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| 系統識別號 |
U0026-0812200915133047 |
| 論文名稱(中文) |
介白素-20在心血管疾病中的研究 |
| 論文名稱(英文) |
Study of Interleukin-20 in Cardiovascular Diseases |
| 校院名稱 |
成功大學 |
| 系所名稱(中) |
基礎醫學研究所 |
| 系所名稱(英) |
Institute of Basic Medical Sciences |
| 學年度 |
97 |
| 學期 |
2 |
| 出版年 |
98 |
| 研究生(中文) |
陳威宇 |
| 研究生(英文) |
Wei-Yu Chen |
| 電子信箱 |
s5894157@mail.ncku.edu.tw |
| 學號 |
s5894157 |
| 學位類別 |
博士 |
| 語文別 |
英文 |
| 論文頁數 |
97頁 |
| 口試委員 |
指導教授-張明熙
口試委員-林茂村
召集委員-江美治
口試委員-趙麗洋
口試委員-林以行
口試委員-任卓穎
|
| 中文關鍵字 |
神經膠質細胞
缺血性中風
內皮細胞
介白素-20
細胞激素
缺氧
動脈硬化
|
| 英文關鍵字 |
ischemic stroke
atherosclerosis
interleukin-20
cytokines
glia cells
endothelial cells
hypoxia
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| 學科別分類 |
|
| 中文摘要 |
介白素-20 屬於介白素-10 家族並發現參與許多複雜的發炎性疾病，如乾癬，類風濕性關節炎與腎臟疾病。粥狀動脈硬化是伴隨免疫細胞浸潤的一種慢性發炎疾病，目前已經有許多的細胞激素與趨化激素被認為是動脈硬化相關因子。然而介白素與動脈硬化的關係仍然是未知的，因此我們想要探討介白素-20是否與動脈硬化有關。我們利用免疫化學染色法偵測小鼠與病人動脈硬化斑塊區域中介白素-20及其細胞素受體的表現情形。我們發現介白素-20主要表現在巨噬細胞浸潤區域，另外介白素-20及其受體也表現在血管內壁的小血管的內皮細胞上，而這樣的表現情形在沒有動脈硬化的正常的血管是相對較稀少的。我們也利用反轉錄聚合反應偵測基因的表現，介白素-20的基因轉錄本在缺氧處理或是氧化低密度脂蛋白處理的單核球細胞中增加的。而介白素-20的受體的表現在人類臍靜脈內皮細胞的表現也會因為缺氧刺激而增加。此外，介白素-20也引發內皮細胞表現趨化激素。最後，我們利用肌肉電擊的方式將介白素-20的基因送入脂蛋白-E缺陷小鼠後，發現介白素-20處理的小鼠動脈硬化程度較為嚴重。我們的研究顯示介白素-20是一個促進動脈硬化的細胞激素，並可能藉此促進粥狀動脈硬化的產生。除此之外，本研究更深入探討缺氧的模式是否調控介白素-20 的表現。細胞實驗中，細胞缺氧可以促進表皮細胞(HaCaT)，腎臟上皮細胞(HEK293)，軟骨細胞(Chondrocytes)，單核球細胞(monocytes)與神經膠質瘤細胞(Glioblastoma cells)表現大量的介白素-20 。抑制缺氧誘發因子(HIF-1alpha)能夠抑制由氯化鈷(CoCl2)所引發的介白素-20。此外，我們也鑑定出在介白素-20 啟動子區域中兩個可能的缺氧調控片段。經由啟動子活性分析也証實氯化鈷模擬的缺氧反應能夠活化冷光報告基因之表現。動物實驗我們發現缺血性中風的大鼠血清與腦組織中介白素-20 都有大量的增加並主要局限於缺氧病灶區域內的膠狀細胞(glia cells)。導入介白素-20 的單株抗體能夠有效的改善大鼠缺血性中風所引起的腦壞死區域。此外，細胞實驗也証實神經膠質瘤細胞株(GBM8901)能表現介白素-20 及其受體，介白素-20作用於膠質細胞能促進細胞增生與促進介白素-1beta，介白素-8 與MCP-1。我們認為介白素-20 的表現在體外細胞實驗與體內的缺血性中風的模式中都能受到缺氧狀態的調控。此調控機制在缺血性中風的腦組織中可能扮演促進腦損傷的機制。由此研究得到結論，介白素-20能受到缺氧環境的調控並扮演促進發炎反應的角色。此外，在病變組織中表現增加的介白素-20可能扮演促進動脈硬化斑塊生成與促進缺血性中風後腦損傷的角色。
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| 英文摘要 |
IL-20, an IL-10 family member, is involved in various inflammatory diseases, such as psoriasis, rheumatoid arthritis, intervertebral disc herniation, and renal diseases. Atherosclerosis is a chronic inflammatory disease with immune-cell infiltration. Various cytokines and chemokines have been characterized as pro- or anti-atherogenic factors. However, the association between IL-20 and atherosclerosis is undetermined. Therefore, we sought to investigate whether IL-20 is associated with atherosclerosis. We examined the expression of IL-20 and its receptor complex IL-20R1/IL-20R2 in atherosclerotic lesions of humans and mice using immunohistochemical staining. IL-20 was expressed in macrophage-rich areas. Both IL-20 and IL-20R1/IL-20R2 were expressed by endothelial cells lining the intimal microvessels, vasa vasorum, but rarely in non-atherosclerotic arteries. IL-20 transcripts increased in hypoxic monocytes and monocytes treated with oxidized low-density lipoprotein. The expression of IL-20R1 and IL-20R2 was also upregulated by HUVECs in response to hypoxic treatment. IL-20 upregulated the transcripts of CXCL9 and CXCL11 