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研究生:鄭書孟
研究生(外文):Shu-Meng Cheng
論文名稱:中西藥物對動脈硬化相關免疫細胞之作用機轉
論文名稱(外文):Effects of Chinese and Western Drugs on Immune Effector Cells Associated with Atherosclerosis
指導教授:賴振宏賴振宏引用關係
指導教授(外文):Jenn-Haung Lai
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
中文關鍵詞:CarvedilolGinkgo biloba extractIrbesartan單核球細胞T 淋巴球AP-1NF-kappa B
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動脈粥狀硬化是心臟血管疾病中一種慢性進展的發炎病症,而免疫作用細胞,如單核球細胞及T淋巴球細胞,參與了動脈粥狀硬化的發生及進展,且跟急性冠心症候群的發作有密切的關係。如何調節相關於動脈粥狀硬化之免疫作用細胞的發炎反應,是目前藥物治療的一種新課題。本篇論文選擇一些中西藥物,來探討藥物對活化免疫作用細胞的影響,並研究這些藥物對免疫作用細胞的調控機轉,藉以釐清它們在臨床治療上的效用。
第一部份我們探討Carvedilol是否可以調控脂多醣體誘發單核球細胞對於產生第十介白質的效應。首先,將正常健康人類單核球細胞及U937細胞株,先接受不同濃度的Carvedilol來培養兩個小時,然後給予脂多醣體刺激3到24小時後,收集上清液,來測試第十介白質的表現;同時,另一組U937細胞株接受不同濃度的Carvedilol或Labetalol來培養,約1到2個月後,給予脂多醣體刺激24小時,然後測試第十介白質的表現。本實驗發現人類單核球細胞及U937細胞株,若僅接受一次Carvedilol的培養,並無法提高因脂多醣體誘發單核球細胞而產生的第十介白質的濃度。但是,利用U937細胞株接受不同濃度的Carvedilol來持續培養至1到2個月後,再給予脂多醣體刺激,則可以發現第十介白質的濃度與Carvedilol的濃度呈現正相關的現象;但是這種現像,在Labetalol的實驗中卻沒有發現。因此,本實驗觀察到因為Carvedilol的抗氧化作用,使得對於動脈硬化的發炎反應過程有更進一步的瞭解,同時也瞭解Carvedilol更廣效的治療效果。
接著第二部分,我們試著探討Carvedilol是否可以調控顆粒球-巨噬細胞菌落刺激因子誘發單核球細胞產生第十介白質的影響。首先,我們發現如果單獨一次的Carvedilol來治療單核球細胞,則在濃度0.3到10 mM的情況下,可以產生與劑量相關性的抑制第十介白質的產生,對於U937細胞株及人類單核球細胞均是一樣。接著我們發現Carvedilol的濃度小於10 mM,對U937細胞株是沒有毒性作用;但是如果濃度超過10 mM以上,則會使U937細胞株產生細胞凋亡的現象。我們也發現,對於第十介白質的抑制現象,也發生在抑制第十介白質的訊息核醣核酸這個層次上。最後,如果將U937細胞株長期以Carvedilol來持續培養1到2個月,結果我們也發現1.0 mM的Carvedilol可以略微提高第十介白質的產生;同時在第十介白質訊息核醣核酸的這個層次上亦被發現可以略微提高。因此,本實驗證明了Carvedilol可以經由管制單核球第十介白質的產生,來調控相關於動脈硬化的發炎反應過程。
第三部分,我們探討中藥"銀杏萃取物"對於人類周邊T細胞活化時的影響。首先,我們發現銀杏萃取物可以抑制活化T細胞所產生的細胞激素,包括第二介白質、第四介白質、gamma干擾素和alpha腫瘤壞死因子及T細胞活化表面標記 (CD25);利用電泳移動轉換分析法,證實銀杏萃取物可以抑制AP-1去氧核醣核酸的結合能力,但對NF-kappa B 的去氧核醣核酸的結合能力並無影響;同時也發現,它可以抑制c-jun N-Terminal Kinase (JNK),但對Extracellular Signal-Regulated Protein Kinase (ERK) 的活性無影響。最後,利用轉殖分析法證明銀杏萃取物可以抑制Jurkat細胞內AP-1 的轉錄能力。從以上實驗可以更瞭解銀杏萃取物對於心血管及腦血管的病變,在治療上所產生的效益,可能是經由調控JNK-AP-1訊息傳導徑路而來。
第四部分,我們探討Irbesartan對於人類周邊T細胞活化的影響。首先我們發現Irbesartan可以抑制活化T細胞產生的gamma干擾素及alpha腫瘤壞死因子;而利用電泳移動轉換分析法,證實Irbesartan可以抑制數種刺激劑引發的AP-1去氧核醣核酸的結合能力,但對NF-kappa B則無影響;而對於AP-1抑制的能力,也發現在管制AP-1上游的激酶,如p38 MAPK及JNK上,但對ERK無作用;利用轉殖分析法,亦證明Irbesartan可以抑制Jurkat細胞內AP-1 轉錄的能力。因此,Irbesartan對相關於動脈硬化的發炎反應,可以經由抑制人類周邊T細胞的活化而達到臨床治療患者的效果。
從以上四部份的研究,我們可以發現這些藥物其臨床的好處,尤其是針對心血管疾病相關的動脈硬化而言,可能部份經由調控免疫作用細胞而來。

Atherosclerosis is an inflammatory disease. Immune effector cells including monocytes and T lymphocytes have been shown to play important roles in the development of acute coronary syndrome. Moreover, these activated immune effector cells involved in the process of chronic inflammation, suggested to be a hallmark of atherosclerosis. It is a new subject to find out how Chinese and Western medicines modulate the inflammatory processes associated with atherosclerosis. Therefore, our studies pick out some drugs to evaluate how they can regulate immune effector cells.
