博碩士論文 101224028 詳細資訊




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姓名 陳仕祐(Chen, Shih-Yu)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 PDE4與PDE3抑制劑對膠原蛋白誘發DBA/1小鼠關節炎及釋放發炎激素IFN-γ與IL-17A的協同調控作用
(PDE4 and PDE3 Inhibitors Synergistically Inhibit Collagen-Induced Arthritis and IFN-γ and IL-17A Release in DBA/1 Mice)
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摘要(中) 類風濕性關節炎(Rheumatoid arthritis, RA)是一種關節病變的慢性發炎自體免疫疾病,其發病機制相當複雜,確切病因至今仍甚不明瞭。許多研究顯示,提升免疫發炎細胞內cAMP濃度可降低發炎介質產生並改善發炎作用。而環狀核苷酸磷酸二酯酶4 (phosphodiesterase 4, PDE4)為免疫細胞中主要水解cAMP的酵素,因此可調控該細胞內cAMP濃度,進而影響免疫功能。臨床上,PDE4抑制劑Roflumilast與Apremilast已分別被用來治療慢性阻塞性肺病(COPD)、牛皮癬與牛皮癬關節炎。有文獻指出,PDE4抑制劑在RA小鼠模型實驗中可有效降低關節炎的發生率及發炎程度,並減少血管翳的形成和降低軟骨受損,但其作用機制仍有待釐清。已知CD4+ T細胞亞群Th1及Th17與RA的致病過程息息相關,因此本研究利用膠原蛋白誘發小鼠關節炎(collagen-induced arthritis, CIA)模型進一步探討增加cAMP或抑制PDE4是否可調控Th1及Th17細胞釋放IFN-γ與IL-17A並影響關節發炎程度。結果顯示,以第二型膠原蛋白(type II collagen, CII)激臖之DBA/1小鼠,其局部淋巴結細胞(來自i.d./i.d.模型)釋放IFN-γ及IL-17A量與CII處理呈專一性劑量反應關係。再者,免疫小鼠之脾臟細胞(來自i.d./i.p.模型)也有相同的結果。進一步研究顯示,以CII刺激i.d./i.d.模型之淋巴結細胞與i.d./i.p.模型之脾臟細胞,其Th1細胞激素IFN-γ的釋放會被cAMP增升劑dibutyryl-cAMP、adenylyl cyclase活化劑forskolin與PDE4抑制劑rolipram顯著抑制,表示rolipram是藉由增加Th1細胞內cAMP以減低IFN-γ的生成。再者,i.d./i.p.模型之脾臟細胞,而非i.d./i.d.模型之淋巴結細胞,其釋放Th17細胞激素IL-17A也會有相似的抑制作用。此外,PDE3抑制劑cilostazol也會顯著降低IFN-γ與IL-17A的釋放,只是抑制程度較rolipram輕微。實驗進一步使用CII致敏(primed)小鼠之局部淋巴結和脾臟細胞並以anti-CD3與anti-CD28抗體刺激其IFN-γ與IL-17A釋放,結果顯示兩種細胞產生IFN-γ主要也是由PDE4所調控,至於IL-17A,PDE4抑制劑只能顯著降低脾臟細胞的作用而無法抑制淋巴結細胞的反應。值得注意的是,在不同模型中,同時以rolipram與cilostazol處理兩種細胞幾乎可完全抑制IFN-γ與IL-17A釋放,這表示兩種抑制劑具有協同抑制作用。為此,我們進一步使用rolipram與cilostazol進行活體實驗,結果顯示兩種抑制劑合併處理CIA小鼠可顯著抑制其關節發炎程度。再者,利用PDE4B基因剔除鼠進行CIA模型實驗得知,單獨剔除PDE4B基因無法減緩小鼠關節發炎作用,然而將cilostazol施予PDE4B基因剔除小鼠,其關節發炎程度較對照組PDE4B野生型小鼠則有顯著改善。綜合上述結果得知,抑制PDE4可有效減低CII誘導Th1與Th17免疫發炎反應,而PDE3抑制劑則具有協同抑制作用。因此我們推論研發PDE4與PDE3雙效抑制劑(dual inhibitors)將有助於減緩RA病情。
摘要(英) Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease. It targets multiple joints with complex pathological processes. To date, the etiology of RA is not fully understood. Accumulating evidence indicates that cAMP-elevating agents can negatively modulate many inflammatory responses in virtually all immune inflammatory cells and thereby ameliorate inflammatory diseases. Type 4 phosphodieasterases (PDE4s) are the predominant cAMP-hydrolyzing enzymes in most immune cells, hence being important in controlling the intracellular cAMP concentration and immune functions. So far, the PDE4 inhibitors Roflumilast and Apremilast are used in clinic to treat chronic obstructive pulmonary disease (COPD) and psoriasis and psoriatic arthritis, respectively. Using the animal models of RA, several studies have shown that the incidence and severity of arthritis as well as articular pannus formation and cartilage damage are significantly reduced by PDE4 inhibitors in experimantal animals. However, the molecular mechanisms of these effects still remain unclear. It is known that the helper Th1 and Th17 cells are involved in the pathogenesis of RA by secreting the cytokines IFN-γ and IL-17A, respectively. Thus, in this study we used collagen-induced arthritis (CIA) model to determine whether inhibition of PDE4 can regulate the IFN-γ and IL-17A release as well as the arthritic severity in CIA mice. Using type II collagen (CII) to immunize DBA/1 mice by two protocols (i.e., i.d./i.d. and i.d./i.p. models), we first observed that CII-induced IFN-γ and IL-17A release in local lymph node cells (by