博碩士論文 992204001 詳細資訊




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姓名 梁梓祺(Tzu-chi Liang)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 PDE4和cAMP訊號傳導於小鼠骨髓細胞分化為樹突細胞之角色
(Role of PDE4 and cAMP signaling in differentiation of dendritic cells from mouse bone marrow cells)
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摘要(中) 樹突細胞(Dendritic cells, DCs)為抗原呈現細胞,於先天及後天免疫系統扮演重要的角色。樹突細胞於周邊組織中有吞入抗原、移動至局部淋巴組織的能力,且隨著細胞的成熟,可活化抗原專一的T細胞。已知在許多發炎細胞(包含樹突細胞)內,增加cAMP濃度能抑制多種發炎反應。然而cAMP訊號傳導如何調控樹突細胞分化、成熟及功能,至今仍不甚明瞭。Type 4 phosphodieasterases (PDE4s)為水解cAMP的酵素,表現於大部分發炎細胞中,可調控許多發炎反應。為此,本研究欲探討PDE4或cAMP信號傳導是否會調節樹突細胞的分化與成熟,我們首先利用GM-CSF刺激小鼠骨髓細胞分化為未成熟樹突細胞,並以流式細胞儀分析CD11c螢光抗體標染的樹突細胞。結果顯示,培養第八天後的細胞中有81.7 ± 1.1 %為未成熟樹突細胞,此分化程度可分別被PDE4抑制劑Rolipram、 PDE3抑制劑Cilostazol結合Rolipram、 cAMP類似物dibutyryl cAMP (dbcAMP)及非選擇性PDE抑制劑IBMX所抑制,抑制程度分別為12.26 ± 1.3 %、 35.5 ± 1.6 %、 18.3 ± 1.4 %及16.8 ± 2.4 %。同時,細胞表面CD11c的螢光強度,也被該等藥劑所抑制,抑制程度分別為21.8 ± 2 %、 35 ± 2.9 %、 58.8 ± 0.3 %及41.4 ± 2.21 %。Cilostazol 單獨處理細胞則無抑制作用。此外,利用PDE4基因剔除鼠之骨髓細胞進行實驗發現Rolipram抑制樹突細胞分化的影響,主要是經由抑制PDE4B、其次為PDE4A所致。在LPS誘導樹突細胞成熟期間,CD11c+細胞群及CD11c+的平均螢光強度均會顯著下降,而CD11c+CD86+ 細胞群(成熟樹突細胞)則增加約3.2倍,但細胞表面CD86的平均螢光強度與未經LPS處理之CD11c+CD86+細胞群相當。若以所有圈選的(gated)細胞分析成熟樹突細胞,我們發現,Rolipram會抑制LPS刺激所產生的CD11c+CD86+ 細胞群,抑制程度為21.4 ± 2.36 %;但若僅就CD11c+細胞群中之CD11c+CD86+細胞進行比較,Rolilpram卻無顯著抑制作用。利用PDE4基因剔除鼠樹突細胞進一步分析,發現Rolipram抑制樹突細胞成熟可能是經由抑制PDE4A和PDE4B所致。此外,如同LPS誘導樹突細胞成熟,dbcAMP或Rolipram單獨處理未成熟樹突細胞也有不同程度誘導細胞成熟的作用。至於研究樹突細胞功能,我們利用卵蛋白(OVA)致敏小鼠脾臟CD4+ T 細胞與樹突細胞共同培養,在OVA刺激下,T細胞會被活化而增生,然而PDE4B-/-樹突細胞對此增生反應有減弱的現象。綜合以上結果得知,PDE4,特別是PDE4B會調控樹突細胞的分化及功能。這些發現可作為未來研發PDE4抑制劑用以治療與樹突細胞有關之發炎疾病的理論基礎。
摘要(英) Dendritic cells (DCs) are antigen presenting cells important in both innate and adaptive immune systems. DCs in peripheral tissues are capable of capturing antigens and migrating to local lymphoid tissues where the DCs become mature and enable to activate antigen-specific T cells. Elevation of intracellular cAMP concentration suppresses various inflammatory responses in almost all inflammatory cell types, including DCs. However, the information on how cAMP signaling regulates the differentiation, maturation and function of DCs is limited. Type 4 phosphodieasterases (PDE4s), enzymes that degrade cAMP with high affinity, are the predominant PDE isozymes expressed in most inflammatory cells, and are critical in regulation of various inflammatory responses. To determine whether PDE4, thereby the cAMP signaling, regulates DC differentiation and maturation, in this study we stimulated mouse bone marrow cells with GM-CSF in the presence of cAMP-elevating agents to assess their effects on DC differentiation. Flow cytometry analyses revealed that 81.7 ± 1.1 % cells harvested on day 8 of culture developed into immature DCs (imDCs), demonstrated by the expression of CD11c on these cells. This process was inhibited by the PDE4 inhibitor Rolipram, the combination of Rolipram and the PDE3 inhibitor cilostazol, dibutyryl cAMP (dbcAMP), and the non-selective PDE inhibitor IBMX at both the CD11+ population (12.26 ± 1.3 %, 35.5 ± 1.6 %, 18.3 ± 1.4 %, and 16.8 ± 2.4 %, respectirely) and the level of CD11c expression (i.e. CD11c mean fluorescence intensity; 21.8 ± 2 %, 35 ± 2.9 %, 58.8 ± 0.3 % and 41.4 ± 2.21 %, respectirely). However, Cilostazol alone lacked these effects. The experiments using PDE4 null bone marrow cells further demonstrated that PDE4B and possibly PDE4A, but not PDE4D, mediated the Rolipram effect on the differentiation of imDC population. During LPS induced DC maturation, the CD11c+ population and the mean fluorescence intensity (MFI) of CD11c+ were significantly decreased (p<0.05), whereas the CD11c+CD86+ population (mature DCs) was increased by approximately 3.2 folds. This increase however was not accompanied by an increase in MFI of CD86. Rolipram also showed an inhibition (21.4 ± 2.36 %) in the LPS-induced CD11c+CD86+ population when the total gated cells were analyzed, but this decrease was not obtained when the CD11c+ population was analyzed. Further study on PDE4 null DCs suggested that the Rolipram effect on the CD11+CD86+ population was probably mediated by inhibiton of both PDE4A and PDE4B. Similar to LPS, our results showed that dbcAMP or Rolipram alone also induced DC maturation albeit at less extent. In a functional study using ovalbumin (OVA) – primed spleen CD4+ T cells, we found that DC-induced T cell proliferation in response to OVA was attenuated in PDE4B-deficient DCs compared to PDE4B wild - type DCs. Taken together, these findings indicate an involvement of PDE4, particularly PDE4B, in the development and function of DCs. They also form the basis for the development of PDE4 inhibitors for the treatment of inflammatory diseases that are mediated by DCs.
關鍵字(中) ★ 樹突細胞
★ 磷酸雙酯酶
★ 抗原呈現細胞
關鍵字(英) ★ Dendritic cell
★ Cyclic nucleotide phosphodiesterase
★ Antigen presenting cell
論文目次 中文摘要 i
英文摘要 iii
誌謝 v
目錄 vi
圖目錄 viii
縮寫檢索表 ix
一 緒論 1
1-1 樹突細胞與免疫反應 1
1-2 Adenosine 3’,5’-cyclic monophosphate (cAMP)之訊息傳導 2
1-3 cAMP與免疫發炎反應之調控 4
1-4 環狀核苷酸磷酸二酯酶(Cyclic nucleotide phosphodiesterases; PDE) 5
1-4-1 PDE的分類、結構及功能 5
1-4-2 PDE4結構特性及其活性調控 7
1-5 PDE4與樹突細胞 8
二 研究動機與目的 10
三 材料與方法 11
3-1 材料 11
3-1-1 實驗小鼠 11
3-1-2 實驗藥品 11
3-2 實驗方法 12
3-2-1 小鼠骨髓細胞分離 12
3-2-2 小鼠骨髓細胞培養分化為未成熟樹突細胞(immature dendritic cell; imDC) 12
3-2-3 培養未成熟樹突細胞(imDC)分化成為成熟樹突細胞(mDC) 13
3-2-4 流式細胞儀技術分析(Fluorescence-Activated Cell Sorting; FACS) 14
3-2-5 卵蛋白抗原致敏作用(Ovalbumin-priming) 14
3-2-6 小鼠脾臟細胞分離及CD4+ T細胞純化 14
3-2-7 絲裂霉素(Mitomycin C)處理抗原呈現細胞 15
3-2-8 淋巴細胞混合反應(Mix lymphocyte reaction; MLR) 16
四 實驗結果 17
4-1 cAMP訊息傳導對小鼠骨髓細胞分化為未成熟樹突細胞之影響 17
4-1-1 PDE抑制劑與cAMP類似物dibutylyl-cAMP (dbcAMP)對小鼠骨髓細胞分化成未成熟樹突細胞之影響 17
4-1-2 剔除PDE4基因對小鼠骨髓細胞分化為未成熟樹突細胞之影響 18
4-2 cAMP訊息傳導對小鼠骨髓細胞分化為成熟樹突細胞之影響 19
4-2-1 LPS對小鼠骨髓細胞分化為成熟樹突細胞之影響 19
4-2-2 cAMP與PDE抑制劑對LPS刺激樹突細胞成熟分化之影響 20
4-2-3 剔除PDE4基因對LPS刺激樹突細胞成熟分化之影響 21
4-2-4 PDE4抑制劑與cAMP對樹突細胞成熟分化之影響 22
4-3 PDE4B-/-小鼠樹突細胞對於卵蛋白致敏(ovalbumin-priming)小鼠脾臟CD4+ T 細胞增生之影響 23
五 討論 25
5-1 cAMP及PDE4訊息傳導對小鼠骨髓細胞分化成未成熟樹突細胞之影響 25
5-2 LPS對小鼠骨髓細胞分化為成熟樹突細胞之影響 27
5-3 PDE4抑制劑與cAMP對樹突細胞成熟分化之影響 28
5-4 PDE4B-/-小鼠樹突細胞對卵蛋白致敏(ovalbumin-priming)小鼠脾臟CD4+ T 細胞細胞增生之影響 29
六 圖與圖解 30
參考文獻 42
附圖 53
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指導教授 金秀蓮(Shiow-lian Jin) 審核日期 2013-7-17
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