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研究生： 朱敬儀
Ching-yi Chu
論文名稱： P388D1老鼠巨噬細胞分泌胞殺素誘導漿細胞瘤自戕現象之研究
Induction of apoptosis in plasmacytoma cells by a cytotoxic factor secreted by P388D1 mouse macrophage-like cell line
指導教授： 曾哲明
Tseng, Jer-Ming
學位類別： 博士
Doctor
系所名稱： 生命科學系
Department of Life Science
畢業學年度： 87
語文別： 中文
中文關鍵詞： 巨噬細胞 、漿細胞瘤胞殺素 、自戕
英文關鍵詞： Macrophage, PCF(plasmacytoma cytotoxic factor), Apoptosis, Fas, FasL, bCL-2, Caspase 3, PARP
論文種類： 學術論文
相關次數： 點閱：368  下載：7 
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    • 巨噬細胞的重要功能之一為對腫瘤細胞的胞殺作用。本研究發現老鼠巨噬細胞P388D1細胞株培養基上清液對MOPC-315漿細胞瘤細胞株具有胞殺作用， 對MPC-11也有胞殺作用， 但對J558細胞株卻完全沒有胞殺作用。本實驗先以40~60%飽和度之硫酸銨沉澱胞殺活性物質，再利用抗漿細胞瘤胞殺素之單株抗體CB7.C2製備之親和性色層分析管柱，純化漿細胞瘤胞殺素(Plasmacytoma Cytotoxic Factor ; 簡稱PCF)。純化之PCF經SDS-PAGE、Native Gel電泳分析及西方吸漬法鑑定，得知PCF為一由分子量62及103 kDa次單位所組成之蛋白質。其對1x104個MOPC-315細胞的50%胞殺作用為3.11μg/ml 。以TUNEL(Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)分析經PCF處理之MOPC-315細胞，發現細胞有明顯之DNA斷裂現象，為細胞自戕的典型徵兆。由Annexin V-FITC 法測試得知，PCF處理之MOPC-315細胞瘤細胞膜上，磷酯酉先絲氨酸(phosphatidylserine)由內膜移位至外膜，進一步證明其細胞自戕現象。以PI(Propidium iodide)染色，也發現PCF處理之MOPC -315細胞，DNA顯著流失。此細胞自戕現象能被單株抗體CB7.C2所中和，更進一步證實PCF為誘導MOPC-315細胞自戕作用的主要因子。由RT-PCR方法證實 , PCF處理24小時之MOPC-315細胞的Fas mRNA表現量增加10倍, FasL mRNA則呈暫時性增加3.7倍 ; 而與抑制細胞自戕有關的胞內因子Bcl-2 mRNA及蛋白表現量減低 。 由Fas誘導的細胞內傳遞因子CPP32/Caspase 3活性增強 , CPP32的受質PARP﹝poly(ADP-ribose)polymerase﹞斷裂現象增加。顯示PCF誘導細胞自戕的胞內途徑可能與Fas-FasL 自戕路線相似 , 並受到抗自戕基因Bcl-2 的調控。

    Tumoricidal activity is one of the major effector functions of activated macrophages. In this study, the culture supernatant of P388D1 murine macrophage-like cells was found having a cytotoxic effect on Plasmacytoma MOPC-315 and MPC-11, but not on J558 myeloma cells. Large-scaled purification of the plasmacytoma cytotoxic factor （PCF）in the culture supernatant of P388D1 macrophage-like cells was done by ammonium sulfate fractionation（40~60% saturation）, followed by immunoaffinity chromatography using anti-PCF monoclonal antibody, CB7.C2. The affinity-purified PCF had 50% cytotoxicity of 3.11 mg/ml for 15104 MOPC-315 cells and composed of two major bands of the estimated molecular weights of 62 & 103KDa on SDS-PAGE gel and a single band on native gel. However , CB7.C2 recognized the single band of 62KDa in Western blotting of the SDS-PAGE gel and a single band in Western blotting of native gel, suggesting that the native form of PCF could be composed of 62 & 103 kDa subunits. Data from TUNEL〔terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphasphate（dUTP）nick-end-labeling〕indicated that a significant amount of DNA fragmentation was induced in PCF-treated MOPC-315 cells. Using Annexin V staining technique, the PCF-induced apoptosis can be confirmed by phosphatidylserine redistribution on the plasma membrane of PCF-treated cells. Furthermore, the result of PI permeability assay suggested that PCF-mediated apoptosis involved DNA loss in apoptotic cells and was shown dose-dependent, time-dependent ,which can be neutralized by CB7-C2 monoclonal antibody. Measuring the expression of Fas , FasL and Bcl-2 mRNA level by RT-PCR showed that the expression of Fas and FasL mRNA were increased, but the expression of Bcl-2 mRNA was suppressed in PCF-treated MOPC-315 cells. Analyzing by immunoblotting, the expression of Bcl-2 protein was also reduced. CPP32/caspase 3 activity increased in the early stage and PARP[poly（ADP-ribose） polymerase ] was cleavaged in 36 hour after the PCF-treatment. Taken together, these observations indicated that a new protein which composed of 62 & 103 kDa subunits was secreted by P388D1 macrophage-like cells. This protein showed its apoptotic effect on MOPC-315 plasmacytoma cells via the signal pathway of Fas-FasL system that was regulated by Bcl-2.

    中文摘要 ..................................................................................................................................................................... Ⅰ 英文摘要 ..................................................................................................................................................................... Ⅱ 圖 次 ............................................................................................................................................................................ Ⅳ 表 次 ............................................................................................................................................................................. Ⅶ 縮寫字對照表 ............................................................................................................................................................... Ⅷ 第壹章 導論 ..................................................................................................................................................................... 1 一、文獻探討 ........................................................................................................................................................... 2 二、研究動機與目的 ................................................................................................................................................6 三、實驗流程圖 ..................................................................................................................................................... 8 第貳章 P388D1老鼠巨噬細胞分泌胞殺素 誘導MOPC-315漿細胞瘤自戕 .......................................................... 9 中文摘要 ............................................................................................................................................................... 10 壹、緒論 ............................................................................................................................................................... 11 貳、實驗材料 ....................................................................................................................................................... . 13 一、細胞株(cell lines)及融合瘤 (hybridoma) ...................................................................................................... 