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系統識別號 U0026-2307201314501900
論文名稱(中文) 分析介白素二十在風濕性關節炎及癌症的基因調控
論文名稱(英文) In vitro analysis of IL-20 gene regulation in rheumatoid arthritis and cancer
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) Department of Biochemistry and Molecular Biology
學年度 101
學期 2
出版年 102
研究生(中文) 蔡念純
研究生(英文) Nian-Chun Tsai
學號 s16001028
學位類別 碩士
語文別 中文
論文頁數 61頁
口試委員 指導教授-張明熙
口試委員-張文粲
口試委員-鄭宏祺
中文關鍵字 細胞激素  雌激素  類風濕性關節炎  表關遺傳學 
英文關鍵字 cytokines  17ß-estradiol  rheumatoid arthritis  epigenetics 
學科別分類
中文摘要 多功能促發炎的IL-20細胞激素,是IL-10家族中的其中一員,IL-20參與在許多種發炎的疾病當中,譬如:牛皮癬、動脈粥狀硬化和腎臟病變。近幾年來的研究發現,DNA 甲基化和組蛋白乙醯化與自體免疫疾病、類風濕性關節炎和癌症有相關性。近期的文獻也發現IL-20的單株抗體和雌激素對於骨質疏鬆症都是有效的治療方法,我們也發現IL-20參與在肺癌和乳癌當中,然而我們對於IL-20與雌激素之間的調控關係還不清楚,以及IL-20在類風濕性關節炎和癌症中是否會調控DNA 甲基化和組蛋白乙醯化來影響基因表現也尚未被研究。因此,我們要研究在類風濕性關節炎相關的細胞和癌症細胞中IL-20的基因調控。我們發現IL-20的表現量,在CIA的滑液纖維母細胞和前驅成骨細胞會受到17β-雌二醇所抑制。同樣地,在CIA的滑液纖維母細胞和前驅成骨細胞內IL-20所誘導的基因,IL-6, IL-1β, and MMP-9皆會受到17β-雌二醇所抑制。除此之外,在CIA的滑液纖維母細胞中,IL-20可以誘導DNMT3a, DNMT3b, HDAC1, 和HDAC3的表現。而且,IL-20不只可以在A549這個肺癌細胞中誘導IL-6, IL-1β, and TNF-α的表現,也可以在MDAMB231乳癌細胞中,誘導IL-6和TGF-β的表現。在A549中,我們也發現了DNMT1和DNMT3a的表現,可以被IL-20所誘導;在MDAMB231中,IL-20可以誘導DNMT1, DNMT3a,和DNMT3b的表現量。除此之外,DNMT抑制劑可以抑制IL-20所誘發的細胞增生。因此,17β雌二醇在CIA的滑液纖維母細胞中,會降低IL-20以及IL-20所誘導的IL-6, IL-1β, 和MMP-9的表現;除此之外,IL-20在癌症以及類風濕性關節炎中,也可以誘導DNMTs的表現去參與基因的調控,所以,本研究結果證實,IL-20在類風濕性關節炎及癌症的致病機轉中,可能經由DNA甲基化及組蛋白乙醯化來調控基因,影響此二疾病的結果。
英文摘要 The pleiotropic inflammatory cytokine IL-20, a member of the IL-10 family, is involved in various inflammatory diseases, such as psoriasis, atherosclerosis, and renal failure. Recent studies indicated that DNA methylation and histone acetylation has been observed in cancer and autoimmune diseases like rheumatoid arthritis (RA). Previous studies showed that anti-IL-20 mAb has a therapeutic potential for treating osteoporosis. Other studies also found that IL-20 is involved in cancer. However, little is known about the regulation of IL-20 by estrogen and whether IL-20 plays a critical role in the pathogenesis of RA and cancer through DNA methylation/ histone acetylation. Therefore, the aim of this study is to investigate the gene regulation of IL-20 in several RA-associated cell lines and cancer cells. We found that IL-20 expression was significantly inhibited in 17ß-estradiol-treated CIA synovial fibroblasts and osteoblastic MC-3T3E1 cells in vitro. 17ß-estradiol decreased IL-20-induced IL-6, IL-1ß, and MMP-9 expression in CIA synovial fibroblasts and osteoblastic MC-3T3E1 cells. In addition, we found that IL-20 induced the expression of DNMT3a, DNMT3b, HDAC1, and HDAC3 in CIA synovial fibroblasts. However, the expression of IL-6, IL-1ß, and TNF-α were not only induced by IL-20 in A549 and MDAMB231. We also found that DNMT1, DNMT3a, and DNMT3b mRNA levels were significantly enhanced in A549 and MDAMB231 treated with IL-20. DNMT1, DNMT3a, and DNMT3b mRNA levels were also significantly enhanced in MDAMB231 treated with IL-20. In addition, DNMT inhibitor can inhibit the cell proliferation which was enhanced by IL-20. Therefore, 17ß-estradiol decreased IL-20 and IL-20-induced IL-6, IL-1ß, and MMP-9 expression in CIA synovial fibroblasts. Therefore, all conclude that IL-20 can regulate genes via induction of DNMTs mRNA and then, affect the pathogenesis of cancer and RA.
