並且和處理劑量及處理時間呈現正相關性，而預先處理雷帕霉素則會抑制這個效果。分析粒細胞集落刺激因子五端序列顯示位於−283到+35包含有集落刺激因子元件及八核苷酸元件的片段對於脂磷壁酸調控啟動子最大活性是必需的。研究雷帕霉素和脂磷壁酸對於和集落刺激因子元件及八核苷酸元件結合的蛋白的蛋白量的作用時，西方點墨法及電泳遷移變動分析法顯示脂磷壁酸誘導核因子-κB p50及p65的入核作用，增加磷酸化的抑制因子-κB-α、CCAAT/增強子結合蛋白β和八核苷酸結合因子-2的蛋白量，提高核因子-κB和CCAAT/增強子結合蛋白β與去氧核醣核酸的結合，而雷帕霉素會抑制其中由脂磷壁酸誘導增加的八核苷酸結合因子-2的蛋白量，但不影響其他作用。八核苷酸結合因子-1的表現則不受雷帕霉素和脂磷壁酸的改變。接著探討八核苷酸結合因子-2在脂磷壁酸誘導粒細胞集落刺激因子表現中扮演的關鍵角色。以核糖核酸干擾對八核苷酸結合因子-2的表現進行基因抑制會降低脂磷壁酸誘導粒細胞集落刺激因子的訊息核糖核酸量。此外，使用pCG-Oct-2質體轉染大量表現八核苷酸結合因子-2能克服雷帕霉素對於脂磷壁酸誘導增加粒細胞集落刺激因子的訊息核糖核酸量及啟動子活性的抑制作用。這篇研究顯示雷帕霉素減少脂磷壁酸處理的巨噬細胞中粒細胞集落刺激因子的表現是透過抑制八核苷酸結合因子-2的表現。 | zh_TW |
| dc.description.abstract | The study consists of two parts. The first part reports an inhibitory effect of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), on the lipopolysaccharide (LPS)-induced expression of both inducible nitric oxide synthase (iNOS) and granulocyte-colony stimulating factor (G-CSF) in macrophages and its underlying mechanism. The study arose from an observation that pre-treatment with rapamycin or transfection with dominant-negative (DN)-mTOR expression plasmid inhibited the LPS-induced increase in octamer-binding factor-2 (Oct-2) protein levels through an mTOR-dependent pathway in mouse RAW264.7 macrophages. As both iNOS and G-CSF are potential Oct-2 target genes, we tested the effect of rapamycin on their expression and found that it reduced the LPS-induced increase in iNOS and G-CSF mRNA levels, iNOS and G-CSF protein levels, NO production and G-CSF promoter activity. Blocking of mTOR-signaling using a DN-mTOR expression plasmid resulted in inhibition of the LPS-induced increase in iNOS and G-CSF protein levels and NO production, supporting the essential role of mTOR. The involvement of Oct-2 in LPS-induced iNOS and G-CSF expression was further supported by the finding that forced expression of Oct-2 using the pCG-Oct-2 plasmid overcame the inhibitory effect of rapamycin on the LPS-induced increase in iNOS and G-CSF mRNA levels. Chromatin immunoprecipitation (ChIP) assays showed that LPS enhanced the binding of Oct-2 to the iNOS and G-CSF promoters and that this effect was inhibited by pre-treatment with rapamycin. Moreover, RNA interference knockdown of Oct-2 expression reduced iNOS and G-CSF expression in LPS-treated cells. The inhibitory effect of rapamycin on the LPS-induced increase in Oct-2 protein levels and on the iNOS and G-CSF mRNA levels was also detected in human THP-1 monocyte-derived macrophages. This study demonstrates that rapamycin reduces iNOS and G-CSF expression at the transcription level in LPS-treated macrophages by inhibiting Oct-2 expression. The second part investigated the effect of rapamycin on the lipoteichoic acid (LTA)-induced expression of G-CSF in macrophages and its underlying mechanism. Our data showed that LTA treatment induced G-CSF expression in RAW264.7 and bone marrow-derived macrophages in a dose- and time-dependent manner and that this effect was inhibited by pre-treatment with rapamycin. Analysis of the G-CSF 5’ flanking sequence revealed that the −283 to +35 fragment, which contains CSF and octamer elements, was required for maximal promoter activity in response to LTA stimulation. When the effects of rapamycin and LTA on levels of proteins that bind to the CSF and octamer elements were investigated, Western blot analyses and electrophoretic mobility shift assays (EMSAs) showed that LTA induced nuclear translocation of NF-κB p50 and p65, increased protein levels of phospho-IκB-α, C/EBPβ and Oct-2, and enhanced the DNA binding of NF-κB and C/EBPβ, and that rapamycin inhibited the LTA-induced increase in Oct-2 protein levels, but not the other effects. Neither rapamycin nor LTA altered the expression of Oct-1. We then investigated the critical role of Oct-2 in LTA-induced G-CSF expression. Knockdown of Oct-2 expression by RNA interference resulted in a decrease in LTA-induced G-CSF mRNA levels. Moreover, forced expression of Oct-2 by transfection with the pCG-Oct-2 plasmid overcame the inhibitory effect of rapamycin on the LTA-induced increase in G-CSF mRNA levels and promoter activity. This study demonstrates that rapamycin reduces G-CSF expression in LTA-treated macrophages by inhibiting Oct-2 expression. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T06:35:15Z (GMT). No. of bitstreams: 1 ntu-100-F92442002-1.pdf: 8817951 bytes, checksum: 98c612939d29d92b8443dce4cc3d0e06 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
