環狀核苷酸磷酸二酯酶4B對小鼠樹突細胞分化與CXCR4表現之調控

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陳冠福(Kuan-Fu Chen) 查詢紙本館藏

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論文名稱

環狀核苷酸磷酸二酯酶4B對小鼠樹突細胞分化與CXCR4表現之調控
(Effects of phosphodiesterase 4B on mouse dendritic cell differentiation and CXCR4 expression)

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摘要(中)

樹突細胞(Dendritic cells)為抗原呈現細胞，於先天與後天免疫作用中扮演重要的角色。該細胞在吞噬抗原後會分化為成熟樹突細胞，並藉由細胞表面的趨化受體如CXCR4與CCR7由周邊組織移動至局部淋巴結，以進行抗原專一的T細胞活化。已知在許多發炎細胞中，增加cAMP濃度會抑制多種發炎反應，包含樹突細胞的分化與功能。Type 4 phosphodiesterases (PDE4s)為免疫細胞內主要水解cAMP的酵素，其可藉由調控cAMP濃度與cAMP訊息傳導進而影響多種發炎反應。本實驗室先前研究顯示，PDE4抑制劑rolipram會降低小鼠骨髓細胞分化為未成熟樹突細胞。然而，該作用是由何種PDE4亞型(PDE4A、4B、4C及4D)所調控，以及PDE4亞型是否會參與樹突細胞的成熟分化與免疫功能仍不甚瞭解。為此，本研究首先利用granulocyte-macrophage colony-stimulating factor (GM-CSF)誘導野生型與PDE4基因剔除小鼠骨髓細胞分化為未成熟樹突細胞，以流式細胞儀分析結果顯示，分化九天的野生型CD11c+樹突細胞群達86.8 ± 0.6 %，而剔除PDE4B基因會使CD11c+樹突細胞群顯著下降，但剔除PDE4A與4D則無此抑制作用。再者，於LPS或Ovalbumin (OVA)抗原誘導樹突細胞成熟過程中，以rolipram處理或剔除PDE4各亞型均不會影響樹突細胞的成熟分化(檢測CD11c+CD86+細胞群)。然而，僅剔除PDE4B或以rolipram單獨處理未成熟樹突細胞均會增加CD11c+CD86+細胞群。進一步實驗顯示，於樹突細胞成熟過程中，處理rolipram或剔除PDE4B會促使CD11c+CXCR4+細胞群上升，此結果表示PDE4B在成熟樹突細胞內會抑制CXCR4表現。此外，將PDE4基因剔除鼠的骨髓細胞分化為樹突細胞，再以此細胞與OVA致敏的小鼠脾臟CD4+ T細胞共同培養，結果顯示，在OVA處理下，野生型樹突細胞會使T細胞增生，相同的，剔除PDE4亞型(PDE4A-/-、PDE4B-/-或PDE4D-/-)的樹突細胞對T細胞也有相同的增生作用，此結果表示，PDE4在樹突細胞內不會參與CD4+ T細胞的活化增生。綜合以上結果得知，PDE4B會參與未成熟樹突細胞的分化作用以及成熟樹突細胞中CXCR4的表現。這些結果也為研發PDE4B選擇性抑制劑以治療樹突細胞有關的發炎疾病提供了學理的基礎。

摘要(英)

