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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 呂紹俊(Shao-Chun Lu) | |
| dc.contributor.author | Tzu-Ling Kuo | en |
| dc.contributor.author | 郭姿伶 | zh_TW |
| dc.date.accessioned | 2021-06-16T13:04:03Z | - |
| dc.date.available | 2016-09-24 | |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-08-05 | |
| dc.identifier.citation | 參考文獻
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/61486 | - |
| dc.description.abstract | 高膽固醇血症會促進動脈硬化損傷的形成，而單核球細胞分化形成的巨噬細胞和 oxidized LDL (oxLDL) 往往被發現存在於損傷區域。一般認為，oxLDL 會藉由巨噬細胞的清道夫受體辨認而內化進入細胞，因此造成脂質堆積和發炎的現象。一些研究發現，在動脈損傷區域會有嗜中性白血球和它所產生的介質存在，血漿中也有較高的顆粒性白血球群落刺激因子 (granulocyte colony-stimulating factor, G-CSF)，而已知 G-CSF 具有增加和聚集白血球至發炎區域的能力。除此之外，在早期動脈損傷中，扮演調控血管內膜細胞增生的重要角色－顆粒球巨噬細胞群落刺激因子 (granulocyte macrophage colony-stimulating factor, GM-CSF) 也被發現存在於動脈損傷區域。另外，先前動物實驗的結果指出，注射 G-CSF 和 GM-CSF 會促進粥狀動脈硬化的形成。以上的結果都說明 G-CSF 和 GM-CSF 在粥狀動脈硬化疾病的發展扮演重要的角色，然而究竟它們的表現是否是由 oxLDL 所誘導的仍不清楚。
在這個研究，我們探討由急性心肌梗塞患者或是餵食高膽固醇高血脂飼料的紐西蘭大白兔的血漿以離子交換層析法分離得到的 native LDL (nLDL) 與帶負電的 LDL (LDL(-)) 以及藉由銅離子誘導氧化而成的 oxidized LDL (oxLDL) 是否能夠造成人類單核球細胞分化的巨噬細胞中 G-CSF 和 GM-CSF 的表現增加。實驗結果發現，LDL(-) 會顯著促進巨噬細胞中 G-CSF 和 GM-CSF mRNA 表現和蛋白質分泌，並且它們兩者的表現是與處理時間和 LDL(-) 劑量呈現正向關係，但是在 nLDL 和 oxLDL 卻只有增加些微的表現。而 LDL(-) 誘導 G-CSF 和 GM-CSF 的作用會在 LOX-1 knock-down 的細胞中幾乎消失；利用抑制劑和 shRNA knockdown 的方法，我們的研究結果顯示，LDL(-) 誘導 G-CSF 和 GM-CSF 表現透過活化 NF-κB、ERK2 及 JNK。然而，LDL(-) 誘導 G-CSF 和 GM-CSF 表現並不會因為 cytochalasin D (抑制胞吞作用的藥劑) 處理而減少， v 推測 LDL(-) 誘導的訊息傳遞可能不需要 LDL(-) 與受體結合後的胞吞作用，但需要更進一步研究才能證實。當 HDL 和 LDL(-) 同時處理細胞時，能些微減少 LDL(-) 誘導的 G-CSF、GM-CSF、TNF-α 和 IL-1β 表現。 綜合以上，我們的實驗結果指出 LDL(-) 在人類單核球細胞分化而成的巨噬細胞中主要是透過 LOX-1 及活化 NF-κB、ERK2 和 JNK 的訊息傳遞途徑誘導 G-CSF 和 GM-CSF 表現。而以上 LDL(-) 的誘導作用可能是在吞噬作用之前就已產生訊號。以上結果說明，對於 G-CSF 和 GM-CSF 的產生，LDL(-) 是一個相當重要的調節者，更提供了 LDL(-) 與粥狀動脈硬化疾病的發展的另一層關聯。 | zh_TW |
| dc.description.abstract | Hypercholesterolemia promotes the formation of atherosclerotic lesions in which oxidized LDL (oxLDL) and monocyte-derived macrophages are frequently found. It is generally believed that oxLDL is recognized and internalized by macrophages via scavenger receptors and resulted in lipid accumulation and inflammation. Results of several studies indicate the presence of neutrophils and neutrophil-derived mediators in atherosclerotic lesions, which is accompanied with higher serum granulocyte colony-stimulating factor (G-CSF), a critical mediator to increase neutrophils and recruitment of neutrophils to inflammatory sites. Moreover, granulocyte macrophage colony-stimulating factor (GM-CSF), a critical regulator of intimal cell proliferation in early atherosclerotic lesions, is also expressed in atherosclerotic lesions. Animal studies showed that treatment with either G-CSF or GM-CSF enhances the progression of atherosclerosis. These results suggest that G-CSF and GM-CSF play important roles in the progression of atherosclerosis. However, if expression of G-CSF and GM-CSF were induced by oxLDL is unknown.
