環狀核苷磷酸二酯酶4對LPS刺激小鼠巨噬細胞產生IP-10之影響

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黃珮瑜(Pei-yu Huang) 查詢紙本館藏

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論文名稱

環狀核苷磷酸二酯酶4對LPS刺激小鼠巨噬細胞產生IP-10之影響
(Effects of Phosphodiesterase 4 on LPS-stimulated IFNγ-induced Protein 10 Production in Mouse Macrophages)

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摘要(中)

趨化激素IFNγ-induced protein 10（IP-10）又稱為CXCL10，可由多種免疫及非免疫細胞所產生，它與許多發炎和自體免疫疾病有關。文獻指出，不同的促發炎介質包括LPS會刺激巨噬細胞釋放IP-10，然而目前對IP-10產生的調控機制還不太清楚。已知在多數發炎細胞中活化cAMP的訊息傳導可有效抑制細胞激素的產生，而分解cAMP的磷酸二酯酶PDE4在發炎細胞中為調控cAMP濃度的主要酵素。因此，本研究主要的目的是想探討在巨噬細胞中PDE4是否參與調控IP-10的產生以及它的作用機制。利用LPS處理Raw 264.7 和小鼠腹腔巨噬細胞，我們發現IP-10的釋放會隨著時間和濃度的增加而上升，而PDE4抑制劑rolipram會有效的抑制IP-10的釋放，其IC50分別約為0.2 μM 和 0.02 μM。同時，Rolipram也會抑制IP-10 mRNA的表現。再者，以PKA活化劑6-Bnz-cAMP處理巨噬細胞，其LPS刺激IP-10的釋放也會隨著藥劑濃度的增加而下降，然而Epac活化劑8-pCPT-2’-O-Me-cAMP只在高濃度時才有部分抑制作用。此外，PKA inhibitor Rp-8-CPT-cAMPS也會部份回復rolipram對IP-10的抑制作用。由這些結果顯示，rolipram對IP-10的抑制主要是藉由活化cAMP/PKA的路徑所致。我們進一步利用LPS處理PDE4基因剔除小鼠之腹腔巨噬細胞，發現PDE4B-/-細胞釋放IP-10會顯著下降，且其下降程度與rolipram處理PDE4B+/+巨噬細胞相當，同時rolipram不再進一步抑制PDE4B-/-巨噬細胞釋放IP-10。PDE4A-/-與PDE4D-/-細胞其IP-10的反應與PDE4A+/+與PDE4D+/+細胞一致。這些結果證明rolipram對IP-10的抑制作用是由於抑制PDE4B活性所致。另外，利用小鼠脾臟T細胞進行趨化反應，結果顯示IP-10誘導T細胞的移動也會被rolipram抑制。综合以上結果得知，在小鼠巨噬細胞中PDE4B對LPS刺激IP-10的產生與釋放是不可或缺的，且剔除或抑制PDE4B活性會活化cAMP/PKA訊息傳導進而抑制IP-10的反應。

摘要(英)

IFNγ-induced protein 10 (IP-10), also known as CXCL10, is a chemokine that can be produced by a variety of immune and non-immune cells during an inflammatory condition, and is associated with several inflammatory disorders. Accumulating evidence indicates that IP-10 is secreted by macrophages in response to various pro-inflammatory mediators, including lipopolysaccharide（LPS）. The regulatory mechanism underlying the production of IP-10, however, remains unclear. Activation of cAMP signaling is known to have negatively modulatory effects on cytokine production in most inflammatory cells. Type 4 phosphodiesterases（PDE4）, the enzymes responsible for cAMP degradation, play a key role in regulation of cAMP concentration in inflammatory cells. Thus, in this study, we aimed to determine whether and how PDE4 is involved in regulation of IP-10 production in macrophages in response to LPS. By stimulation of Raw 264.7 and mouse peritoneal macrophages with LPS, we observed that the IP-10 release increased in a time- and dose-dependent manner, and the PDE4 inhibitor rolipram effectively suppressed the IP-10 release with the IC50 of approximately 0.2 μM and 0.02 μM, respectively. The inhibition of IP-10 by rolipram was also obtained at the transcriptional level. Additionally, the LPS-induced IP-10 release was does-dependently inhibited by the PKA activator 6-Bnz-cAMP, but less effectively by the Epac activator 8-pCPT-2’-O-Me-cAMP. Moreover, the rolipram-inhibited IP-10 release was partially reversed by the PKA inhibitor Rp-8-CPT-cAMPS. These results indicated that the effect of rolipram on the IP-10 response was primarily mediated by the PKA activation. Using PDE4-deficient peritoneal macrophages treated with LPS, we found that the release of IP-10 in PDE4B-/- macrophages, but not PDE4A-/- or PDE4D-/- macrophages, was significantly decreased, to the level similar to that in the PDE4B+/+ macrophages treated with rolipram. Moreover, rolipram did not further decrease the IP-10 release in PDE4B-/- macrophages. These results demonstrated that the effect of rolipram on the IP-10 release was mediated by inhibition of PDE4B activity. Using mouse splenic T cells in a chemotactic reaction, we found that the IP-10-induced migration of T cells was also attenuated by rolipram. Taken together, these findings demonstrate that PDE4B is essential in the LPS-stimulated IP-10 production in mouse macrophages, and by activation of cAMP/PKA signaling ablation or inhibition of PDE4B can downregulate the IP-10 response.

