環狀核苷酸磷酸二酯酶4B對於小鼠T細胞功能之調節

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侯喬茵(Chiao-yin Hou) 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對於小鼠T細胞功能之調節
(Regulation of Murine T cell Functions By Phosphodiesterase 4B)

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摘要(中)

CD4+ T細胞是後天免疫系統的重要調節者，而CD4+ Th2細胞的發炎反應會導致不同的過敏病症。已知增加細胞內環狀腺苷單磷酸(cAMP)濃度可抑制T細胞的活化，並抑制免疫發炎細胞的聚集與增生，因此增加細胞內cAMP濃度被視為是治療T細胞引起之發炎疾病的有效方法。第四型環狀核苷酸磷酸二酯酶 (PDE4) 是分解cAMP的專一性酵素，在T細胞中PDE的表現以PDE4為主，抑制PDE4可增加細胞內cAMP的濃度進而抑制T細胞的活化與相關的發炎反應。本研究利用PDE4A-/-、PDE4B-/-、PDE4D-/-小鼠與相同品系之野生型小鼠的T細胞進行實驗，首先以非TCR-專一性抗原Concanavalin A (ConA)處理脾臟T細胞，我們發現，在野生型與PDE4A-/-細胞中，ConA可顯著增加細胞生長速率與IL-2的產生，而此反應在PDE4B或PDE4D剔除T細胞中則明顯降低，若以rolipram（PDE4抑制劑）共同處理細胞，野生型與PDE4A-/-細胞的反應會顯著被抑制，而對PDE4B-/-或PDE4D-/-細胞的抑制程度則相對較低，顯示PDE4B與PDE4D,而非PDE4A，會參與或調控ConA引發的T細胞增生與IL-2產生。此外，H89會將rolipram對細胞增生與IL-2釋放的抑制返回到和ConA單獨刺激的情況相當，因此得知rolipram是經由增加cAMP、活化PKA以調節T細胞的發炎反應。同時，利用小鼠過敏性氣喘模型進行實驗，以過敏原ovalbumin（OVA）激釁（sensitized）及鼻道刺激（nasal challenged）野生型與PDE4B-/-小鼠，我們發現野生型小鼠之氣管周邊淋巴結細胞在OVA處理下，其生長速率與Th2細胞激素如IL-4與IL-5的分泌均會顯著上升，而PDE4B-/-淋巴結細胞對OVA的反應則明顯下降，表示氣喘過敏原所引發的Th2免疫反應需要PDE4B的參與。我們進一步發現，OVA致敏（primed）小鼠之周邊淋巴（如脾臟）T細胞，其細胞增生率也會被剔除PDE4B所抑制。綜合上述結果顯示，PDE4B在過敏性氣喘致病過程中扮演重要的角色，抑制或去除PDE4B可減緩Th2細胞所導致的發炎反應，如免疫細胞增生與Th2細胞激素的產生，因此本研究為研發PDE4B專一性抑制劑做為抗過敏性氣喘藥物提供了理論基礎。

摘要(英)

CD4+ T cells play a key role in regulation of acquired immune responses. The inflammatory responses of CD4+ Th2 cells may lead to different allergic conditions and diseases. Evidence indicates that elevation of intracellular cAMP concentrations can attenuate T cell activation and proliferation and cell recruitment to the inflammatory sites. Thus, manipulation of cAMP levels in T cells is regarded as an attractive strategy in treatment of allergic inflammatory diseases. Type 4 phosphodiesterases (PDE4), the enzymes that degrade cAMP with high affinity, express at high levels in T cell, and are critical in regulation of T cell responses. In this study, we used PDE4-deficient mice in C57Bl/6 and Balb/c genetic backgrounds to investigate how PDE4s regulate T cell functions under different antigen stimulations. Using non TCR-specific antigen concanavalin A (ConA) to stimulate spleen T cells, we observed that in the wild-type and PDE4A-/- cells ConA induced cell proliferation and IL-2 production, whereas the responses were significantly reduced in the PDE4B-/- and PDE4D-/- cells. The PDE4 inhibitor rolipram was shown to suppress these responses significantly in the wild-type and PDE4A-/- cells, and more importantly, the PKA inhibitor H89 restored the responses to levels similar to those with the ConA treatment alone. These findings demonstrated that PDE4B and PDE4D, but not PDE4A, are involved in regulating ConA-induced T cell proliferation and IL-2 production, and the inhibitory effects of rolipram is mediated by PKA activation. Using the allergen ovalbumin (OVA) to sensitize and challenge the wild-type and PDE4B-/- mice, we observed that the cell proliferation and Th2 cytokine release (IL-4 and IL-5) in response to OVA were induced in peri-broncheal lymph node cells of wild-type mice. This induction, however, was significantly blocked in the PDE4B-/- cells, demonstrating that PDE4B is involved in the allergen induced Th2 cell responses. In addition to the local lymph node T cells, the peripheral spleen T cells of the OVA-primed PDE4B-/- mice also displayed a decrease in cell proliferation to OVA stimulation. Taken together, these results indicate that PDE4B plays an important role in the pathogenesis of allergic asthma. Inhibition or ablation of PDE4B can significantly attenuate Th2-driven inflammatory responses. The findings also provide the experimental base for developing PDE4B selective inhibitors as novel anti-inflammatory agents.

