環狀核苷酸磷酸二酯酶4對LPS刺激小鼠巨噬細胞產生IL-1Ra之影響

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楊景行(Jing-xing Yang) 查詢紙本館藏

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論文名稱

環狀核苷酸磷酸二酯酶4對LPS刺激小鼠巨噬細胞產生IL-1Ra之影響
(Effects of Cyclic Nucleotide Phosphodiesterase 4 on LPS-stimulated IL-1Ra Production in Mouse Macrophages)

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摘要(中)

Interleukin-1 receptor antagonist (IL-1Ra)是IL-1家族的成員之一，可以與IL-1的受體結合而抑制IL-1受體的訊息傳導。文獻指出，利用LPS刺激免疫細胞TNF-?與IL-1β的產生會被IL-1Ra所抑制，故IL-1Ra被認為是一種抗發炎的細胞激素。此外，IL-1Ra在臨床用於治療許多發炎疾病，包括類風溼性關節炎。在本研究中，我們證實利用LPS刺激Raw 264.7細胞及小鼠腹腔巨噬細胞，IL-1Ra釋放量會隨著LPS刺激的時間及濃度增加而上升。Rolipram是PDE4抑制劑，可使巨噬細胞內cAMP的濃度上升，進而使LPS所誘導的IL-1Ra釋放顯著增加，EC50約為0.3~1 μM；同時，Rolipram也會增加IL-1Ra的轉錄作用。我們發現利用PKA活化劑6-Bnz-cAMP處理巨噬細胞可增加IL-1Ra的釋放，而Epac活化劑8-pCPT-2’-O-Me-cAMP則無此作用。此外，PKA抑制劑Rp-8-CPT-cAMPS也可阻斷Rolipram所增加的IL-1Ra。這些結果指出，Rolipram是經由活化cAMP/PKA訊息傳導來調節IL-1Ra的釋放。我們進一步利用PDE4剔除小鼠的腹腔巨噬細胞來分析PDE4四個亞型(PDE4A、4B、4C及4D)如何調節IL-1Ra的產生。結果顯示，LPS刺激PDE4B-/-巨噬細胞其IL-1Ra釋放量與利用LPS與Rolipram共同處理的野生型細胞相當，表示Rolipram使IL-1Ra釋放上升是由於抑制PDE4B所致。此外，利用anti-IL-1Ra抗體將巨噬細胞釋放的IL-1Ra中和做進一步分析，結果顯示LPS刺激所釋放的IL-1Ra可部分抑制TNF-a的釋放，然而Rolipram所增加的IL-1Ra卻無法抑制TNF-a釋放。綜合以上結果，我們發現抑制或剔除PDE4B可活化cAMP/PKA的訊息傳導，使LPS刺激IL-1Ra的釋放上升，然而此訊息傳導不能直接影響TNF-a的釋放。

摘要(英)

Interleukin-1 receptor antagonist (IL-1Ra) is a member of the IL-1 cytokine family that binds to IL-1 receptors and subsequently prevents IL-1 from triggering a signal in the cell. IL-1Ra can be produced by a variety of cell types in response to inflammatory stimuli. Accumulating evidences indicates that IL-1Ra functions as an anti-inflammatory cytokine that can block LPS-induced TNF-a and IL-1β production in inflammatory cells. Moreover, the human recombinant IL-1Ra is currently used as a therapeutic agent for rheumatoid arthritis. In this study, we demonstrated that stimulation of Raw 264.7 cells and mouse peritoneal macrophages with LPS increased IL-1Ra release in a time- and dose-dependent manner. The cAMP-specific phosphodiestrase PDE4 inhibitor Rolipram, a cAMP-elevating agent, significantly enhanced the LPS-stimulated IL-1Ra release with the EC50 of approx. 0.3~1 uM. This induction of IL-1Ra by LPS and Rolipram was also observed at the transcriptional level. Moreover, the increase in the IL-1Ra release was mimicked by the treatment of the cells with the PKA activator 6-Bnz-cAMP, whereas the Epac activator 8-pCPT-2’-O-Me-cAMP did not produce the similar effect. In addition, the Rolipram-enhanced IL-1Ra production was reversed by the PKA inhibitor Rp-8-CPT-cAMPS. These results indicated that the effect of Rolipram was mediated by activation of the cAMP/PKA signal pathway. To further dissect among the four PDE4 subtypes (PDE4A, 4B, 4C, 4D) which one is responsible for the regulation of the IL-1Ra production, PDE4-deficient peritoneal macrophages were employed. The results showed that ablation of PDE4B enhanced LPS-stimulated IL-1Ra release to the level similar to that produced by the WT cells treated with both LPS and Rolipram, indicating the effect of Rolipram was mediated by inhibition of PDE4B. Additionally, using anti-IL-1Ra antibody to deplete IL-1Ra in the culture medium, our results indicated that in the presence of LPS alone the TNF-a release could be suppressed by the release of IL-1Ra in the medium. However, the Rolipram-enhanced IL-1Ra release was not responsible for the inhibition of TNF-a release caused by Rolipram. Taken together, these findings suggested that ablation or inhibition of PDE4B activates cAMP/PKA signaling and leads to upregulation of LPS-stimulated IL-1Ra production, which however does not contribute to its down-regulation of TNF-a release in mouse macrophages.