in HUVEC cells. Furthermore, in vivo administration of IL-20 expression vector using intramuscular electroporation promoted atherosclerosis in Apolipoprotein E-deficient mice. Therefore, IL-20 may act as a pro-atherogenic factor. In this study, we also investigated whether hypoxia in vitro and an in vivo model of ischemic stroke would upregulate IL-20 expression. In vitro, IL-20 expression increased in hypoxic HaCaT , HEK293 cells, chondrocytes, monocytes and glioblastoma cells. Inhibiting HIF-1alpha inhibited CoCl2-induced IL-20 expression. We identified two putative hypoxia response elements in human il20-gene promoter. Promoter activity assays showed that CoCl2-mimicked hypoxia activated luciferase reporter-gene expression. In vivo, experimental ischemic stroke upregulated IL-20 in the sera and brain tissue of rats. IL-20 stained positively in glia-like cells in peri-infarcted lesions, but not in contralateral tissue. Administration of IL-20 monoclonal antibody ameliorated ischemia-induced brain infarction of rats after experimental ischemic stroke. In vitro, RT-PCR analysis showed that glioblastoma cells GBM8901 cells expressed IL-20 and its receptor subunits IL-20R1, IL-20R2, and IL-22R1. IL-20 induced cell proliferation in GBM8901 cells by activating the Jak2/STAT3 and ERK1/2 pathways. IL-20 also induced production of IL-1beta, IL-8, and MCP-1 in GBM8901 cells. We conclude that IL-20 was responsive to hypoxia in vitro and in the ischemic stroke model and that upregulation of IL-20 in the ischemic brain may contribute to brain injury. In summary, IL-20 is a pro-inflammatory cytokine and regulated by hypoxia. The upregulation of IL-20 may contribute to the pathogenesis of atherosclerosis plaque progression and brain injury after ischemic stroke.
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| 論文目次 |
Table of Contents
中文摘要 I
Abstract III
誌謝 V
Abbreviation List VII
Table of Contents X
List of Tables and Figures XII
I. Background 1
A. Interleukin (IL)-20, a member of IL-10 family cytokines 1
B. Identification, cloning, and structure of IL-20 1
C. Receptors and signal transduction of IL-20 2
D. Expression of IL-20 and its receptor subunits 3
E. Biological function of IL-20 4
F. Angiogenesis and Atherosclerosis 8
G. Hypoxia and Ischemic stroke 10
II. Rationale 12
III. Specific aims 14
A. To study the role of IL-20 in atherosclerosis 14
B. To study the role of IL-20 in hypoxia and experimental ischemic stroke 14
IV. Material and methods 15
A. Study of IL-20 in atherosclerosis 15
B. Study of IL-20 in ischemic stroke 21
V. Results 29
A. Study of IL-20 in atherosclerosis 29
B. Study of IL-20 in ischemic stroke 35
VI. Discussion 44
A. Study of IL-20 in atherosclerosis 44
B. Study of IL-20 in experimental ischemic stroke 49
C. The role of IL-20 in different diseases 54
D. Therapeutic potential of IL-20 targeting by specific antibody 55
VII. Conclusion 57
VIII. References 58
IX. Tables 67
X. Figures and figure legends 69
XI. Publications 94
XII. Biographical note 97
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