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研究生:羅愷玉
研究生(外文):Kai-Yu Lo
論文名稱:丙戊酸對於週邊血液單核球衍生的樹突狀細胞功能之調控
論文名稱(外文):Regulation of valproic acid on the function of peripheral blood mononuclear cell-derived dendritic cells
指導教授:呂思潔呂思潔引用關係
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:54
中文關鍵詞:丙戊酸樹突狀細胞
外文關鍵詞:valproic aciddendritic cells
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雙極性躁鬱症是種慢性精神疾病,主要症狀為情緒在亢奮到沮喪間不斷反覆轉變,根據先前的研究中發現雙極性躁鬱症的病人體內有免疫系統異常的現象產生。丙戊酸為目前治療雙極性躁鬱症的首選藥物之一,屬於情緒穩定藥物且有神經保護及滋潤的功能。相關研究指出丙戊酸具有抑制GSK-3?珨P組蛋白乙烯化酶(histone deacetylases, HDACs)的能力並能透過降低表現細胞激素所需的轉錄因子NF-?羠活性調降促發炎細胞激素的產生。推測丙戊酸可能具有免疫調節的功能。此研究以免疫系統中的未成熟樹突狀細胞作為研究目標,研究丙戊酸對於週邊血液單核球分化的未成熟樹突狀細胞的影響,探討丙戊酸是否會經由調控未成熟樹突細胞功能的路徑,進而達到免疫調節的功能。目前研究結果顯示,丙戊酸對於樹突狀細胞上的第二型主要組織相容性複合體(MHC class II)、CD86、CD80、CD83、CD40及CD14表面分子不會有影響;在樹突狀細胞分化過程中加入丙戊酸刺激後發現樹突狀細胞上group I CD1分子CD1a, CD1b, CD1c的表現量有隨刺激濃度調降的現象,但丙戊酸在樹突狀細胞以LPS、poly I:C和TNF?悃踸E的成熟過程中不調控CD1分子表現。接受丙戊酸刺激過後的樹突狀細胞可增強活化異體T淋巴球之增生;且發現GSK-3?狶磻蹌特B415286與HDACs抑制劑sodium butyrate (SB)和suberoylanilide hydroxamic acid (SAHA)同樣也具有調降group I CD1分子的功能。因此我們推論丙戊酸有可能同時經由GSK-3?狺咠DACs路徑去影響group I CD1分子表現。此外,在加入不同濃度的丙戊酸時,可觀察到介白質素-6 (interleukin-6; IL-6)的分泌量會隨著濃度增加而提升,腫瘤壞死因子-???n(TNF-??) 的分泌量不改變,介白質素-8 (interleukin-8; IL-8)及介白質素-10 (interleukin-10; IL-10)的分泌量會隨著濃度增加而降低;在GSK-3?狶磻蹌砥GSB415286及HDAC抑制劑:SAHA刺激的條件下同樣可觀察到IL-6分泌量的上升。綜合以上現象顯示丙戊酸可能經由抑制GSK-3?狺咠DAC調節未成熟樹突狀細胞的表面分子表現、細胞激素分泌以及刺激T細胞增生的能力改變,丙戊酸在免疫調節中可能扮演極重要的角色。
Bipolar disorder (BD) is a chronic psychosis, characterized by persistent mood changes involving both elevated and depressed mood states. According to previous researches, patients with BD have been reported to have altered immune functions. Valproic acid (VPA) is one of the most effective medicines for BD. VPA stabilized the emotion and have neuroprotective effect, also can be glycogen synthase kinase 3???n(GSK-3???w and histone deacetylases(HDACs) inhibitor. VPA may modulate immune system by down-regulated NF-?羠 expression and pro-inflammatory cytokines secretion in patients of BD. We presume VPA may have immunomodulaty function. In this study, we investigated the regulation of immature dendritic cells (iDCs) function by VPA. Our results show VPA does not affect the surface markers (MHC class II, CD86, CD80, CD83, CD40 and CD14) on iDCs. However, VPA decrease the expressions of group I CD1 moleculars (CD1a, CD1b, and CD1c) on iDCs, but do not effect CD1 moleculars expression during DC maturation . In addition, in the allogenic mixed lymphocyte reaction, DCs stimulated by VPA can induce allogenic T cells proliferate level. We found that GSK-3?? inhibitors, SB415286, and HDACs inhibitors, sodium butyrate (SB) and suberoylanilide hydroxamic acid (SAHA) also down-regulated group I CD1s levels. The report shows the level of interleukin-6 (IL-6) increased by VPA, and the level of IL-8, IL-10 and TNF-?? decreased by VPA. The GSK-3?? inhibitors, SB415286, and HDACs inhibitors, SAHA also enhance the secretion of IL-6. In summary, we found the VPA may modulate immune function on iDCs.
中文摘要......................第 i頁
英文摘要......................第 ii頁
表目錄.......................第 iii頁
圖目錄.......................第 iv頁
壹、前言 .......................第 1 頁
貳、實驗目的 .....................第 7 頁
參、實驗方法與材料
一、常用溶液.....................第 8 頁
二、樹突狀細胞培養..................第 9 頁
三、藥物處理.....................第 10 頁
四、流式細胞儀分析..................第 10 頁
五、細胞激素磁珠分析.................第 11 頁
六、酵素連結免疫吸附分析法..............第 12 頁
七、西方墨點法....................第 12 頁
八、異體混合淋巴球反應測試..............第 13 頁
九、反轉錄聚合酵素鏈鎖反應作用............第 14 頁
十、Nile Red染色..................第 15 頁
十一、統計方法....................第 16 頁
肆、實驗結果與分析
一、丙戊酸不影響未成熟樹突狀細胞上其他CD marker的變化........................第 17 頁
二、丙戊酸在樹突狀細胞分化階段調控CD86分子表現量........................第 17 頁
三、單核球分化成未成熟樹突狀細胞後CD marker的篩選........................第 17 頁
四、丙戊酸在樹突狀細胞分化階段調降group CD1分子表現量........................第 17 頁
五、丙戊酸刺激未成熟樹突狀細胞是否可活化PPARγ影響CD36與TLR4表現量...................第 21 頁
六、丙戊酸及鋰鹽可以調控未成熟樹突狀細胞的細胞激素分泌量........................第 21 頁
七、丙戊酸可刺激樹突狀細胞增生T淋巴球的能力........................第 23 頁
八、丙戊酸不影響成熟階段樹突狀細胞表面分子的表現........................第 24 頁
九、丙戊酸降低未成熟樹突狀細胞內酯質液滴的含量........................第 24 頁
伍、討論 ......................第 25 頁
陸、圖表 ......................第 28 頁
參考文獻 ......................第 49 頁
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