謝誌 ii 摘要 iii Abstract vi List of Abbreviations ix Table of Contents xiii List of Figures xvi List of Tables xxiii Chapter I. Introduction 1 Chapter II. Materials and Methods 12 2.1 Materials 12 2.2 Methods 15 2.2.1 Cell culture 15 2.2.2 Plasmid construction 16 2.2.3 Transient transfection 18 2.2.4 RNA isolation and reverse transcription-polymerase chain reaction (RT-PCR) 19 2.2.5 Protein preparation and Western blot analysis 19 2.2.6 Reporter gene activity assay 21 2.2.7 Quantification of G-CSF in the culture medium 21 2.2.8 Quantification of NO production (nitrite) in the culture medium 23 2.2.9 Chromatin immunoprecipitation (ChIP) assay 24 2.2.10 Nuclear and cytoplasmic extracts preparation 25 2.2.11 Electrophoretic mobility shift assay (EMSA) 26 2.2.12 Statistical analysis 27 Chapter III. Results 28 Part I. Rapamycin inhibits LPS induction of G-CSF and iNOS expression in macrophages by reducing the levels of Oct-2. 28 3.1.1 Rapamycin inhibits the LPS-induced increase in Oct-2 protein levels in RAW264.7 macrophages. 28 3.1.2 Rapamycin decreases LPS-induced iNOS expression in RAW264.7 macrophages. 31 3.1.3 Rapamycin inhibits G-CSF expression in LPS-treated RAW264.7 macrophages. 32 3.1.4 Oct-2 is directly involved in LPS-induced iNOS and G-CSF expression in RAW264.7 macrophages. 33 3.1.5 LPS-induced expression of Oct-2, G-CSF and iNOS in the THP-1 human monocyte/macrophage cell line is sensitive to rapamycin treatment. 34 Part II. Rapamycin inhibits LTA induction of G-CSF expression in macrophages by reducing the levels of Oct-2. 35 3.2.1 LTA up-regulates G-CSF expression in a dose- and time-dependent manner in RAW264.7 macrophages. 35 3.2.2 Determination of the G-CSF 5’ flanking sequence essential for maximal activation by LTA in RAW264.7 macrophages 36 3.2.3 Rapamycin attenuates LTA-induced G-CSF expression in RAW264.7 macrophages. 37 3.2.4 Effects of rapamycin and LTA on levels of transcriptional factors involved in transcriptional regulation of G-CSF in RAW264.7 macrophages 38 3.2.5 Rapamycin inhibits the LTA-induced increase in G-CSF and Oct-2 expression in bone marrow-derived macrophages. 41 3.2.6 Critical role of Oct-2 in the LTA-induced expression of G-CSF in RAW264.7 macrophages 41 Chapter IV. Discussion 43 Part I. Rapamycin inhibits LPS induction of G-CSF and iNOS expression in macrophages by reducing the levels of Oct-2. 43 Part II. Rapamycin inhibits LTA induction of G-CSF expression in macrophages by reducing the levels of Oct-2. 49 Chapter V. Overall Conclusion and Perspective 54 Chapter VI. Figures 56 Chapter VII. Tables 126 References 128 List of Publications 146 | |
| dc.language.iso | en | |
| dc.subject | 雷帕霉素 | zh_TW |
| dc.subject | 粒細胞集落刺激因子 | zh_TW |
| dc.subject | 可誘導型一氧化氮合成酶 | zh_TW |
| dc.subject | 脂多糖 | zh_TW |
| dc.subject | 脂磷壁酸 | zh_TW |
| dc.subject | 巨噬細胞 | zh_TW |
| dc.subject | 哺乳動物雷帕霉素靶蛋白 | zh_TW |
| dc.subject | 八核苷 | zh_TW |
| dc.subject | 酸結合因子-2 | zh_TW |
| dc.subject | macrophage | en |
| dc.subject | octamer-binding factor-2 (Oct-2) | en |
| dc.subject | mammalian target of rapamycin (mTOR) | en |
| dc.subject | Granulocyte-colony stimulating factor (G-CSF) | en |
| dc.subject | inducible nitric oxide synthase (iNOS) | en |
| dc.subject | lipopolysaccharide (LPS) | en |
| dc.subject | lipoteichoic acid (LTA) | en |
| dc.subject | rapamycin | en |
| dc.title | 雷帕霉素透過降低八核苷酸結合因子-2的蛋白量而抑制脂多糖或脂磷壁酸誘導巨噬細胞表現粒細胞集落刺激因子及可誘導型一氧化氮合成酶 | zh_TW |
| dc.title | Rapamycin inhibits LPS or LTA induction of G-CSF and iNOS expression in macrophages by reducing the levels of Oct-2 | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 張淑芬(Shwu-Fen Chang),李明學(Ming-Shyue Lee),徐立中(Li-Chung Hsu),姜安娜(An-Na Chiang) | |
| dc.subject.keyword | 粒細胞集落刺激因子,可誘導型一氧化氮合成酶,脂多糖,脂磷壁酸,巨噬細胞,哺乳動物雷帕霉素靶蛋白,八核苷,酸結合因子-2,雷帕霉素, | zh_TW |
| dc.subject.keyword | Granulocyte-colony stimulating factor (G-CSF),inducible nitric oxide synthase (iNOS),lipopolysaccharide (LPS),lipoteichoic acid (LTA),macrophage,mammalian target of rapamycin (mTOR),octamer-binding factor-2 (Oct-2),rapamycin, | en |
| dc.relation.page | 146 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-07-25 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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