i.d./i.d. model) and spleen cells (by i.d./i.p. model) was dose dependently increased. The secretion of Th1 cytokine IFN-γ in both tissue cells was significantly decreased by dibutyryl-cAMP (cAMP analog) and forskolin (adenylyl cyclase activator), as well as by the PDE4 inhibitor rolipram, indicating that the inhibitory effect of rolipram was mediated by an increase of cAMP in Th1 cells. In addition, the release of IL-17A in the spleen cells, but not the lymph node cells also was suppressed by these cAMP-elevationg agents. Moreover, like rolipram, the PDE3 inhibitor cilostazol also significantly attenuated the secretion of IFN-γ and IL-17A while having less extent. In a CII-primed model, anti-CD3/CD28 antibody-induced IFN-γ release in the mouse local lymph node and spleen cells was also significantly reduced by rolipram, but not by cilostazol. As for IL-17A, inhibition of PDE4 caused a significant decrease in IL-17A release in the spleen cells but not the lymph node cells. It was noted that in all CIA models tested IFN-γ and IL-17A release was almost completely inhibited when the two tissue cells were treated with rolipram in combination with cilostazol. Thus, the two inhibitors were used together to treat CIA mice and the results showed that the inhibition of both PDE4 and PDE3 significantly attenuated the arthritic severity. Moreover, using the CIA model in the PDE4B null mice revealed that ablation of PDE4B did not affect the development of arthritis, while administration of cilostazol to PDE4B null mice appeared to reduce the disease severity when compared with the control wild type mice. Taken together, these results indicate that inhibition of PDE4 can effectively reduce the CII-induced Th1 and Th17 responses, and inhibition of PDE3 exerts synergistic inhibitory effects in CIA mice. Our findings provide an experimental basis for developing PDE3/4 dual inhibitors for RA therapy.
關鍵字(中) ★ 類風濕性關節炎
★ 膠原蛋白誘發關節炎
★ CD4+ T 細胞
★ IFN-γ
★ IL-17A
關鍵字(英) ★ rheumatoid arthritis
★ collagen-induced arthritis
★ CD4+ T cell
★ IFN-γ
★ IL-17A
論文目次 摘要 i
Abstract iii
誌謝 v
目錄 vi
圖目錄 viii
縮寫檢索表 ix
一、緒論 1
1-1 類風濕性關節炎(Rheumatoid arthritis, RA)臨床特徵與治療 1
1-2 類風濕性關節炎的致病因子 1
1-3 CD4+ T細胞與類風濕性關節炎 2
1-4 膠原蛋白誘發關節炎模型 (collagen-induced arthritis model, CIA model) 4
1-5 腺嘌呤環狀核苷酸(cyclic adenosine monophosphate, cAMP)訊號傳導路徑 5
1-6 cAMP與免疫發炎作用 6
1-7 環狀核苷酸磷酸二酯酶(cyclic nucleotide phosphodiesterase, PDE)結構與活性 7
1-8 PDE4家族酵素 9
1-9 PDE4抑制劑與免疫發炎反應 10
1-10 PDE4與類風溼性關節炎 11
二、研究動機與目的 13
三、實驗材料與方法 14
3-1 材料 14
3-1-1 實驗動物 14
3-1-2 實驗藥材 14
3-1-3 溶液與藥劑配製 16
3-1-3-1 第二型膠原蛋白注射試劑之配製 16
3-1-3-2 RPMI 1640基本細胞培養液及完全細胞培養液 16
3-1-3-3 B-cell panning培養皿之製備 17
3-2 方法 17
3-2-1 膠原蛋白誘導關節炎 (collagen-induced arthritis, CIA) 17
3-2-2 小鼠關節炎臨床病徵評估 19
3-2-3 淋巴結細胞分離與培養 19
3-2-4 脾臟細胞分離與培養 20
3-2-5 酵素聯結免疫吸附分析 ( enzyme-linked immunosorbent assay, ELISA) 20
3-2-6 C57BL/6 品系之PDE4B剔除對偶基因轉移至DBA/1小鼠 22
3-2-7 統計分析 22
四、實驗結果 23
4-1 cAMP增升劑對第二型膠原蛋白刺激i.d./i.d.模型DBA/1小鼠局部淋巴結細胞釋放IFN-γ及IL-17A之影響 23
4-2 cAMP增升劑對第二型膠原蛋白刺激i.d./i.p.模型DBA/1小鼠脾臟細胞釋放IFN-γ及IL-17A之影響 24
4-3 PDE抑制劑對anti-CD3/CD28抗體刺激第二型膠原蛋白致敏(primed)之DBA/1小鼠局部淋巴結與脾臟細胞釋放IFN-γ及IL-17A之影響 26
4-4 合併處理PDE4與PDE3抑制劑可顯著減緩CIA小鼠關節發炎程度 28
4-5剔除PDE4B無法減緩第二型膠原蛋白刺激DBA/1小鼠關節發炎嚴重程度 28
4-6 PDE3抑制劑於第二型膠原蛋白刺激PDE4B基因剔除鼠關節發炎的影響 29
五、討論 30
六、圖與圖解 34
參考文獻 45
附錄 59
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指導教授 金秀蓮(S.-L. Catherine Jin) 審核日期 2016-8-24
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