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論文名稱:馬兜鈴酸對於LPS or IFN-gamma所誘發的iNOS基因表現之抑制機轉
論文名稱(外文):Aristolochic Acid Inhibits iNOS Gene Expression Induced by LPS or IFN-gamma in RAW 264.7 Macrophages
指導教授:劉秉慧 教授
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馬兜鈴酸 ( Aristolochic acid, 簡稱AA) 為馬兜鈴屬植物所萃取出來的成份之一,主要由Aristolochic acid I 和Aristolochic acid II 所組成,馬兜鈴酸已被證實會造成人類或哺乳類動物腎毒性和致癌性。本研究的主要目的在於利用LPS/IFN-γ所活化的小鼠巨噬細胞株(RAW 264.7 cell lines) 作為發炎反應模式,探討馬兜鈴酸抑制iNOS基因表現的影響,並且進一步探討馬兜鈴酸抑制機轉。
利用50 ng/ml的LPS或10 ng/ml 的IFN-γ處理RAW 264.7 細胞株18 小時,發現Nitric oxide (NO) 的生成和細胞內iNOS蛋白質及 mRNA 的表現量皆上升,但是當馬兜鈴酸 (30至100 μM) 和LPS/IFN-γ同存在時,會令LPS/IFN-γ所誘導的NO、iNOS蛋白質和iNOS mRNA 顯著減少。為了證實馬兜鈴酸是否在轉錄層次上影響iNOS 基因的表現,我們將含有不同長度的iNOS 啟動子建構於冷光報導基因載體,並將其分別轉染至進入RAW 264.7 細胞株,結果發現50 μM馬兜鈴酸抑制的能力主要作用在iNOS啟動子區域中的NF-κB 轉錄因子結合區 (位於啟動子核苷酸-86/-76中),此外利用electrophoretic gel mobility shift assay (EMSA) 得知50 μM馬兜鈴酸能夠抑制NF-κB結合至DNA 的能力,西方墨點法亦發現馬兜鈴酸會抑制LPS所活化NF-κB上游的I-κB磷酸化表現。另外兩個已知可被NF-κB所活化的基因Tumor necrosis factor-alpha和Interleukin-6,其在細胞中的mRNA表現量也會因為馬兜鈴酸 (50至100 μM)的存在而被明顯抑制。為了探討馬兜鈴酸是否會影響iNOS mRNA 的穩定度,我們利用以Cytomegalovirus (CMV) 啟動子所驅動的冷光報導基因作為載體,在其尾端分別建構iNOS mRNA 3’-UTR和SV40 late poly(A) signal (SVpA),結果推測馬兜鈴酸並不會藉由影響iNOS mRNA 3’-UTR 的功能而使iNOS mRNA的表現量減少。
由以上實驗我們認為馬兜鈴酸可以有效的抑制由LPS/IFN-γ所誘導的iNOS 基因表現,主要是影響iNOS 基因轉錄層次中NF-κB訊息傳遞,而不是藉由轉錄後層次中iNOS mRNA 穩定度的影響。

Aristolochic Acid (AA), a group of natural compound widely found in Artistolochia species, is composed of AAI and AAII. AA I in the herbal medicine is found to be nephrotoxic and carcinogenic to human. To study the immunosuppressive ability of AAI, lipopolysaccharide (LPS) or Interferon gamma (IFN-γ) -stimulated RAW 264.7 macrophage cells were used as a model to examine the effects of AAI on the expression of the inducible nitric oxide synthase (iNOS) gene.
When RAW 264.7 macrophages were treated with LPS (50 ng/ml) or IFN-γ (10ng/ml) for 18 h, the levels of nitric oxide (NO), iNOS protein and iNOS mRNA expression were all significantly increased. However, the presence of AAI (30-100μM) down-regulated the expression of LPS/IFN-γ-induced NO, iNOS protein and mRNA in a dose-dependent manner. To confirm whether AAI was able to decrease iNOS gene expression at the transcription level, we constructed a series of luciferase reporter plasmids which contained various promoter regions (-1588 to +121) of iNOS gene. AAI was found to inhibit the LPS/IFN-γ-induced iNOS expression by modulating the nuclear factor-κB (NF-κB) binding element located at nucleotides −86 to −76. The results of electrophoretic gel mobility shift assay (EMSA) also supported the inhibitory effect of AAI on the DNA binding activity of NF-κB. In addition, Western blotting demonstrated LPS-induced I-κB phosphorylation was significantly suppressed by AAI. Treatment of RAW 264.7 with AAI also down-regulated the LPS-induction of TNF-α and IL-6, two NF-κB regulated genes. Furthermore, the exposure of transient transfectant to AAI did not affect the luciferase activities of reporter construct that contained iNOS mRNA 3''-UTR, indicating that AAI does not inhibit iNOS gene expression at the post transcriptional level.
Taken together, the data herein suggest that in activated RAW 264.7 macrophages, AAI regulates iNOS gene expression at the transcriptional level, and inhibition of NF-κB activation may be associated with the immunomodulatory effect of AAI.

一、 馬兜鈴酸對RAW 264.7小鼠巨噬細胞存活率的影響------------41
二、 馬兜鈴酸抑制LPS所誘發之一氧化氮生成量--------------------41
三、 馬兜鈴酸抑制LPS所誘發的 iNOS 蛋白生成量----------------44
四、 馬兜鈴酸抑制LPS所誘發的 iNOS mRNA成量----------------44
五、 馬兜鈴酸抑制LPS所誘發的iNOS promoter 活性-------------46
六、 馬兜鈴酸抑制LPS所誘發之NF-κB 與DNA 結合能力-------48
七、 馬兜鈴酸抑制LPS所誘發之I-κB 蛋白質磷酸化影響---------50
八、 馬兜鈴酸對LPS所誘發之 TNF-alpha、IL-6、COX-2 mRNA生成量的影響------------------------------------------------------------51
九、 馬兜鈴酸對iNOS mRNA 3’UTR 的影響--------------------------51
一、 馬兜鈴酸抑制IFN-γ所誘發之NO成量----------------------------56
二、 馬兜鈴酸抑制IFN-γ所誘發之 iNOS 蛋白生成量--------------56
三、 馬兜鈴酸抑制IFN-γ所誘發的 iNOS mRNA成量--------------59
四、 馬兜鈴酸抑制IFN-γ所誘發的iNOS promoter 活性-----------59
五、 馬兜鈴酸抑制IFN-γ所誘發之STAT-1 蛋白質磷酸化----------64

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