First, as known, interleukin-10 (IL-10) is an important mediator regulating the inflammatory responses. We wanted to recognize how carvedilol modulated in-vitro lipopolysaccharide (LPS)-induced IL-10 expression in monocytic cells. Both human peripheral blood monocytic cells and purified CD14+ monocytes belonging to primary cells were isolated from whole blood of healthy donors. U937 cells, one monocytic cell line, were cultured. Initially, these three monocytic cells were pre-treated with carvedilol (concentrations varied from 0.1-1.0 mM) for 2 hours and then LPS was added to induce IL-10 production for 3-24 hours before collecting supernatant. In the other hand, some U937 cells were long-term pretreated with both carvedilol and labetalol of varied concentrations for 1 to 2 months before LPS stimulation. We found that one-time carvedilol pretreatment at concentrations between 0.1 and 1.0 mM could not upregulate LPS-induced IL-10 production in human peripheral blood monocytic cells, purified CD14+ monocytes or U937 cells. Long-term labetalol pretreatment of U937 cells for 1-2 months at concentrations of 0.3-1.0 mM had no any effect on LPS-stimulated IL-10 production. However, long-term carvedilol pretreatment for U937 cells up to 1 to 2 months at concentrations of 0.1-1.0 mM could dose-dependently upregulate the LPS-stimulated IL-10 expression. Both carvedilol and labetalol pretreatment in concentrations of 0.1-1.0 mM showed no cytotoxic effects to U937 cells. Therefore, carvedilol could modulate the inflammation-based atherosclerosis via antioxidant effects to upregulate IL-10 production.
Next, as reported, both granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-10 are important mediators regulating inflammatory responses associated with atherogenesis. Then, the effects of carvedilol on GM-CSF-induced IL-10 production were examined on human monocytic cell line, U937, and purified human monocytes. We showed that one-time carvedilol pretreatment at concentrations 0.3-10 mM dose-dependently inhibited GM-CSF-induced IL-10 production in U937 cells. In addition, we found carvedilol to be non-cytotoxic at concentrations equal to or less than 10 mM. However, at concentrations higher than 10 mM, carvedilol induced programmed cell death in U937 cells. The inhibition of GM-CSF-induced IL-10 production by carvedilol was also observed at the expression of mRNA. Furthermore, the down-regulated IL-10 production was demonstrated in GM-CSF-activated purified human peripheral blood monocytes. Second, long-term carvedilol pretreatment of U937 cells up to 1-2 months at concentrations of 1.0 mM mildly upregulated the production of IL-10 and IL-10 mRNA. Our observations that carvedilol modulated GM-CSF-induced IL-10 production may have some implication in understanding the broad-spectrum effects of carvedilol in regulating inflammatory reactions.
