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系統識別號 U0026-0707201510365400
論文名稱(中文) Eps8/Src路徑在巨噬細胞所調控的先天性免疫能力中所扮演的角色
論文名稱(英文) The role of Eps8/Src axis in macrophage-mediated innate immunity
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 103
學期 2
出版年 104
研究生(中文) 謝銘育
研究生(英文) Ming-Yu Hsieh
學號 S58981078
學位類別 博士
語文別 英文
論文頁數 126頁
口試委員 指導教授-呂增宏
口試委員-劉校生
口試委員-賴明德
口試委員-蔡曜聲
口試委員-洪文俊
口試委員-莊宗顯
中文關鍵字 Src  Toll-like Receptors (TLR)  iNOS  Eps8  細胞激素  巨噬細胞  細胞移行 
英文關鍵字 cytokine  Macrophages  Src  Toll-like Receptors (TLR)  iNOS  Eps8  migration 
學科別分類
中文摘要 在先前的研究中我們已經證明在病原相關分子(PAMPs)活化巨噬細胞的路徑當中,iNOS/Src/FAK是一個通用的路徑。而且Eps8參與在TLR4所誘導的通用路徑當中,促進吞噬作用以及殺菌作用。在第一篇研究中我們發現在聚肌胞苷酸 (polyI:C)刺激巨噬細胞下TLR3 的Y759位置會有早期和晚期兩個階段的磷酸化。 除了短時間的第一階段TLR3 Y759位置的磷酸化,在雙股RNA的刺激後期,我們還發現了第二階段的TLR3 Y759位置的磷酸化,而且與Src的表現量還有IFN-β的產生有關。有趣的是,不論在in vitro或是in vivo實驗中皆發現Src可以磷酸化TLR3 的Y759位置。然而,Src的抑制會破壞晚期TLR3 Y759位置的磷酸化,而且降低IRF3和IRF7的入核量以及IFN-β的產生。重新表現Src則會回復所有因Src被抑制而改變的分子機制。值得注意是,在iNOS缺乏的巨噬細胞中我們也觀察到透過抑制Src的表現,polyI:C所誘導TLR3 的Y759位置磷酸化、IRF3和IRF7的入核以及IFN-β的產生都受到抑制。在巨噬細胞受到LPS的刺激下(LPS,一種TLR4的配體,已知會誘導Src與IFN-β的產生),抑制TLR3的表現會造成Src蛋白的不穩定,降低IRF3和IRF7在核中的表現量以及減少IFN-β的產生。異位表達原始的TLR3會回復Src的活性和ifn-β轉錄能力,但異位表達Y759位置磷酸突變的TLR3則無法回復Src的活性和ifn-β轉錄能力。總括來說,這些結果可以推測在巨噬細胞產生IFN-β的路徑中,iNOS/Src/TLR3 路徑軸是不可或缺的。在第二個研究中,我們觀察到Eps8的表達是受到PAMP誘導並且需要iNOS / Src。當Eps8減少同時會降低Src的活性,並且抑制巨噬細胞的移動能力。值得注意的是,在病原相關分子刺激Src受抑制的巨噬細胞中,異位表達Eps8可以回復部分Src的活性以及細胞移行能力。這些結果表明Eps8會調控TLR4誘導的訊息傳遞並且參與在TLRs刺激巨噬細胞由Src所調控的細胞移行能力中。在第三個研究中,我們發現降低Src的表現量會去抑制NO的產生和細胞激素的分泌;如果將Src 的表達量回復的話,NO的產生和激素的分泌則會有回復的現象。抑制Eps8也會降低LPS所誘導的iNOS的表現以及Src的活性。的確,Eps8會透過NF-κB訊息的活化來調控NO的產生以及TNF-α、IL-1β和IL-6的分泌。總括來說,我們的實驗證據指出Eps8和Src在LPS誘導NF-κB的活性中是不可或缺的,而且對於巨噬細胞所調控的先天免疫系統有很大的貢獻。
英文摘要 We earlier demonstrated iNOS/Src/FAK axis as a general mechanism of macrophage motility in response to various pathogen-associated molecular patterns (PAMPs) and Eps8 took part in TLR4-mediated signal transduction, enhancing phagocytosis and bacterial killing effect. In the first study, we found that dsRNA stimulation induces biphasic TLR3 Tyr-759 phosphorylation in macrophages. In addition to the immediate TLR3 Tyr-759 phosphorylation, we identified a second wave of Tyr-759 phosphorylation accompanied by an increase of both Src and ifn-β transcription in the later phase of dsRNA stimulation. Interestingly, Src phosphorylated TLR3 Tyr-759 in vitro and in vivo. However, knockdown of Src abolished the late phase of TLR3 Tyr-759 phosphorylation and decreased the nuclear accumulation of interferon regulatory factors 3 and 7 (IRF3 and -7) and IFN-β production. Reintroduction of Src restored all of these molecular changes. Notably, via down-regulation of Src, dsRNA-elicited TLR3 Tyr-759 phosphorylation, the nuclear accumulation of IRF3/IRF7, and IFN-β generation were inhibited in inducible nitric-oxide synthase (iNOS)-null macrophages. TLR3 knockdown destabilized Src and reduced the nuclear level of IRF3/IRF7 and IFN-β production in macrophages exposed to LPS (a TLR4 ligand known to induce Src and IFN-β expression). Ectopic expression of wild type TLR3, but not its 759-phenylalanine mutant, restored Src activity and ifn-β transcription. Taken together, these results suggested an essential role of the iNOS/Src/ TLR3 axis in IFN-β production in macrophages. In the second study, we observed that expression of Eps8 was PAMP-inducible and iNOS/Src-dependent. Attenuation of Eps8 simultaneously impaired Src activity and suppressed macrophage mobility. Notably, ectopic Eps8 partly restored motility and Src activity in Src-attenuated macrophages exposed to PAMPs. These findings indicated Eps8 modulating TLR4-mediated signal transduction and taking part in Src-mediated