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系統識別號 U0026-1007201214354100
論文名稱(中文) EGF receptor pathway substrate No.8 藉由增加TLR4-MyD88交互作用而促進內毒素誘導巨噬細胞進行吞噬作用
論文名稱(英文) EGF receptor pathway substrate No.8 facilitates phagocytosis by increasing TLR4-MyD88 interaction in LPS-stimulated macrophages
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 100
學期 2
出版年 101
研究生(中文) 陳彥任
研究生(英文) Yen-Jen Chen
學號 s58941222
學位類別 博士
語文別 英文
論文頁數 85頁
口試委員 指導教授-呂增宏
口試委員-賴明德
口試委員-劉校生
口試委員-戴明泓
口試委員-陳鴻震
中文關鍵字 Eps8  Src  Toll-like receptor 4  巨噬細胞  吞噬作用  內毒素 
英文關鍵字 Eps8  Src  Toll-like receptor 4  macrophage  phagocytosis  Lipopolysaccharide 
學科別分類
中文摘要 巨噬細胞在人體的防禦系統,包括先天性免疫及適應性免疫反應中扮演重要的角色。當人體受到病原菌感染時,會引起發炎反應,同時會活化巨噬細胞分泌活性氮以及釋放許多細胞激素,並且造成細胞型態改變,促進細胞移動以及細菌的吞噬作用。目前研究指出,在內毒素刺激下,主要是活化Toll-like receptor 4而提升巨噬細胞吞噬細菌的能力來幫助細菌的清除。然而,目前對於其作用機轉則不清楚。在本篇文章中,我們發現LPS誘導巨噬細胞內Src蛋白質的表現量增加是TLR4和MyD88-dependent,當細胞大量表現src siRNA時,則會降低內毒素所誘導的吞噬作用,然而在送入siRNA-resistant Src之後,吞噬作用則有回復的情形。有趣的是,我們發現Eps8,為Src的受質之一,在內毒素刺激下,也會促進其蛋白質的表達,將細胞內Eps8 knockdown或大量表達PH-truncated Eps8 (i.e. 261-p97Eps8) 時,細胞的吞噬能力會有顯著的下降。此外,我們也發現Eps8和TLR4會形成複合物而共同存在於細胞質以及phagosome中。當細胞表現eps8 siRNA 或261-p97Eps8時,則會破壞Eps8-TLR4複合物的形成而抑制內毒素所誘導TLR4和MyD88的結合,並且伴隨著抑制細胞內Src, FAK以及p38 MAPK的活性。最後,我們發現抑制Eps8 蛋白質的表現會抑制巨噬細胞清除細菌的能力。 因此,綜合以上結果,我們認為在內毒素的刺激下,Eps8會藉由增加TLR4和MyD88的結合而促進巨噬細胞進行吞噬作用。
英文摘要 Macrophage-mediated phagocytosis and subsequent degradation of pathogens by macrophages play a pivotal role in host innate immune responses to microbial infection. Recent studies have shown that Toll-like receptors (TLRs) play an important role in promoting the clearance of bacteria by up-regulating the phagocytic activity of macrophages under LPS stimulation. However, the underlying mechanism is not well defined. In the present study, we demonstrated the induction of Src in LPS-treated macrophages was TLR4- and MyD88-dependent and attenuation of Src by src-specific siRNA reduced LPS-promoted phagocytosis. And reintroduction of siRNA-resistant Src could restore the defect. Interestingly, we observed Eps8 was also up-regulated under LPS stimulation in a Src-dependent manner and Eps8 knockdown or overexpression of PH-truncated Eps8 (i.e. 261-p97Eps8) decreased LPS-mediated macrophage phagocytosis. In addition, confocal microscopy indicated Eps8 and TLR4 were colocolized in the cytosol and at the phagosome in RAW264.7 cells. Consistently, both Eps8 and TLR4 immunoprecipitated together from the lysates of RAW264.7 cells with or without LPS stimulation. This Eps8-TLR4 complex formation was required for LPS-induced TLR4-MyD88 interaction and the following activation of Src, FAK, and p38 MAPK. Importantly, Eps8 knockdown reduced bacterium killing ability of macrophages. Thus, Eps8 is a key protein regulating LPS-stimulated TLR4-MyD88 interaction and the following macrophage phagocytosis.