論文目次 Abtstract……………………………………………………………………. I
中文摘要…………………………………………………………………..... II
致謝………………………………………………………………………....III
目錄………………………………………………………………….…….... V
圖目錄…………………………………………………………………….VIII
附錄目錄……………………………………………………………….….. IX
縮寫檢所表……………………………………………………………...….. X
第一章 緒論
1-1 細胞激素(Cytokine)……………………………………………………….. 1
1-2 介白素10(Interleukin-10)…………………………………………………. 1
1-3 介白素20(Interleukin-20)…………………………………………………. 2
1-4 類風溼性關節炎(Rheumatoid arthritis)…………………………………...... 2
1-5 骨質疏鬆症(Osteoporosis)………………………………………………… 3
1-6 癌症(Cancer)……………………………………………………………….. 4
1-7 表觀遺傳學(Epigenetics)………………………………………………….. 4
第二章 研究目的與動機…………………………………………………………….. 8
第三章 材料與方法
3-1實驗材料…………………………………………………………………………..…9
 3-1-1 細胞來源與背景……………………………………………………….….....9
 3-1-2 實驗動物…………………………………………………………………..…..9
 3-1-3 蛋白質來源……………………………………………………………….…..10
 3-1-4 實驗室之菌株、質體與培養基……………………………………….....10
3-2 實驗方法…………………………………………………………………..…….14
 3-2-1第二型膠原蛋白誘導大鼠關節炎(Type II collagen-induced arthritis………….14
 3-2-2 collagen-induced arthritis(CIA)大鼠關節滑液纖維母細胞(synovial fibroblasts)之分離與培養………………………………………………………………………….15
 3-2-3同步定量聚合酶連鎖反應(Real Time Polymerase Chain reaction,Real Time PCR) …………….……………………………………………………..........................15
 3-2-4 Promoter plasmid transfection (promter plasmid 來自於陳柏任學長所建立)...16 
3-2-4-1 Seeding…………………………………..……………………………....16
3-2-4-2 Transfection………..…………………...…………………………..…....17
  3-2-4-3 Change medium and treatment……………..………………………...…17
  3-2-4-4 Cell harves……………………………………………..……..…….....…17
 3-2-4-5 Luciferase activity 測定…………………………….…..…….…...……18
3-2-4-6 β-gal測定……..……………………………………….……………...…18
 3-2-5 細胞增生能力分析(Cell proliferation assay )…………………………..…….19
 3-2-6西方點墨法(Western blotting) ………………………………………..……….19
第四章 實驗結果
 4-1前驅成骨細胞(MC3T3E1)中,IL-20會促進CCL2、IL-6和MMP-9的 mRNA 表現量……………………………………………………………………………………….21
4-217-β雌二醇處理CIA的滑液纖維母細胞和前驅成骨細胞(MC3T3E1),可以抑制IL-20的mRNA表現量…………………………………………………………………21
4-3以17-β雌二醇處理CIA的滑液纖維母細胞可以抑制RANKL、IL-1β、IL-6、MMP-1、MMP-3、MMP-9和MMP-13的mRNA表現量…………………………22
4-4以17-β雌二醇處理前驅成骨細胞可以抑制TNF-α、IL-1β、MMP-9、CCL2和IL-6的mRNA表現量………………………………………………………………...22
 4-5以17-β雌二醇處理前驅成骨細胞(MC3T3E1)可以誘導OPG和ER-β的mRNA表現量………………………………………………………………………………….23
 4-617-β雌二醇並不會影響IL-20 promoter full length構築在pGL-3 enhancer的活性……………………………………………………………………………………….24
 4-7在CIA的滑液纖維母細胞中,IL-20會誘導DNMT3a、 DNMT3b、HDAC1和HDAC3的mRNA表現量…………………………………………………………..…24
 4-8在人類肺腺癌的肺泡上皮細胞(A549)中,IL-20會促進IL-β、 IL-6和TNF-α的mRNA表現量…………………………………………………………………...….….25
 4-9在人類肺腺癌的肺泡上皮細胞(A549)和人類乳腺癌的細胞株(MDAMB231)中,IL-20會誘導DNMTs的mRNA表現量……………………………………………...25
 4-10在人類乳腺癌的細胞株(MDAMB231)中,IL-20會促進IL-6和TGF-β的mRNA表現量……………………………………………………………………………….....26
 4-11DNMT inhibitor可以抑制IL-20所促進的細胞增生的能力…………………….26
第五章 討論…………………………………………………………………………....27
參考文獻……………………………………………………………………………..….31
圖…………………………………………………………………………………….....…36
附錄……………………………………………………………………………….…...…51
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