In this study, we investigated if native LDL, naturally occurring electronegative LDL (LDL(-)) and Cu+2-induced oxLDL were able to induce G-CSF and GM-CSF expression in human macrophages. The LDL(-) was isolated from plasma of high-fat/cholesterol fed New Zealand rabbits or patients with acute myocardial infarction by ion exchange chromatography. We found that LDL(-) remarkably promoted G-CSF and GM-CSF expression and secretion in THP-1-derived macrophages in a time- and dose-dependent manner; while native LDL and Cu+2-induced oxLDL exert much lower effects. LDL(-)-induced G-CSF and GM-CSF expession were almost abolished in LOX-1 knock-down cells. Using pharmaceutical vii inhibitors and shRNA knockdown strategies, our results demonstrate that induction of G-CSF and GM-CSF by LDL(-) required activation of NF-κB, ERK2 and JNK. However, LDL(-)-induced G-CSF and GM-CSF production was not inhibited by cytochalasin D, an inhibitor of endocytosis, suggesting that LDL(-)-induced signal transduction may not dependent on receptor-mediated endocytosis. However, the possibility requires further investigation. Incubation with HDL partially decreased LDL(-)-induced expression of G-CSF, GM-CSF, TNF-α and IL-1β. Taken together, our results show that LDL(-) induces G-CSF and GM-CSF expression via LOX-1 and through activation of NF-κB, ERK2 and JNK signaling pathway in THP-1-derived macrophages. All these effects of LDL(-) might generate before endocytosis. These results suggest that LDL(-) is an important modulator of G-CSF and GM-CSF expression that further link between LDL(-) and atherosclerosis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T13:04:03Z (GMT). No. of bitstreams: 1 ntu-102-R00442012-1.pdf: 1810695 bytes, checksum: 326a4574a2e839585fe7f28665dc0e1a (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 目錄
論文口試審定書 I 序言 II 中文摘要 IV ABSTRACT VI 第一章 緒論 1 第一節 文獻回顧 2 (一) 脂蛋白 (LIPOPROTEINS) 2 (二) 粥狀動脈硬化 (ATHEROSCLEROSIS) 4 (三) LECTIN-LIKE OXIDIZED-LOW DENSITY LIPOPROTEIN RECEPTOR-1 (LOX-1) 5 (四) NATIVE LDL (NLDL) 和 ELECTRONEGATIVE LDL (LDL(-)) 7 (五) 群落刺激因子 (COLONY STIMULATING FACTORS, CSFS) 8 (六) MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) 的訊息傳遞 12 第二節 實驗動機與目的 15 第二章 材料與方法 17 第一節 實驗材料 18 第二節 細胞培養 20 第三節 分離脂蛋白 21 第四節 製備慢病毒 (LENTIVIRUS) 22 ix 質體資訊 22 暫時性轉染(TRANSIENT TRANSFECTION) 26 收取合成好的慢病毒 27 慢病毒感染 27 第五節 細胞 MRNA 表現分析 27 細胞 RNA 抽取 27 反轉錄聚合酶連鎖反應 (RT-PCR) 28 第六節 即時定量聚合酶連鎖反應 (REAL-TIME QUANTITATIVE PCR) 30 第七節 引子資訊 30 第八節 西方點墨法 (WESTERN BLOTTING) 31 抽取細胞蛋白 31 定量蛋白質 32 樣品前處理 32 SDS-PAGE 電泳 32 半濕式蛋白質轉印 33 抗體結合免疫分析 33 第九節 酵素結合免疫吸附法 (ENZYME-LINKED IMMUNOSORBENT ASSAY, ELISA) 34 第十節 免疫螢光染色 (IMMUNOFLUORESCENCE STAINING) 35 第三章 實驗結果 36 第一節 LDL(-) 誘導巨噬細胞內 G-CSF 和 GM-CSF 表現 37 第二節 LDL(-) 會透過 LOX-1 誘導 G-CSF 和 GM-CSF 表現 38 第三節 LDL(-) 可能不依賴吞噬作用誘導 G-CSF 和 GM-CSF 表現 39 第四節 LDL(-) 需要 ERK 和 JNK 誘導 G-CSF 和 GM-CSF 表現 39 第五節 ERK2 對於 LDL(-) 誘導 G-CSF 和 GM-CSF 表現是重要的 40 x 第六節 LDL(-) 活化 NF-ΚB 促使 P65 入核而增加 G-CSF 和 GM-CSF 表現 41 第七節 HDL 具有減少 