論文目次 中文摘要……………………………………………………………Ⅰ
ABSTRACT……………………………………………………………Ⅱ
致謝…………………………………………………………………Ⅲ
CONTENTS……………………………………………………………Ⅴ
FIGURE CONTENTS……………………………………………………Ⅶ
ABBREVIATIONS……………………………………………………..Ⅸ
Ⅰ. Introduction…………………………………………………………1
A. Overviews of infection and the mammalian immune system………………………………1
B. The innate immunity…………………………………………………………………2
a. Toll-like receptors (TLRs)……………………………………………………………………2
1. Structure of TLRs and their ligands………………………………………………………………….2
2. TLRs signaling pathways…………………………………………………………………3
b. RIG-I-like receptors (RLRs)……………………………………………………………………4
1. Structures and ligands of the RLRs family…………………………………………………………4
2. RLRs signaling pathway…………………………………………………………4
c. NOD-like receptors (NLRs)……………………………………………………………5
1. Structures and ligands of the NLRs family………………………………………………………5
2. The NOD1 and NOD2 signaling pathways……………………………………………………5
C. Phagocytosis………………………………………………5
a. The steps of phagocytosis in phagocytes……………………………………………………5
b. The role of TLRs in phagocytosis……………………………………………………6
D. Eps8 (EGF receptor pathway substrate No. 8)……………………………………………………7
a. Structural features of Eps8…………………………………………………………………7
b. The role of Eps8 in tumorigenesis……………………………………………………8
Ⅱ. Specific aims……………………………………………………………10
Ⅲ. Materials and Experimental procedures……………………………11
1. Reagents and antibodies……………………………………………………11
2. Bacterial
strain…………………………………………………………11
3. Animals……………………………………………………………11
4. Cell culture and collection of PEMs or BMDMs…………………………………………..…………11
5. Generation of macrophages expressing nonspecific siRNA, src siRNA, fak siRNA, luciferase siRNA, eps8 siRNA, myd88 siRNA, or 261-p97Eps8………………………….………12
6. Lysate preparation and immunoblot analysis……………………………………………….………….13
7. Phagocytosis…………………………………………………13
8. Confocal microscopy……………………………………………………………13
9. Bacterial killing assay…………………………………………………………14
10. Statistical analysis………………………………………………………………14
Ⅳ. Results…………………………………………………………15
1. LPS-induced Src is TLR4-dependent and plays important roles in regulating macrophage phagocytosis…………………………………………………………15
2. Concomitant up-regulation of p97Eps8 and Src in LPS-stimulated macrophages……….16
3. Attenuation of Eps8 reduces LPS-stimulated Src Pi-416, FAK Pi-Y861, actin polymerization, and phagocytosis…………………………………………………………16
4. FAK is required for LPS-induced Eps8 and macrophage phagocytosis…………….……..17
5. Eps8 is required for LPS-induced TLR4-MyD88 complex formation in macrophages…………………………………………………………18
6. PH-truncated 261-p97Eps8 inhibits LPS-induced TLR4-MyD88 complex formation, Src Pi-Y416, FAK Pi-Y861, and phagocytosis in macrophages……………………………….18
7. Eps8 sustains TLR4-mediated activation of p38 MAPK………………………………….………19
8. Complex formation between Eps8 and FAK in RAW cells………………………………………19
9. Eps8 does not regulate LPS-induced PYK2 Pi-Y402 in macrophages……………………..20
10. Attenuation of Eps8, Src, or FAK impairs intracellular killing of E. coli in macrophages……………………………………………………………20
Ⅴ. Conclusion…………………………………………………………...22
Ⅵ. Discussion………………………………………………………………23
Ⅶ. References………………………………………………………………30
Ⅷ. Figures…………………………………………………………………..40
Ⅸ. Appendix………………………………………………………………...65

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