13 二、實驗動物 ........................................................................................................................................................ 13 三、細胞培養液及其配方 .................................................................................................................................. 14 1.Dulbecco's Modified Eagle Medium (DMEM) 培養液 .............................................................................. . 14 2.無血清DMEM培養液 .................................................................................................................................. 14 3.RPMI-1640培養液 ........................................................................................................................................ 14 4.無血清RPMI-1640培養液 ............................................................................................................................ 14 四、試劑及其配方 ................................................................................................................................................ 14 1.Phosphate Buffered Saline(PBS) ....................................................................................................................... 15 2.純化IgG單株抗體試劑 ................................................................................................................................. 15 3.製備免疫親和性色層分析 管柱試劑 ........................................................................................................ 15 4.免疫親和性色層分析管柱純化漿細胞瘤胞殺素(PCF)試劑 ................................................................. 15 5.蛋白質微量定量分析試劑 ........................................................................................................................... 16 6.SDS PAGE試劑 ................................................................................................................................................ 16 7.自然膠體電泳 .................................................................................................................................................. 16 8.銀染法試劑 ....................................................................................................................................................... 17 9.西方吸漬法試劑 .............................................................................................................................................. 17 10.MTT assay試劑 .................................................................................................................................................. 18 11.TNF-α定量測定試劑 ..................................................................................................................................... 18 12.蛋白質微定序樣品製備試劑 ........................................................................................................................ 19 五、一般化學藥品 .................................................................................................................................................... 20 六、儀器設備 ..............................................................................................................................................................20 參、實驗方法 ................................................................................................................................................................22 第一部分: 漿細胞瘤胞殺素(Plasmacytoma Cytotoxic Factor) 的純化與鑑別 ......................................................22 一、CB7.C2單株抗體親和性 管柱的備製 ....................................................................................................... 22 1.CB7.C2單株抗體之備製 ............................................................................................................................. 22 2.CB7.C2單株抗體之純化 ............................................................................................................................ 22 3.CB7.C2單株抗體親和性膠柱之備製 ....................................................................................................... 23 二、PCF之純化 ................................................................................................................................................ ....23 1.P388D1巨噬細胞株培養液之收集 ....................................................................................................... .. 23 2.硫酸銨鹽析 ................................................................................................................................................. 24 3.CB7.C2單株抗體親和性膠柱純化漿細胞瘤胞殺素 ............................................................................ 24 4.PCF的濃縮 ................................................................................................................................................... 24 三、PCF之定量及鑑別 ........................................................................................................................................ 24 1.BIO-RAD微量蛋白質定量法......................................................................................................................24 2.蛋白質SDS-PAGE電泳分析 ...................................................................................................................... 24 A.備製10%聚丙醯電泳膠(Separating gel)及4%stacking 膠體 ................................................................. 25 B.電泳 .............................................................................................................................................................25 3.自然膠片(Native gel)電泳分析 .................................................................................................................. .25 A. 備製7.5%聚丙醯電泳膠(Separating gel)及4%Stacking 膠體 ........................................................... . 25 B.電泳 .......................................................................................................................................................... 25 4.銀染法(Silver Stain) ...................................................................................................................................... 25 5.西方吸漬法(Western Blotting) ..................................................................................................................... 26 6.