The third part was to investigate the effect of Ginkgo biloba extract (GBE) on human peripheral T cells while activation. As known, GBE has antioxidant properties and has been applied clinically. However, it was unknown whether GBE can conduct its biological effects on human peripheral T cells. To gain insight into the mechanism of this drug’s action, we investigated the effects of GBE on activated human peripheral T lymphocytes. We found that GBE can dose-dependently inhibit cytokine production such as interleukin-2, interleukin-4, tumor necrosis factor-alpha and interferon-gamma from activated T cells. Further, we also showed that GBE suppressed the expression of IL-2 receptor-alpha (CD25), cell surface markers induced after T-lymphocyte activation. Molecular investigation further indicated that the inhibition of both human T-lymphocyte and Jurkat-cell activation correlated with the down-regulation of activator protein-1 (AP-1) DNA-binding activities, assessed by electrophoretic mobility shift assay. Results from transient transfections disclosed that GBE also inhibited AP-1 transcriptional activities in Jurkat cells. Finally, we revealed that GBE is unique in its ability to inhibit the activation of c-Jun NH2-terminal protein kinase (JNK). Our observations might extend a potential therapeutic mechanism of GBE with cell-mediated capacity, namely the inhibition of activated T lymphocytes via down-regulation of activator protein-1 activity, to prevent or treat some of disease processes associated with inflammatory pathology.
Finally, irbesartan was used to study its effects on human T cells. It is known to be a promising antihypertensive drug with beneficial effects on atherosclerotic processes. In the progression of atheroslcerosis, human T lymphocytes play an important role. Nowadays, it is unknown how irbesartan modulates activated human T lymphocytes. To gain insight into the mechanisms of irbesartan, we investigated the effects of irbesartan on activated human T lymphocytes. Primary human T lymphocytes were isolated from whole blood. Cytokines were determined by ELISA. The AP-1 and related protein activities were determined by electrophoretic mobility shift assays, kinase assays, Western blotting and transfection assays. Obviously, irbesartan could inhibit production of both tumor necrosis factor-alpha and interferon-gamma from activated T cells, especially in therapeutic concentrations. Molecular investigation further indicated that the inhibition of activated human T-lymphocyte specifically correlated with the down-regulation of AP-1 DNA-binding activities. In-vivo study disclosed that irbesartan also inhibited AP-1 transcriptional activities in Jurkat T cells. Finally, we revealed that irbesartan was unique in its ability to inhibit the activation of both c-Jun NH2-terminal protein kinase and p38 MAPK. Our studies disclosed that irbesartan had cell-mediated capacity, namely by inhibiting activated T lymphocytes via down-regulation of AP-1 activity to attain its novel therapeutic effects on inflammation-based atherosclerotic diseases.
From above studies, we know that these three kinds of drugs could attain their clinically beneficial effects in part through modulating the activation of immune effector cells.

目錄
頁數
正文目錄--------------------------------------------------------------------------------------------------II~III
圖目錄-----------------------------------------------------------------------------------------------------IV~VI
中文摘要--------------------------------------------------------------------------------------------------VII~IX
英文摘要--------------------------------------------------------------------------------------------------X~XIV
正文目錄
頁數
第一章 緒論
第一節 動脈粥狀硬化------------------------------------------------------------------1~2
第二節 訊息傳導徑路------------------------------------------------------------------2~3
第三節 實驗使用之中西藥物簡介---------------------------------------------------3~4
第四節 論文假說------------------------------------------------------------------------4~5
第五節 圖表------------------------------------------------------------------------------5~9
第二章 Carvedilol 調控體外脂多醣體誘發單核球細胞產生第十介白質的作用
第一節 前言------------------------------------------------------------------------------10~11
第二節 實驗材料及方法---------------------------------------------------------------11~13
第三節 實驗結果------------------------------------------------------------------------13~14
第四節 討論------------------------------------------------------------------------------14~17
