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研究生:張永祺
研究生(外文):Yung-Chi Chang
論文名稱:第三號誘餌受體對T細胞及巨噬細胞分化及活化之調控
論文名稱(外文):Modulatory effects of decoy receptor 3 on T cell and macrophage differentiation and activation
指導教授:謝世良
指導教授(外文):Shie-Liang Hsieh
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:微生物暨免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:英文
論文頁數:101
中文關鍵詞:第三號誘餌受體巨噬細胞吞噬作用
外文關鍵詞:DcR3macrophagephagocytosis
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活化腫瘤壞死因子受體 (TNFR) 家族的成員會調控許多生物功能,包括細胞增生、分化、死亡、以及細胞激素 (cytokine) 的分泌。最近一個新被發現的腫瘤壞死因子受體成員,第三號誘餌受體 (decoy receptor 3),被報導可以作為FasL和LIGHT的可溶性同源受體,以中和它們的毒性 (cytotoxicity)。在我們之前的發現指出 [60],第三號誘餌受體不但可以在癌症病人的血清中被偵測到,而且它還可以染上單核細胞 (monocytes) 和B淋巴球 (B lymphocytes) 上的特定分子。所以我們對第三號誘餌受體是否除了中和FasL和LIGHT的毒性外,還具有其他調控免疫系統的能力很有興趣。為了回答這個問題,人類CD4+ T淋巴球和自單核細胞細胞分化成的巨噬細胞 (macrophage) 被用來測試我們的假設。我們發現,第三號誘餌受體並不具有明顯改變正常人T淋巴球增生的能力,但是它對於巨噬細胞的分化和活化則有廣泛的影響。巨噬細胞上的表面抗原CD86表現量在第三號誘餌受體處理後會被調節上升,而CD14、CD16、CD80、HLA-DR的表現量則會下降。此外,除了巨噬細胞的吞噬 (phagocytosis) 能力幾乎完全被第三號誘餌受體所抑制外,巨噬細胞在內毒素 (LPS) 刺激後,分泌的IL-1b、IL-6、TNF-a,和一氧化氮合成脢 (iNOS) 的能力也顯著的被抑制。但是在另一方面,雖然第三號誘餌受體也會抑制凋零死亡 (apoptosis) 細胞被巨噬細胞清除的過程,可是對於伴隨吞噬作而產生的免疫抑制激素 (immune-suppressive cytokine) 的分泌,例如TGF-b1,卻不會完全被抑制。我們所觀察到這些第三號誘餌受體對巨噬細胞多樣化的影響,並不是單純只是經由中和FasL和LIGHT的毒性可達成的。我們認為,第三號受餌誘導是腫瘤所分泌的一個有效分子 (effective molecule),除了可以中和FasL和LIGHT的毒性外,它本身還可以有效而廣泛的抑制免疫系統活化,已達成腫瘤逃避免疫系統攻擊的目的。

Activation of members of TNFR superfamily are involved in the regulation of pleiotropic biological processes such as cell proliferation, differentiation, apoptosis, cytokine production. Recently, a novel member of the TNFR superfamily, DcR3, was identified as soluble cognate receptor for LIGHT and Fas ligand (FasL). In our previous study [60], we found that DcR3 could be detected in the serum, and bind to the surface of monocytes, B cells, but not T cells. Therefore, we are interested to understand whether it has any modulatory effects on host immune system, in addition to its neutralizing effect of FasL and LIGHT. To address this question, human CD4+ T cells and CD14+ monocyte-derived macrophages were used to test our hypothesis. We found that DcR3 did not have obvious effects to regulate T cell proliferation of normal individuals, however, DcR3 had profound effects on macrophage differentiation and activation. The expression of CD86 on macrophages was up-regulated, while CD14, CD16, CD80 and HLA-DR were down-regulated by DcR3. Moreover, phagocytic activity of macrophages was almost completely inhibited by DcR3, and DcR3-treated macrophages were also impaired to secrete IL-1b, IL-6, TNF-a and synthesize iNOS in response to LPS stimulation. In contrast to the inflammatory reactions, the secretion of immune-suppressive cytokine, such as TGF-b1, was not completely suppressed by DcR3, although DcR3 inhibited the engulfment of apoptotic cells by macrophages. The diverse regulatory effects of DcR3 were not via neutralizing FasL and LIGHT, and this observation raised the argument that the DcR3 should not be simply regarded as soluble receptor, but as an effective molecule to modulate host immunity and protect tumor cells from attack of host immune system.

中文摘要1
Abstract2
Introduction3
1.Tumor Necrosis Factor and TNF Receptor Superfamilies3
2.Dceoy Receptor 3 and Its Ligands5
3.Macrophages8
4.Purpose of Experiment13
Materials and Methods14
A.Materials14
1.Reagents and solutions14
2.Culture medium20
3.Cell lines21
B.Methods22
1.Bacterial Culture22
2.Preparation of DNA22
3.Cloning Techniques24
4.Bacterial Transformation25
5.Polymerase Chain Reaction26
6.Electrophoresis27
7.Western blotting28
8.Immunoprecipation29
9.Purification of Recombinant Proteins30
10.Cell Culture30
11.Proliferation Assay32
12.Flow Cytometry Analysis34
13.ELISA for Cytokine Analysis36
14.Macrophage Phagocytosis Aaasy37
15.RT-PCR39
Results42
1.Effects of DcR3 on T cells42
2.Effects of DcR3 on CD14+ Monocytes and Macrophages45
3.Establishment of In Vivo Model System to Study DcR3 Functions52
Conclusion and Discussion55
References60
Figures69
Appendix89

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