關鍵字(中)

★ 環狀核苷酸磷酸二酯酶4
★ 白細胞介素-1受體拮抗劑
★ 巨噬細胞

關鍵字(英)

★ Macrophage
★ IL-1Ra
★ PDE4
★ LPS

論文目次

中文摘要 i
英文摘要 ii
誌謝 iv
目錄 v
圖目錄 vi
縮寫檢索表 vii
一緒論 1
1-1 cAMP與免疫細胞之調控 1
1-2 cAMP訊息傳導路徑 2
1-3 環狀核苷酸磷酸二酯酶(Cyclic Nucleotide Phosphodiesterase；PDE) 3
1-3-1 PDE的分類與結構 3
1-3-2 PDE4與其活性調控 4
1-3-3 cAMP與PDE4抑制劑對單核球與巨噬細胞發炎反應之影響 5
1-4 白細胞介素-1受體拮抗劑(interleukin-1 receptor antagonist；IL-1Ra) 6
1-4-1 IL-1Ra 6
1-4-2 IL-1Ra的作用機制 7
1-4-3 IL-1Ra的產生與調控 8
1-4-4 IL-1Ra的臨床重要性 9
二研究動機與目的 11
三材料與方法 12
3-1 材料 12
3-1-1 實驗用小鼠 12
3-1-2 實驗用細胞株 12
3-1-3 實驗藥品 12
3-2 方法 13
3-2-1 巨噬細胞之培養及處理方法 13
3-2-1-1 Raw 264.7細胞株的培養 13
3-2-1-2 Raw 264.7細胞株的處理 13
3-2-1-3 小鼠腹腔巨噬細胞之收取 14
3-2-1-3-1 B cell panning培養皿之備製 14
3-2-1-3-2 小鼠腹腔巨噬細胞之收取 14
3-2-1-3-3 小鼠腹腔巨噬細胞之處理 14
3-2-2 Raw 264.7細胞RNA之萃取 15
3-2-3 反轉錄聚合酵素鏈鎖反應(reverse transcription polymerase chain reaction；RT-PCR ) 15
3-2-3-1 反轉錄製作cDNA 15
3-2-3-2 聚合酵素鏈鎖反應 16
3-2-4 ELISA 16
四實驗結果 18
4-1 LPS可誘導巨噬細胞釋放IL-1Ra 18
4-1-1 LPS刺激Raw 264.7巨噬細胞釋放IL-1Ra 18
4-1-2 LPS刺激小鼠腹腔巨噬細胞釋放IL-1Ra 19
4-2 Rolipram對巨噬細胞釋放IL-1Ra之影響 19
4-2-1 在LPS刺激之Raw 264.7巨噬細胞內Rolipram對IL-1Ra釋放的影響 19
4-2-2 LPS刺激之小鼠腹腔巨噬細胞內Rolipram對IL-1Ra釋放的影響 20
4-2-3 Rolipram對IL-1Ra mRNA表現的影響 20
4-3 在巨噬細胞中cAMP可增加LPS對IL-1Ra的釋放 20
4-4 PKA活化劑對LPS刺激Raw 264.7細胞釋放IL-1Ra的影響 21
4-5 PKA抑制劑可抑制Rolipram對IL-1Ra釋放的影響 21
4-6 Epac活化劑對LPS刺激Raw 264.7細胞釋放IL-1Ra的影響 21
4-7 剔除PDE4基因對LPS刺激小鼠腹腔巨噬細胞釋放IL-1Ra的影響 22
4-8 剔除PDE4B基因之小鼠腹腔巨噬細胞其增加IL-1Ra之釋放是經由活化PKA訊息傳導路徑 22
4-9 IL-1Ra對Rolipram抑制LPS誘導巨噬細胞釋放TNF-a的影響 23
五討論 25
5-1 cAMP訊息傳導對IL-1Ra釋放的影響 25
5-2 PDE4B促進LPS刺激小鼠腹腔巨噬細胞產生IL-1Ra 26
5-3 PKA與Epac在免疫細胞中所扮演的角色及功能 26
5-4 Rolipram抑制TNF-a釋放與IL-1Ra的關係 27
六圖與圖解 28
參考文獻 42
附圖 51

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指導教授

金秀蓮(S.-L. Catherine Jin)

審核日期

2011-7-27

推文