蛋白質微定序(Micro-Sequencing) ............................................................................................................... 26 四、PCF對MOPC-315，J558，MPC-11等腫瘤細胞株胞殺作用的影響: MTT試驗 ........................................................................................................................................................... 27 五、TNF-α對MOPC-315及L929細胞株胞殺作用之比較: MTT試驗 ........................................................................................................................................................... 27 六、40~60%飽和硫酸銨鹽析的P388D1細胞株培養液中TNF-α含量之測定: 酵素免疫分析法(Enzyme-linked Immunoassay ;ELISA) .............................................................................. 28 第二部分 PCF誘導MOPC-315漿細胞瘤 細胞自戕 .................................................................................................29 一、TUNEL試驗 ...................................................................................................................................................... 29 二、Annexin V-FITC試驗 ...................................................................................................................................... 30 肆、結果 ......................................................................................................................................................................... 31 第一部份 PCF的純化、鑑別及其胞殺作用........................................................................................................... 31 1.P388D1培養液以硫酸銨鹽鹽析處理 ........................................................................................................ 31 2.部份純化之PCF對MOPC-315，MPC-11，J558等漿細胞瘤細胞株胞殺作用的影響........................31 3.不同濃度硫酸銨鹽析之P388D1培養液對MOPC-315漿細胞瘤細胞株胞殺作用之影響 ................ 31 4.純化PCF對MOPC-315漿細胞瘤細胞株胞殺作用及CB7.C2單株抗體中和試驗之影響................... 32 5.TNF-α對MOPC-315及L929細胞株胞殺作用之比較...............................................................................32 6.CB7.C2單株抗體親和性色層分析法純化PCF.......................................................................................... 33 7.PCF之N-端氨基酸微定序 ............................................................................................................................33 第二部份 PCF誘發MOPC-315 漿細胞瘤細胞株自戕........................................................................................... 34 Ⅰ. TUNEL試驗................................................................................................................................................... 34 Ⅱ. Annexin V-FITC試驗..................................................................................................................................... 35 Ⅲ. PCF誘發MOPC-315漿細胞瘤細胞株自戕，胞內DNA含量之變化................................................... 36 伍、討論.......................................................................................................................................................................... 37 第參章 PCF誘導MOPC-315漿細胞瘤細胞 自戕的細胞內傳訊機..............................................................................41 中文摘要......................................................................................................................................................................... 42 壹、緒論..........................................................................................................................................................................43 貳、實驗材料................................................................................................................................................................ 51 一、細胞株(cell lines)及融合瘤(hybridoma)........................................................................................................ 51 二、實驗動物......................................................................................................................................................... 51 　　　 三、細胞培養液及其配方...................................................................................................................................... 51 1.Dulbecco's Modified Eagle Medium （DMEM）培養液............................................................................. 51 2.無血清DMEM培養液................................................................................................................................... 51 3.RPMI-1640培養液..........................................................................................................................................51 4.無血清RPMI-1640培養液............................................................................................................................ 51 四、試劑及其配方..................................................................................................................................................51 1.Phosphate Buffered Saline (PBS）.................................................................................................................. 51 2.純化IgG單株抗體試劑................................................................................................................................. 51 3.RT-PCR試驗....................................................................................................................................................51 4.Bcl-2免疫吸漬法（Immunoblotting）試劑................................................................................................ 54 5.ApoAlertTM CPP32/Caspase-3 Assay Kit .................................................................................................... 55 6.PARP 免疫轉漬法（Immunoblotting）試劑............................................................................................. 56 五、儀器設備........................................................................................................................................................ 57 參、實驗方法................................................................................................................................................................ 59 一、抗漿細胞瘤胞殺素單株抗體CB7.C2的製備及純化.............................................................................. 59 1.