第五節 圖表------------------------------------------------------------------------------18~25
第三章 Carvedilol調控體外顆粒球-巨噬細胞菌落刺激因子誘發U937細胞株及人類
單核球細胞產生第十介白質的作用
第一節 前言-----------------------------------------------------------------------------26~27
第二節 實驗材料及方法--------------------------------------------------------------27~31
第三節 實驗結果-----------------------------------------------------------------------31~32
第四節 討論-----------------------------------------------------------------------------32~36
第五節 圖表-----------------------------------------------------------------------------37~42
第四章 銀杏萃取物在人類周邊T細胞如何調控其c-jun N-Terminal Kinase —
Activator Protein-1的訊息傳導徑路
第一節 前言-----------------------------------------------------------------------------43~44
第二節 實驗材料及方法--------------------------------------------------------------44~49
第三節 實驗結果-----------------------------------------------------------------------49~51
第四節 討論-----------------------------------------------------------------------------51~55
第五節 圖表-----------------------------------------------------------------------------56~61
第五章 Irbesartan 經由調節 Activator Protein-1來抑制人類T細胞的活化
第一節 前言----------------------------------------------------------------------------62~63
第二節 實驗材料及方法-------------------------------------------------------------63~68
第三節 實驗結果-----------------------------------------------------------------------68~70
第四節 討論-----------------------------------------------------------------------------70~73
第五節 圖表-----------------------------------------------------------------------------74~79
第六章 總結-----------------------------------------------------------------------------------------80-82
第七章 參考文獻-----------------------------------------------------------------------------------83~108
圖目錄
頁數
圖1-1 不穩定之動脈硬化斑塊富含T細胞及來自單核球之巨噬細胞------------------6
圖1-2 NF-kB之訊息傳導路徑--------------------------------------------------------------------7
圖1-3 AP-1之訊息傳導路徑----------------------------------------------------------------------8
圖1-4 MAPK之訊息傳導路徑-------------------------------------------------------------------9
圖2-1 人類周邊單核球細胞 (PBMC) 經脂多醣體刺激後,第十介白質的生成量--18
圖2-2 人類單核球細胞 (Monocyte) 經脂多醣體刺激後,第十介白質的生成量-----19
圖2-3 U937細胞經脂多醣體刺激後,第十介白質的生成量------------------------------20
圖2-4
(a) U937細胞經Carvedilol培養24小時之後,細胞之存活率--------------------------21
(b) U937細胞經Labetalol培養24小時之後,細胞之存活率---------------------------22
圖2-5
(a) 長期Carvedilol培養U937細胞後,經脂多醣體刺激產生第十介白質的量----23
(b) 長期Labetalol培養U937細胞後,經脂多醣體刺激產生第十介白質的量-----24
(c) 長期Carvedilol或Labetalol治療U937細胞後,在無脂多醣體刺激下,觀察
第十介白質的生成量------------------------------------------------------------------------------25
圖3-1 U937細胞經GM-CSF刺激後,第十介白質的產生量----------------------------37
圖3-2 高濃度Carvedilol引發U937細胞產生DNA片段化 (Fragmentation)--------38
圖3-3
(a) 5-10 μM Carvedilol可以抑制U937細胞產生第十介白質 mRNA-----------39
(b) 利用Densitometry分析第十介白質mRNA------------------------------------------39
圖3-4 GM-CSF刺激CD14﹢單核球細胞產生第十介白質-----------------------------40
圖3-5 長期Carvedilol培養U937細胞後,以GM-CSF來刺激所產生
第十介白質的量---------------------------------------------------------------------------------41
圖3-6
(a) 長期Carvedilol培養U937細胞可以提高第十介白質 mRNA的產量---------42
(b) 利用Densitometry分析第十介白質mRNA-------------------------------------------42
圖4-1 銀杏萃取物對PMA+ ionomycin刺激T細胞產生細胞激素的效用---------56
圖4-2 銀杏萃取物對anti-CD3 + anti-CD28 mAbs刺激T細胞產生細胞激素
的效用----------------------------------------------------------------------------------------------57
圖4-3 銀杏萃取物抑制活化T細胞CD25 (IL-2Rα) 的表現-------------------------58
圖4-4 銀杏萃取物可以抑制AP-1的DNA結合能力,但對NF-kB並無作用----59
圖4-5 銀杏萃取物抑制JNK的活性,但不抑制ERK的活性------------------------60
圖4-6 銀杏萃取物可以抑制Jurkat cell內AP-1轉錄的能力--------------------------61
圖5-1 Irbesartan 對活化T細胞產生細胞激素的作用----------------------------------74
圖5-2 Irbesartan 可以抑制AP-1而非NF-kB的DNA結合能力---------------------75
圖5-3 Irbesartan可以抑制anti-CD3 + anti-CD28刺激產生的AP-1而非NF-kB
的DNA結合能力-----------------------------------------------------------------------------76
圖5-4 Irbesartan可以抑制TNF-α,IL-1β或H2O2刺激產生的AP-1的DNA
結合能力----------------------------------------------------------------------------------------77
圖5-5 Irbesartan可以抑制AP-1在Jurkat T cells的轉錄能力------------------------78
圖5-6 Irbesartan可以抑制JNK及p38 MAPK的活性,但對ERK的影響較小--79
圖6-1U937細胞在長期Carvedilol 培養後可以增加其第十介白質-----------------81
圖6-2銀杏萃取物對T Cells的作用-------------------------------------------------------81
圖6-3 Irbesartan 對T Cells的作用--------------------------------------------------------82

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