關鍵字(中)

★ T細胞
★ 發炎
★ 磷酸二酯酶
★ 過敏
★ 氣喘

關鍵字(英)

★ phosphodiesterase 4
★ PDE4
★ T-cell
★ inflammation
★ asthma
★ allergy

論文目次

目錄
中文摘要 …………………………………………………………………………… i
英文摘要 …………………………………………………………………………… ii
誌謝 …………………………………………………………………………… iv
目錄 …………………………………………………………………………… v
圖目錄 …………………………………………………………………………… vii
縮寫檢索表 …………………………………………………………………………… viii
壹緒論……………………………………………………………………… 1
1.1 環狀腺苷單磷酸的抗發炎特性與調節T細胞活化…………………… 1
1.2 環狀核苷酸磷酸二酯酶異構酶 (PDE Isozymes) …………………… 2
1.3 PDE4與發炎反應……………………………………………………… 2
1.4 細胞增生劑與T細胞發炎反應………………………………………… 3
1.5 PDE4與T細胞免疫反應……………………………………………… 3
1.6 CD4+ Th2細胞對氣喘的影響………………………………………… 4
1.7 PDE4抑制劑的研發…………………………………………………… 5
1.8 研究目的………………………………………………………………… 6
貳材料與方法……………………………………………………………… 8
2.1 材料……………………………………………………………………… 8
2.1.1 實驗藥材………………………………………………………………… 8
2.1.2 實驗小鼠………………………………………………………………… 8
2.1.3 實驗試劑………………………………………………………………… 8
2.1.3.1 腹腔注射佐劑…………………………………………………………… 8
2.1.3.2 卵蛋白抗原 (OVA; ovalbumin) ……………………………………… 9
2.1.3.3 PBS細胞緩衝溶液……………………………………………………… 9
2.1.3.4 RPMI-1640細胞培養液………………………………………………… 9
2.2 方法……………………………………………………………………… 10
2.2.1 致敏程序………………………………………………………………… 10
2.2.1.1 腹腔注射………………………………………………………………… 10
2.2.1.2 鼻腔激釁………………………………………………………………… 10
2.2.1.3 抗原致敏 (OVA-primed)……………………………………………… 11
2.2.1.4 多次抗原激釁 (OVA-sensitized)……………………………………… 11
2.2.2 細胞分離與培養………………………………………………………… 11
2.2.2.1 分離脾臟細胞…………………………………………………………… 11
2.2.2.2 分離淋巴結細胞………………………………………………………… 12
2.2.2.3 磁珠抗體純化細胞……………………………………………………… 13
2.2.2.4 阻斷細胞生長…………………………………………………………… 14
2.2.2.5 淋巴細胞混合反應……………………………………………………… 14
2.2.3 T細胞功能測定………………………………………………………… 14
2.2.3.1 細胞增生測定…………………………………………………………… 15
2.2.3.2 細胞激素含量測定……………………………………………………… 16
参實驗結果………………………………………………………………… 17
3.1 非專一性抗原ConA對PDE4基因剔除脾臟T細胞之影響………… 17
3.2 cAMP調節劑對ConA刺激脾臟T細胞之影響……………………… 17
3.3 PDE抑制劑對OVA刺激脾臟T細胞增生之影響…………………… 19
3.4 專一性抗原OVA對PDE4B基因剔除脾臟T細胞之影響…………… 20
3.5 專一性抗原OVA對PDE4B基因剔除鼠氣管周邊淋巴細胞之影響… 21
3.6 專一性抗原OVA對PDE4B基因剔除鼠CD4+ T細胞增生之影響… 22
肆討論……………………………………………………………………… 24
4.1 以ConA為抗原產生的細胞發炎反應………………………………… 24
4.2 OVA抗原致敏(primed)小鼠之脾臟細胞及其免疫反應……………… 26
4.3 OVA過敏原激釁(sensitized)引發氣喘的過敏反應…………………… 26
伍結論……………………………………………………………………… 29
陸圖與圖解………………………………………………………………… 30
參考文獻 …………………………………………………………………………… 40

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指導教授

金秀蓮(Siou-lian Catherine Jin)

審核日期

2010-7-21

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