關鍵字(中)

★ 干擾素γ誘導蛋白-10
★ 環狀核苷酸磷酸二酯酶4
★ 環磷酸腺苷
★ 巨噬細胞
★ T細胞
★ 趨化作用

關鍵字(英)

★ IP-10
★ PDE4
★ cAMP
★ macrophages
★ T cells
★ chemotaxis

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 viii
縮寫檢索表 ix
一緒論 1
1-1 環狀核苷磷酸二酯酶（cyclic nucleotide
phosphodiesterases, PDE） 1
1-2 PDE4家族 2
1-3 Adenosine 3′,5′-cyclic monophosphate（cAMP）與
cAMP
訊息傳導路徑 2
1-4 cAMP與免疫反應 3
1-5 趨化激素（Chemokine） 4
1-6 IFN-γ-inducible protein-10（IP-10） 5
1-7 IP-10、cAMP訊息傳導與巨噬細胞 5
1-8 IP-10與T細胞趨化反應 6
1-9 IP-10與免疫疾病 7
二研究動機與目的 8
三材料與方法 9
3-1 材料 9
3-1-1 實驗用小鼠 9
3-1-2 實驗用細胞株 9
3-1-3 實驗藥品 9
3-1-4 趨化反應實驗用品及儀器 10
3-2 方法 10
3-2-1 巨噬細胞之培養及藥物處理 10
3-2-1-1 Raw 264.7細胞株的培養與處理 10
1. Raw 264.7細胞株的培養 10
2. Raw 264.7細胞株的藥物處理 11
3-2-1-2 小鼠腹腔巨噬細胞之收取 11
1. B cell panning培養皿之備製 11
2. 小鼠腹腔巨噬細胞之收取 11
3. 小鼠腹腔巨噬細胞之處理 12
3-2-2 Raw 264.7細胞RNA之萃取 12
3-2-3 即時聚合酶鏈鎖反應（real-time polymerase
chain reaction） 13
1. 反轉錄製作cDNA 13
2. Real-time PCR定量RNA 13
3-2-4 ELISA 14
3-2-5 小鼠脾臟T細胞之培養及處理 14
3-2-5-1 小鼠脾臟T細胞準備 14
3-2-5-2 小鼠脾臟T細胞趨藥性試驗 15
3-2-5-3 Flow cytometry（流式細胞儀）分析 16
四實驗結果 17
4-1 LPS刺激巨噬細胞釋放趨化激素IP-10 17
4-2 Rolipram對LPS刺激巨噬細胞釋放IP-10的影響 17
4-3 Rolipram對LPS刺激Raw 264.7細胞表現IP-10 mRNA的影
響 18
4-4 在巨噬細胞中增加cAMP可降低LPS對IP-10的釋放 18
4-5 PKA活化劑與Epac活化劑對LPS刺激巨噬細胞釋放IP-10的影
響 19
4-6 PKA抑制劑對LPS刺激巨噬細胞釋放IP-10的影響 20
4-7 剔除PDE4A、PDE4B或PDE4D基因對LPS刺激巨噬細胞釋放IP-
10的影響 20
4-8 Rolipram對IP-10誘導T淋巴細胞趨化反應的影響 21
五討論 22
5-1 cAMP訊息傳導對LPS刺激巨噬細胞釋放IP-10之影響 22
5-2 PDE4B對LPS刺激小鼠腹腔巨噬細胞產生IP-10之影響 23
5-3 PKA和Epac在免疫細胞扮演的角色 24
5-4 Rolipram抑制IP-10刺激T淋巴球之趨化反應 25
六圖與圖解 26
參考文獻 38
附圖 46

圖目錄
圖一不同LPS處理時間對Raw 264.7及小鼠腹腔巨噬細胞釋放IP-
10的影響 26
圖二不同濃度之LPS對Raw 264.7及小鼠腹腔巨噬細胞釋放IP-10
的影響 27
圖三不同濃度之Rolipram對LPS刺激Raw 264.7及小鼠腹腔巨噬細
胞釋放IP-10的影響 28
圖四 Rolipram對LPS刺激Raw 264.7細胞表現mRNA的影響 29
圖五 Dibutyryl-cAMP對LPS刺激Raw 264.7及小鼠腹腔巨噬細胞釋
放IP-10的影響 30
圖六活化PKA對LPS刺激巨噬細胞釋放IP-10的影響 31
圖七活化Epac對LPS刺激巨噬細胞釋放IP-10的影響 32
圖八 PKA抑制劑對LPS刺激巨噬細胞釋放IP-10的影響 33
圖九剔除PDE4A、PDE4B或PDE4D對LPS刺激巨噬細胞釋放IP-10的
影響 34
圖十 IP-10吸引小鼠T淋巴細胞之趨化反應 36
圖十一 Rolipram對IP-10誘導T淋巴細胞趨化反應的影響 37

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指導教授

金秀蓮(Shiow-lian Jin)

審核日期

2012-10-23

推文