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研究生:張櫻馨
研究生(外文):Yinghsin Chang
論文名稱:Part-I:大麻成份△9-THC與內生性脂質活化劑anandamide,2-arachidonyl-glycerol影響鼠類J774巨噬細胞功能之研究Part-II:利用baculovirus系統製造TR2融合性蛋白及其單株抗體之製造
論文名稱(外文):Part-I:Studies on the inhibitory effects of cannabinoids on LPS-stimulated murine J774 macrophages Part-II: Generation of baculovirus-expressed TR2 fusion protein and monoclonal antibodies
指導教授:林琬琬林琬琬引用關係
指導教授(外文):WanWan Lin
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:1999
畢業學年度:87
語文別:中文
論文頁數:119
中文關鍵詞:大麻受體接合物腫瘤壞死因子
外文關鍵詞:cannabinoidsTNFanandamide2-arachidonyl-glycerol△9-THCTR2
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Part-I D9-THC是從大麻植物中萃取出來的精神興奮性物質,有關D9-THC對行為的影響及藥理實驗的報導已有許多詳盡的研究,THC會經由兩種不同型式的cannabinoid receptor而達到其藥理作用,CB1是最先被命名的受體,在腦中大量存在,但在其他部位亦有發現,而CB2主要存在於血液組織系統中,這兩種受體會經由與cannabinoid化合物產生不同生物作用,包括免疫抑制及改變中樞系統的功能。Anandamide (AEA)及2-arachidonyl-glycerol (2-AG) 是最近被鑑定出來的CB受體內生性結合物,在in vitro的實驗中會產生的作用與傳統具有活性的cannabinoid化合物相仿。此外,由於AEA及2-AG的構造與花生四烯酸 (AA) 相仿,它們可能是lipoxygenase及cyclooxygenase的受質並可能經由這兩種酵素代謝成有活性的分子。
在我們的實驗中,是要去探討在鼠類J774巨噬細胞中,cannabinoid的免疫調控作用,我們發現D9-THC及AEA濃度在1-30mM的時候可抑制LPS所引發的nitrite及IL-6生成,而且隨著濃度增加,抑制作用愈明顯。2-AG可減少LPS所引發的IL-6生成,但卻會稍微增加nitrite的生成。在iNOS的誘導現象中,D9-THC、AEA及IMMA具有同樣抑制作用。另外,THC也可抑制LPS引發PGE2合成及COX-2的誘導現象。除此之外,D9-THC、AEA及2-AG可抑制LPS引發的IL-6 mRNA表現。 我們為了更進一步去探討AEA及2-AG可能會產生的代謝物對這些作用的影響,觀察了PGE2-ethanolamide、AA及PGE2的作用。我們發現已報導的AEA會經由COX而產生的代謝物, PGE2-thanolamide,不會影響LPS所引發的nitrite 及IL-6 生成,而AA及PGE2卻有增加LPS所誘導的nitrite生成和抑制IL-6的現象發生。COX的抑制物可抵抗AA的作用,暗示COX的代謝產物可能參與AA的作用路徑中,但它們卻不能影響AEA及2-AG的作用。AEA的回收抑制劑,AM404,可稍微抑制LPS所引起的nitrite及IL-6生成,並且也可促進AEA的抑制作用。
為了確定在鼠類J774 巨噬細胞中是否有CB2受體的存在,我們以RT-PCR的方式偵測發現細胞中只有少量CB2 mRNA的表現,並且cannabinoids不具有之前報導中會經由與CB2受體偶合的Gi蛋白結合而抑制cAMP生成的現象產生,反而發現有促進的作用。此外,CB2的拮抗物,SR144528,也不能拮抗cannabinoid化合物的抑制作用。EMSA的實驗發現D9-THC、AEA及2-AG會抑制LPS誘導的AP-1及NF-IL-6的活化現象。但D9-THC會抑制LPS誘導的NF-kB活化反應,而AEA及2-AG卻不能。總而言之,在我們的實驗中發現在鼠類巨噬細胞中,D9-THC、AEA及2-AG對LPS所引發的抑制作用可能是經由一個與CB受體無關的傳遞路徑。
Part-II
TNF受體家族包含了將近10個人類蛋白,而一個新近發現的蛋白TR2 (或是herpes virus entry mediator)是從cDNA基因庫所得到,它位於染色體1p36.22-36.3,基因經轉錄後可合成具283個胺基酸的signal transmembrane protein,其分子量約30 kDa。TR2主要表現在血液組織系統,特別是淋巴組織如脾臟、胸腺等,並且它與T細胞的活化有關。在我們的實驗中,已成功地表現TR2-ECD-Fc融合性蛋白,並製造了七株單株抗體,(4A12 4D10 3E11 4D12 4B12 5F6 及6A11)。4A12是屬於IgG2a的型式,而其他都是屬於IgG1。我們以RT-PCR的方式來偵測TR2 mRNA的表現,發現在人類T細胞株CEM、B細胞株Ramos、白血球細胞株HL-60及內皮細胞株ECV在靜止態就有TR2 mRNA的表現。ECV細胞以IL-1b (10 ng/ml)處理8小時,而A549細胞以IFN-g (100U/ml)刺激8小時,都可看到TR2 mRNA明顯地增加。其他的細胞株HL-60、CEM U937也會因不同的刺激而增加TR2 mRNA的表現。此外,螢光染色的實驗也可看到相近的結果。總而言之,抗TR2單株抗體是一個有用的工具,可幫助我們了解TR2蛋白在宿主免疫系統的反應,並可偵測在發炎反應時釋放的可溶性TR2蛋白。