LDL(-) 誘導細胞激素表現的作用 41 第四章 討論 42 第一節 LDL(-) 刺激巨噬細胞表現 G-CSF 和 GM-CSF 較 OXLDL 更顯著 43 第二節 LDL(-) 可能不需要被吞噬進入細胞就已產生下游訊號 44 第三節 G-CSF 和 GM-CSF 的調控機制相當類似 45 第四節 LDL(-) 活化 NF-ΚB 會造成許多種發炎激素表現 47 第五節 HDL 具拮抗 LDL(-) 誘導促發炎細胞激素表現的作用 48 第六節 LOX-1 是一個有潛力的治療標的 49 第七節 總結 51 第五章 圖表 52 參考文獻 66 附錄 83 xi 圖表目錄 Figure 1. LDL(-) induces G-CSF and GM-CSF mRNA expression in THP-1-derived macrophages 53 Figure 2. LDL(-) induces G-CSF and GM-CSF mRNA expression in THP-1-derived macrophages 54 Figure 3. LDL(-) induces G-CSF and GM-CSF secretion in THP-1-derived macrophages 55 Figure 4. LDL(-) induces G-CSF secretion in THP-1-derived macrophages in a time- and dose-dependent manner 56 Figure 5. Knockdown of LOX-1 by shRNA-LOX-1 significantly decreases LDL(-)-induced G-CSF and GM-CSF mRNA expression and secretion in THP-1-derived macrophages 57 Figure 6. Effects of cytochalasin D on G-CSF and GM-CSF secretion in THP-1-derived macrophages 58 Figure 7. Effects of various kinase inhibitors on G-CSF and GM-CSF secretion in THP-1-derived macrophages 59 Figure 8. LDL(-) induces activation of ERK1/2 in THP-1-derived macrophages 60 Figure 9. U0126 inhibits LDL(-)-induced ERK1/2 activation, and expression of G-CSF and GM-CSF mRNA in THP-1-derived macrophages 61 Figure 10. Knockdown of ERK2 via shRNA-ERK2 decreased LDL(-)-induced G-CSF and GM-CSF protein levels in THP-1-derived macrophages 62 Figure 11. LDL(-) induced activation and nuclear translocation of NF-κB in THP-1-derived macrophages 63 Figure 12. HDL inhibits LDL(-)-induced mRNA levels of pro-inflammatory cytokines in THP-1-derived macrophages 64 Figure 13. HDL represses LDL(-)-induced G-CSF and GM-CSF secretion in THP-1-derived macrophages 65 1 | |
| dc.language.iso | zh-TW | |
| dc.subject | 粥狀動脈硬化 | zh_TW |
| dc.subject | NF-κB | zh_TW |
| dc.subject | 巨噬細胞 | zh_TW |
| dc.subject | LOX-1 | zh_TW |
| dc.subject | 帶負電 LDL | zh_TW |
| dc.subject | 顆粒球巨噬細胞群落刺激因子 | zh_TW |
| dc.subject | 顆粒性白血球群落刺激因子 | zh_TW |
| dc.subject | ERK1/2 | zh_TW |
| dc.subject | Macrophages | en |
| dc.subject | ERK1/2 | en |
| dc.subject | G-CSF | en |
| dc.subject | GM-CSF | en |
| dc.subject | LDL(-) | en |
| dc.subject | LOX-1 | en |
| dc.subject | Atherosclerosis | en |
| dc.subject | NF-κB | en |
| dc.title | 循環中陰電性低密度脂蛋白透過LOX-1及活化NF-κB、ERK2和JNK在巨噬細胞中引起G-CSF 和GM-CSF表現 | zh_TW |
| dc.title | Circulating electronegative LDL induces G-CSF and GM-CSF through LOX-1, and activation of NF-κB, ERK2 and JNK in human macrophages | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 張博淵(Po-Yuan Chang),張淑芬(Shu-Fen Chang),姜安娜(An-Na Chiang) | |
| dc.subject.keyword | 粥狀動脈硬化,ERK1/2,顆粒性白血球群落刺激因子,顆粒球巨噬細胞群落刺激因子,帶負電 LDL,LOX-1,巨噬細胞,NF-κB, | zh_TW |
| dc.subject.keyword | Atherosclerosis,ERK1/2,G-CSF,GM-CSF,LDL(-),LOX-1,Macrophages,NF-κB, | en |
| dc.relation.page | 86 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-08-05 | |
| 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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