PDE抑制劑與cAMP訊號傳導對類風濕性關節炎小鼠模型中CD4+ T細胞釋放IFN-g與IL-17A之調控

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游佩茹(Pei-Ju Yu) 查詢紙本館藏

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論文名稱

PDE抑制劑與cAMP訊號傳導對類風濕性關節炎小鼠模型中CD4+ T細胞釋放IFN-g與IL-17A之調控
(PDE Inhibitors and cAMP Signaling Regulate IFN-g and IL-17A Release from CD4+ T Cells in Mouse Models of Rheumatoid Arthritis)

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摘要(中)

類風濕性關節炎(Rheumatoid arthritis, RA)是一種複雜的慢性自體免疫疾病，目前影響全球1-2%人口，該病主要侵犯關節部位軟、硬骨組織，其致病機制至今仍不完全明瞭。文獻指出，增加免疫細胞內cAMP濃度可有效降低多種免疫發炎反應，進而改善慢性發炎疾病如氣喘、COPD與過敏性皮膚炎等。第四型環狀核苷磷酸雙酯酶 (phosphodiesterase 4, PDE4)是免疫細胞中主要水解cAMP的酵素，抑制PDE4可增加細胞內cAMP，因此臨床上PDE4抑制劑被廣泛研發為抗發炎藥劑。研究指出，PDE4抑制劑處理膠原蛋白誘發關節炎小鼠能改善關節炎症狀，然而其作用機制仍不甚明瞭。已知Th1與Th17細胞激素IFN-與IL-17A在RA致病過程中扮演重要的角色，因此本研究欲探討PDE4或cAMP信號傳導是否在RA致病過程中參與Th1與Th17細胞激素的調控。我們首先利用RA動物模型，即膠原蛋白誘發關節炎(collagen-induced arthritis, CIA)模型誘導C57BL/6與DBA/1小鼠發病，結果顯示，兩種小鼠的誘發率分別為45% (C57BL/6)與91% (DBA/1)，發病高峰期分別約在21-42天與27-33天，而早期認為對CIA有阻抗性之C57BL/6小鼠於本實驗中也能誘發出嚴重的關節炎。接著我們利用不同的致敏方法，即id./id.模型(將雞隻膠原蛋白(CII)先後注射於小鼠尾巴根部皮下)與id./ip.模型(將CII先後注射於小鼠尾巴根部皮下與腹腔內)，使DBA/1小鼠對CII產生免疫反應，之後以小鼠脾臟或腹股溝淋巴結T細胞進行實驗，結果顯示兩種致敏方法均可刺激CII專一性Th1與Th17細胞之活化。同時，我們發現CII或-CD3抗體可刺激兩種淋巴組織T細胞釋放IFN-與IL-17A，而PDE4抑制劑rolipram可有效抑制此等反應（除了腹股溝淋巴結細胞對IL-17A的釋放外）。此外，非選擇性PDE抑制劑IBMX對IFN-與IL-17A的釋放也有相當程度的抑制作用，表示在11個PDE家族中PDE4應是主要調控此等反應的酵素。再者，使用cAMP增升劑如dbcAMP與forskolin處理細胞，其抑制兩種細胞激素的程度與rolipram相似，因此我們推測rolipram的抑制作用是由於增加細胞內cAMP所致。而藉由PKA、Epac活化劑與抑制劑的使用，我們進一步發現rolipram的抑制作用是經由活化PKA訊號傳導所致。此外，PDE3抑制劑cilostazol與PDE7抑制劑BRL 50481對CIA小鼠之Th1與Th17免疫反應多不具抑制作用，然而cilostazol卻能協同rolipram使IFN-與IL-17A的抑制作用更為顯著。為此，我們推測PDE4選擇性抑制劑能改善RA的發炎反應，而PDE3與PDE4雙重抑制劑應可更有效地減緩RA病症。

摘要(英)

Rheumatoid arthritis (RA) is a complicated, chronic autoimmune disorder that affects 1-2% population worldwide. It primarily attacks cartilage and bone of joints. The etiology of the disease still remains to be defined. Accumulating evidence indicates that elevation of intracellular cAMP concentration can suppress a vast spectrum of inflammatory responses in most immune cells and, thereby ameliorate chronic inflammatory diseases, such as asthma, COPD, and atopic dermatitis. Type 4 phosphodiesterases (PDE4s) are the major cAMP-hydrolyzing enzymes in various inflammatory cells. Inhibition of PDE4, thus increasing intracellular cAMP, has been considered an attractive strategy for developing anti-inflammatory drugs. Using collagen-induced arthritis (CIA) models, previous studies show potential benefits of PDE4 inhibitors in RA, while the mechanism of the effect remains unclear. Moreover, the Th1 and Th17 cytokines IFN- and IL-17A, respectively, are known important in the pathogenesis of RA. Therefore, in this study we employed CIA models to access whether PDE4 or cAMP signaling is involved in regulation of Th1 and Th17 responses in RA. By immunization of C57BL/6 and DBA/1 mice with chick collagen II (CII), we found that the disease incidence for the two mouse strains were 45% and 91%, respectively, and the arthritic symptoms developed during 21-42 and 27-33 days, respectively, after collagen immunization. In addition, the C57BL/6 mice, considered genetically resistant to CIA in early studies, also developed severe arthritic conditions. Immunization of DBA/1 mice with CII by different protocols (i.e. the id./id. and id./ip. models) indicated that both models induced the activation of CII-specific Th1 and Th17 cells in the spleen and draining (inguinal) lymph nodes of these mice. In vitro stimulation with CII and/or -CD3 antibody revealed a significant increase in IFN-and IL-17A release in T cells of the two lymphoid tissues from the two models, and these responses were significantly inhibited by the PDE4 inhibitor rolipram except for the release of IL-17A in the inguinal lymph node cells. The non-selective PDE inhibitor IBMX also attenuated IFN- and IL-17A release in these T cells to an extent similar to that of rolipram, indicating PDE4 is the major PDE isozymes in regulation of the Th1 and Th17 responses. Studies with the cAMP-elevating agents dbcAMP and forskolin and with PKA and Epac activators and inhibitors further suggested that the inhibitory effect of rolipram was mediated by activation of the cAMP/PKA axis. The PDE3 inhibitor cilostazol and PDE7 inhibitor BRL 50481 mostly had no effect on the Th1 and Th17 responses, whereas cilostazol showed synergistic effect to the rolipram inhibition. In conclusion, these findings indicate that PDE4 selective inhibitors can efficaciously alleviate inflammation in RA, yet PDE3 and PDE4 dual inhibitors may be more beneficial to RA patients.