Dendritic cells (DCs) are antigen presenting cells (APCs) that play a crucial role in the innate and adaptive immunity. Upon capturing antigen, DCs migrate from peripheral tissues to local lymphoid organs, differentiate into APCs, and then activate antigen-specific T cells. It is well known that elevation of intracellular cAMP concentration attenuates many inflammatory responses in almost all inflammatory cell types, including DCs. Type 4 phosphodieasterases (PDE4s) are predominant cAMP-hydrolyzing PDEs in immune/inflammatory cells which affect inflammatory responses by regulating intracellular cAMP concentration and cAMP signal pathways. Our previous study showed that the PDE4 inhibitor rolipram significantly downregulated the differentiation of mouse bone marrow (BM) cells into immature dendritic cells (imDCs). However, among the four PDE4 isoforms (PDE4A, 4B, 4C and 4D) which isoform is responsible for this differentiation remained to be delineated. Additionally, it is unclear whether PDE4s are involved in DC maturation and their immune functions. In this study, we first used GM-CSF to induce wild-type and PDE4-deficient mouse bone marrow cells to differentiate into immature DCs (imDCs). Flow cytometry analysis revealed that the wild-type CD11c+ population (i.e. imDC) reached 86.8 ± 0.6 % and ablation of PDE4B, but not of PDE4A or PDE4D, significantly reduced the imDC population, indicating that the inhibitory effect of rolipram on imDC differentiation is mediated by inhibition of only PDE4B. Contrarily, DC maturation (identified as CD11c+CD86+) induced by lipopolysaccharide (LPS) or the antigen ovalbumin (OVA) was not altered by rolipram or PDE4 ablation. However, the CD11c+CD86+ population was found to be increased when the imDCs were cultured in the presence of rolipram alone or these cells were PDE4B deficient. Moreover, during LPS- or OVA-induced BMDC maturation, rolipram significantly increased the CD11c+CXCR4+ population and this induction of CXCR4+ cells was demonstrated to be mediated by inhibition of PDE4B, but not PDE4A or PDE4D. In a functional study, we found that the ability of mature DCs to activate T cell proliferation was not affected by ablation of PDE4, as demonstrated by coculturing PDE4-deficient DCs and OVA-primed spleen CD4+ T cells in the presence of OVA. Taken together, these findings demonstrate that PDE4B is involved in the differentiation of imDCs and the CXCR4 expression in mDCs. The data also form the experimental basis for the development of PDE4B selective inhibitors for the treatment of inflammatory diseases that are mediated by DCs.

關鍵字(中)

★ 樹突細胞
★ 環狀核苷酸磷酸二酯酶4

關鍵字(英)

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樹突細胞及其免疫反應 1
1-2 腺嘌呤環狀核苷酸訊息傳導 2
1-3 cAMP與免疫反應 3
1-4環狀核苷酸磷酸二酯酶(PDEs)的結構與功能4
1-5 PDE4調控免疫反應 6
1-6 C-X-C chemokine receptor type 4 (CXCR4)8
1-7 CXCR4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 C10培養液及樹突細胞與T細胞共同培養液配置 12
3-2-2分離小鼠骨髓細胞 12
3-2-3小鼠骨髓細胞分化成未成熟樹突細胞 13
3-2-4未成熟樹突細胞分化為成熟樹突細胞 14
3-2-5流式細胞儀技術分析 14
3-2-6卵蛋白抗原致敏反應 15
3-2-7小鼠脾臟分離與CD4+ T cell純化 15
3-2-8樹突細胞刺激脾臟CD4+ T 細胞增生反應 16
四、實驗結果 17
4-1剔除PDE4B基因降低小鼠骨髓細胞分化為樹突細胞 17
4-2 PDE4抑制劑在LPS或OVA誘導樹突細胞成熟過程中可降低CD11c+樹突細胞群 17
4-3剔除PDE4B可降低LPS或OVA誘導成熟分化之CD11c+樹突細胞群 18
4-4剔除PDE4B不影響小鼠骨髓細胞分化至成熟樹突細胞 19
4-5 PDE4抑制劑提升LPS或OVA誘導樹突細胞成熟時CD11c+CXCR4+細胞群 20
4-6剔除PDE4B可增加樹突細胞成熟分化時CXCR4的表現及CD11c+CXCR4+細胞群 21
4-7剔除PDE4不影響樹突細胞對CD4+ T細胞的活化增生23
五、討論 24
六、圖與圖解28
參考文獻 41
附圖一 46

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指導教授

金秀蓮

審核日期

2016-1-28

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