抗漿細胞瘤胞殺素單株抗體CB7.C2之製備......................................................................................... 59 2.抗漿細胞瘤胞殺素單株抗體CB7.C2之純化..........................................................................................59 二、漿細胞瘤胞殺素（PCF）之收集及硫酸銨鹽析.................................................................................... 59 1.P388D1細胞株培養液之收集................................................................................................................... 59 2.硫酸銨鹽析 ................................................................................................................................................. 59 3. BIO-RAD微量蛋白質定量法................................................................................................................... 59 三、Fas、FasL、Bcl-2及β2m mRNA之RT-PCR分析 .................................................................................... 59 1.MOPC-315細胞株之處理........................................................................................................................... 59 A.Fas之分析................................................................................................................................................ 60 B.FasL之分析...............................................................................................................................................60 C.Bcl-2之分析 ............................................................................................................................................ 60　　　　 2.Total RNA的萃取........................................................................................................................................ 60 3.單股cDNA之合成 .......................................................................................................................................62 4.PCR分析....................................................................................................................................................... 62 A.Fas之PCR分析 ....................................................................................................................................... 62 B.FasL之PCR分析...................................................................................................................................... 62 C.Bcl-2之PCF分析 ......................................................................................................................................63 D.β2m之PCR 分析....................................................................................................................................63 5.電泳分析....................................................................................................................................................... 63 四、Bcl-2免疫吸漬法（Immunoblotting）分析................................................................................................ 64 1.PCF對MOPC-315細胞株Bcl-2表現之影響 ..............................................................................................64 2.中和試驗 ..................................................................................................................................................... .64 五、CPP32 /Caspase 3酵素活性分析................................................................................................................. .65 1.PCF對MOPC-315細胞株CPP32/Caspase 3酵素活性之影響 ..................................................................65 2.中和試驗....................................................................................................................................................... 65 3.抑制作用....................................................................................................................................................... 65 4.CPP32/Caspase 3酵素作用的 人工產物pNA定量分析.......................................................................... 66 六、PARP免疫吸漬法（Immunoblotting）........................................................................................................66 PCF對MOPC-315細胞株PARP裂解之影響..............................................................................................66 肆、結果 ....................................................................................................................................................................... 68 一、Fas mRNA 分析............................................................................................................................................. 68 二、FasL mRNA 分析........................................................................................................................................... 68 三、Bcl-2 mRNA 分析.......................................................................................................................................... 69 四、PCF對MOPC-315漿細胞瘤細胞Bcl-2蛋白表現的影響.......................................................................... 69 五、PCF對MOPC-315漿細胞瘤細胞CPP32/Caspase-3酵素活性的影響 ..................................................... 70 六、PCF對MOPC-315漿細胞瘤細胞PARP裂解的影響................................................................................. 70 伍、討論 ....................................................................................................................................................................... 72 總論......................................................................................................................................................................................78 參考資料............................................................................................................................................................................ 80 圖表說明 ...........................................................................................................................................................................111 附錄 .................................................................................................................................................................................. 139 附錄一　CPP32/Caspase 3酵素作用的人工產物 pNA定量分析標準曲線圖 ...................................................139

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