Part-I
D9-THC is the major psychoactive component of marijuana. The behavioural and pharmacological actions of D9-THC have been intensively studied. Two subtypes of cannabinoid receptors have been identified and mediate the pharmacological effects of D9-THC; CB1 is expressed primarily although not exclusively in brain, and CB2 is found primarily in cells of myeloid lineage. Both receptors are involved in mediating the diverse biological action of cannabinoid compounds, including immune suppression and alterations in central nervous system function. Anandamide (AEA) and 2-arachidonyl-glycerol (2-AG) were recently identified as endogenous ligands for cannabinoid receptors and in vivo produce effects very similar to those of the classical agonists of the cannabinoid receptor. Furthermore, because of its structural similarities to polyunsaturated fatty acids, AEA and 2-AG could serve as substrate for lipoxygenases and cyclooxygenases that metabolize polyunsaturated fatty acids to potent bioactive molecules.
The objective of present study was to investigate the immunomodulatory effects of cannabinoids on murine J774 macrophages. D9-THC (1-10mM) and AEA (3-30mM) were shown to diminish LPS-induced NO and IL-6 production in a concentration-dependent manner. 2-AG inhibited the production of IL-6 but had little increased effect on NO production. In parallel, D9-THC, AEA and IMMA (a ligand for CB receptors) could inhibit iNOS induction in response to LPS, whereas 2-AG could not. D9-THC also could inhibit LPS-induced PGE2 production and COX-2 induction. Besides, D9-THC, AEA and 2-AG could inhibit LPS-induced IL-6 expression. Furthermore, in order to understand the possible involvement of ligand metabolites on these events, we explore the effects of PGE2-ethanolamide, arachidonic acid (AA) and PGE2, which might be the metabolites of AEA and 2-AG. We found that PGE2-ethanolamide, the reported AEA metabolite, neither influenced the LPS-induced NO nor IL-6 production. On the other hand, AA and PGE2 could increase NO production, but inhibit IL-6 production. COX inhibitors could reverse the effects of AA, suggesting the involvement of COX metabolites in AA response, while they cannot prevent the inhibitory effects of AEA and 2-AG. In addition, AM404, an AEA uptake inhibitor, slightly inhibited LPS-induced NO and IL-6 release, while potentiated the inhibition by AEA.
To characterize CB2 expression in J774 macrophages, we found that only a weak CB2 mRNA expressed and that cannabinoids potentiate cAMP formation rather than inhibition, as predicted from the Gi-coupled CB2 receptor signaling. The CB2 antagonist, SR144528, could not antagonize the inhibitory effects of cannabinoids. Electrophoretic mobility shift assay shows the inhibitory effects of D9-THC, AEA and 2-AG on LPS-induced activation of AP-1 and NF-IL-6. D9-THC could also inhibit LPS-induced NF-kB activation, but AEA and 2-AG could not. All these results suggest that the cannabinoids, D9-THC, AEA and 2-AG, elicit the inhibitory effects on LPS-stimulated macrophages possibly via a cannabinoid receptor -independent pathway.
Part-II
The tumor necrosis factor receptor (TNFR) superfamily consists of approximately 10 characterized members of human proteins. A newly identified member, TR2 (or herpes virus entry mediator) from a search of an expressed sequence tag data base is encoded by a single gene, which maps to chromosome 1p36.22-36.3, and the TR2 open reading frame sequence encodes a 283-amino acid single transmembrane protein (30 kDa). TR2 is expressed mainly in hemopoietic tissues, particularly in lymphoid tissues such as spleen and thymus, and is involved in T cell activation. In this study, we have successfully expressed TR2-ECD-Fc fusion protein and generated seven monoclonal antibodies (4A12, 4D10, 3E11, 4D12, 4B12, 5F6 and 6A11). One antibody is IgG2a isotype and the others are IgG1 type. TR2 mRNAs, as detected by RT-PCR, are normaly expressed in human T-cell line CEM, B-cell line Ramos, peripheral blood mononuclear cells (PBMC), leukocyte cell line HL-60 and endothelial cell line ECV. TR2 mRNA expression could be induced by various stimuli in T-cell line CEM, monocyte cell line U937 leukocyte, cell line HL-60, endothelial cell line ECV and pulmonary A549 epithelial cells. ECV cells treated with IL-1b (10 ng/ml) for 8 hr and A549 cells treated with IFN-g (100 U/ml) for 8hr expressed greater amount of TR2 mRNA. In parallel, the immunostaining of TR2 in both cell lines was increased after cytokine stimulation. In conclusion, the antibodies for TR2 are useful tools to understand the role of TR2 in host immune response and to detect the presence of soluble TR2 during various inflammatory diseases.

第一部分:
中文摘要……………………………………………………………..1
英文摘要……………………………………………………………..3
緒言…………………………………………………………………..5
材料及方法………………………………………………………….17
結果………………………………………………………………….27
討論………………………………………………………………….36
圖表………………………………………………………………….43
參考文獻……………………………………………………………65
第二部分:
中文摘要…………………………………………………………….80
英文摘要…………………………………………………………….81
緒言………………………………………………………………….82
材料及方法………………………………………………………….86
結果………………………………………………………………….96
討論………………………………………………………………...100
圖表………………………………………………………………...104
參考文獻…………………………………………………………...117

Part-I
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