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-g
★ IL-17A

關鍵字(英)

論文目次

目錄
中文摘要 i
英文摘要 iii
誌謝 v
目錄 vi
圖目錄 viii
表目錄 ix
縮寫檢索表 x
一、緒論 1
1-1 類風濕性關節炎(Rheumatoid arthritis, RA) 1
1-1-1 類風濕性關節炎的致病機制 1
1-1-2 T細胞與類風濕性關節炎 3
1-1-3 TNF-, IL-1, IFN-, IL-17與類風濕性關節炎 4
1-1-4 膠原蛋白誘發關節炎模型 (collagen-induced arthritis, CIA) 7
1-2 環狀線苷單磷酸 (Adenosine 3’, 5’-cyclic monophosphate, cAMP)之訊息傳導 9
1-2-1 cAMP訊息傳導與免疫發炎反應 10
1-3 環狀核苷酸磷酸二酯酶 (Cyclic nucleotide phosphodiesterases, PDEs) 11
1-3-1 PDE4結構、功能與表現 12
1-3-2 PDE4與T細胞免疫發炎反應 14
1-4 PDE4/cAMP訊息傳導與類風濕性關節炎 15
二、研究動機與目的 17
三、材料與方法 18
3-1 材料 18
3-1-1 實驗藥材 18
3-1-2 實驗小鼠 19
3-1-3 實驗試劑 19
3-1-3-1 第二型膠原蛋白 19
3-1-3-2 皮下注射佐劑 19
3-1-3-3 腹腔注射試劑 20
3-1-3-4 RPMI 1640細胞培養基 20
3-1-3-5 去除B細胞 (B cell panning)培養皿之製備 20
3-2 實驗方法 20
3-2-1 膠原蛋白誘導小鼠關節炎 (Collagen-induced arthritis, CIA) 20
3-2-2 小鼠膠原蛋白誘發關節炎之病症嚴重程度評估 21
3-2-3 淋巴結細胞分離與培養 22
3-2-4 脾臟細胞分離與培養 22
3-2-5 以磁珠抗體純化CD4+ T細胞 23
3-2-6 以磁珠抗體製備抗原呈現細胞 24
3-2-7 Mitomycin C處理抗原呈現細胞 25
3-2-8 CD4+ T細胞與抗原呈現細胞共同培養 25
3-2-9 細胞激素含量測定 25
四、實驗結果 27
4-1 第二型膠原蛋白誘發C57BL/6與DBA/1小鼠關節炎(collagen-induced arthritis, CIA) 之比較 27
4-2 Rolipram抑制膠原蛋白刺激id/ip模型小鼠脾臟細胞釋放IFN-及IL-17A 27
4-3 PDE抑制劑與cAMP增升劑對id/id及id/ip模型小鼠腹股溝淋巴細胞釋放IFN-與IL-17A之影響 28
4-4 PDE抑制劑與cAMP增升劑對id/ip模型小鼠脾臟細胞釋放IFN-與IL-17A之影響 30
4-5 Rolipram抑制膠原蛋白與-CD3抗體刺激id/ip模型小鼠脾臟細胞釋放IFN-與IL-17A之cAMP訊息傳導路徑 32
4-6 PDE抑制劑與cAMP增升劑對膠原蛋白致敏(primed)小鼠腹股溝淋巴結CD4+ T細胞釋放IFN-與IL-17A之影響與其cAMP訊息傳導路徑 33
4-7 PDE抑制劑與cAMP增升劑對id/ip模型小鼠脾臟CD4+ T細胞釋放IFN-與IL-17A之影響與其cAMP訊息傳導路徑 34
五、討論 36
5-1 膠原蛋白誘發C57BL/6與DBA/1小鼠關節發炎之比較 36
5-2 PDE4/cAMP訊息傳導對T細胞釋放IFN-與IL-17A之調控 37
5-3 Rolipam抑制CIA小鼠T細胞釋放IFN-與IL-17A之訊息傳導路徑 40
六、圖與圖解 42
參考文獻 59
附錄 74

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指導教授

金秀蓮(S.-L. Catherine Jin)

審核日期

2013-10-23

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