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研究生:陳盈方
研究生(外文):Yin-Fang Chen
論文名稱:樟芝免疫調節蛋白活化巨噬細胞分子機制之探討
論文名稱(外文):Studies on the Molecular Mechanism of Macrophages Activation by Immunomodulatory Protein ACA1 from Taiwanofungus camphoratus
指導教授:許輔許輔引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:園藝學研究所
學門:農業科學學門
學類:園藝學類
論文出版年:2005
畢業學年度:93
語文別:英文
論文頁數:121
中文關鍵詞:樟芝免疫調節蛋白 ACA1免疫調節分子機制
外文關鍵詞:ACA1Immunomodulatorymolecular mechanism
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樟芝 (Taiwanofungus camphoratus) 為台灣傳統極具發展潛力之藥用真菌,並具有免疫調節及抗腫瘤之活性。樟芝免疫調節蛋白 ACA1 為醣蛋白,其 cDNA已成功選殖並構築於 pET-32a 表現載體,以大腸桿菌為宿主進行表現,可得重組樟芝免疫調節蛋白 rACA1。本論文之研究目的為探討 rACA1 活化巨噬細胞的分子機制。首先我們發現 rACA1 可誘導巨噬細胞株 RAW 264.7 和小鼠腹腔巨噬細胞產生一氧化氮和腫瘤壞死因子 (TNF-alpha)。為了進一步探討細胞膜上 receptor 是否參與 rACA1 活化巨噬細胞產生腫瘤壞死因子,我們利用正常小鼠 (C57BL/6) 和TLR4 免疫缺陷鼠 (C57BL/10ScN) 之腹腔巨噬細胞進行試驗,結果顯示 rACA1 可活化正常小鼠 (TLR4+/+) 及免疫缺陷鼠 (TLR4-/-) 之腹腔巨噬細胞。另一方面,利用小鼠 TLR2 單株抗體進行中和試驗,則發現 rACA1 誘導巨噬細胞產生腫瘤壞死因子之作用,會顯著受到 anti-TLR2 抗體中和而下降。此外,我們轉染 dominant-negative MyD88載體至 RAW 264.7 中表現,亦發現 rACA1 活化巨噬細胞之訊息傳導路徑,會受到 dominant-negative MyD88 之阻礙,無法活化巨噬細胞產生腫瘤壞死因子。綜合上述,我們推測 rACA1 活化巨噬細胞至少會經由 TLR2/MyD88 訊息傳導路徑。
Taiwanofungus camphoratus, a traditional and potential medicinal mushroom in Taiwan, is known to have immunomodulatory and antitumor activities. ACA1, which is a glycoprotein obtained from T. camphoratus and is capable to activate mouse macrophages and splenocytes, has been cloned into pET32 vector and successfully expressed in E. coli to obtain normal protein, rACA1. Here, we investigate the bioactivity of rACA1 on murine macrophages and the membrane receptor and the intracellular signaling pathway responsible for the activation of macrophages by rACA1. rACA1 is demonstrated to the production of nitric oxide (NO) and TNF-alpha both in RAW 264.7 cells and peritoneal macrophages from normal mice. To investigate the membrane receptor involved in the activation of TNF-alpha production, we further examine the effects of rACA1 on the production of TNF-alpha in mouse peritoneal macrophages isolated from wild type C57BL/6 and from functional Toll-like receptor 4 (TLR4)-deficient C57BL/10ScN mice. The results show that rACA1 induces TNF-alpha production by macrophages isolated from both C57BL/6 and C57BL/10ScN mice. However, anti-TLR2 mAb is demonstrated to block the activation of rACA1 toward peritoneal cells, which indicates that TLR2 is highly involved in rACA1 signaling. Further we examine the effect of rACA1 on the activation of an adapter protein, MyD88, which is a downstream mediator of TLR2. rACA1 of macrophages activation was obstructed by dominant-negative MyD88 to produce TNF-alpha. Taken together, these results suggest that rACA1-mediated induction of TNF-alpha production in macrophages is mediated, at least in part, by TLR2/MyD88 signaling pathway.
中文摘要 1
Abstract 2
Chapter 1 Preface 3
Chapter 2 Introduction 5
2.1 Introduction of Taiwanofungus camphoratus 5
2.1.1 Morphology, component and bioactivity of Taiwanofungus camphoratus 5
2.1.2 Immunomodulatory protein ACAs and its activity 13
2.2 Mechanism of pathogen activating innate immunity 17
2.2.1 Physiological function of macrophages 17
2.2.2 The relationship between Toll-like receptor family and macrophage activation 19
2.2.3 Innate recognition of lipopolysaccharide by Toll-like receptor 4-MD-2 22
2.2.4 MyD88 dependent and independent signaling pathway 24
2.3 Recognition of fungal pathogens by Toll-like receptors 32
2.4 Objectives and strategy of this study 34
Chapter 3 Materials and Methods 37
3.1 Materials 37
3.1.1 Reagents 37
3.1.2 Systems and Kits 38
3.1.3 Equipments 39
3.1.4 Animals 41
3.2 Methods 41
3.2.1 Sample preparation 41
3.2.1.1 Preparation of recombinant ACA1 (rACA1) 41
3.2.1.2 Bioactivity of rACA1 41
3.2.1.3 LPS contamination of ACA1 45
3.2.2 Detection of TLRs-dependent signaling pathway by TNF-alpha secretion 48
3.2.2.1 Interaction between ACA1 and macrophages 48
3.2.2.2 Determination of TLR4-dependent pathway 51
3.2.2.3 Neutralization test of alphaTLR2 monoclonal antibody 53
3.2.3 Establishment of dominant negative MyD88 transient transfection system 55
3.2.3.1 Cell culture 55
3.2.3.2 Preparation of murine macrophage cDNA 55
3.2.3.3 Construction of dominant negative MyD88 57
3.2.3.4 Transient transfection 61
3.2.3.5 Bioassay 63
3.2.3.6 Reporter assay 63
3.2.4 Statistical analysis 63
Chapter 4 Results 65
4.1 Sample preparation 65
4.1.1 Preparation of recombinant ACA1 (rACA1) 66
4.1.1.1 Bioactivity of rACA1 67
(1) Effect of rACA1 on macrophage-like RAW 264.7 65
(2) Effect of rACA1 on Balb/C peritoneal cells 66
4.1.1.2 Exclusion of LPS contamination of rACA1 68
(1) LAL assay 68
(2) Autocalved rACA1 activity 69
4.2 Involvement of rACA1 on TLRs-dependent signaling pathway 71
4.2.1 Interaction between ACA1 and macrophages 71
4.2.2 Investigation of TLR4-dependent pathway 72
4.2.3 Involvement of TLR2 in rACA1 activating macrophages 74
4.3 Involvement of MyD88 in rACA1 activating macrophages 76
4.3.1 Construction of dominant negative MyD88 76
4.3.2 Transient transfection of RAW 264.7 macrophages 77
Chapter 5 Discussion and Conclusion 80
5.1 Discussion 80
5.2 Conclusion 86
References 87
Figures and Appendix 97
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