cell migration in TLRs-stimulated macrophages. In the third study, we found that Src knockdown impaired LPS-induced NO production and cytokines secretion, which was reverted by ectopically expressed avian Src. Attenuation of Eps8 also reduced LPS-mediated iNOS expression and Src activation. Indeed, via activation of NF-κB signaling, Eps8 affected NO production and the secretion of TNF-α, IL-1β, and IL-6. Taken together, our data indicates that Eps8 and Src are necessary for LPS mediated NF-κB activation and contributes to macrophage-mediated innate immunity.
論文目次 Table of contents
Abstract in Chinese ............. i
Abstract in English ............. iii
Acknowledgements .............. v
List of Figure ............. viii
Abbreviation .............. xii
Chapter Ι. General introduction ........... 1
Immune system .............. 1
Macrophage ............. 1
Toll-like receptor ............. 2
Src ............... 3
Eps8 ................ 4
Specific aims ............. 5
Chapter ΙΙ. The inducible nitric-oxide synthase (iNOS)/Src axis mediates toll-like
receptor 3 tyrosine 759 phosphorylation and enhances its signal transduction, leading
to interferon-β synthesis in macrophages. (Publish in J. Biol. Chem. 2014,
289:9208-9220.) .............. 7
Abstract .............. 7
Introduction ............. 8
Materials and Experimental procedures ......... 11
vii
Results .............. 16
Discussion ............... 24
Chapter ΙΙΙ. Eps8 protein participates in toll-like receptor-engaged macrophage
migration. ............... 48
Abstract .............. 48
Introduction ............. 48
Materials and Experimental procedures ......... 51
Results .............. 56
Discussion ............... 60
Chapter IV. Eps8 protein facilitates cytokine secretion via NF-κB activation in
LPS-stimulated macrophages. .......... 79
Abstract .............. 79
Introduction ............. 79
Materials and Experimental procedures ......... 82
Results .............. 86
Discussion ............... 91
Chapter V. General discussion ........... 110
Chapter VI. General conclusion ......... 112
References .............. 113
Appendix .............. 124
viii
List of Figure
Chapter II.
FIGURE 1. Concomitant increase of Src, iNOS, TLR3 Pi-Y759, nuclear
accumulation of IRF3 and IRF7, and ifn-β transcript in polyI:C-treated macrophages.
............... 29
FIGURE 2. Src interacts with TLR3 and phosphorylates TLR3 Y759. .. 31
FIGURE 3. NO activates Src to phosphorylate TLR3 Y759 and increase the level of
ifn-β transcript. ............ 33
FIGURE 4. Src is important in polyI:C-induced IFN-β secretion in macrophages. 35
FIGURE 5. iNOS participates in Src induction and the IFN-β production in
macrophages stimulated with polyI:C. ........ 36
FIGURE 6. Src is critical in NO-induced IFN-β secretion in macrophages. ... 38
FIGURE 7. iNOS/Src axis is required for polyI:C-mediated nuclear accumulation of
IRF3 and IRF7 in macrophages. ......... 39
FIGURE 8. Src mediates TLR3 Y759 phosphorylation, nuclear accumulation of
IRF3 and IRF7, and the expression of ifn-β in macrophages exposed to LPS. ... 42
FIGURE 9. TLR3 and its Y759-phosphorylation are important for polyI:C- and
LPS-induced IFN-β production in macrophages. ........ 43
FIGURE 10. NO-mediated induction of Src, TLR3 Pi-Y759, and IFN-β is
TRIF-independent in peritoneal macrophages and bone marrow derived macrophages.
............... 45
FIGURE 11. TLR3 participates in v-Src-mediated cell transformation. ... 47
ix
Chapter III.
Figure 12. Concomitant reduction of LPS-mediated mobility and Eps8 induction in
C3H/HeJ macrophages. ........... 63
Figure 13. Reduced Src activation and cell migration in Eps8-attenuated
macrophages exposed to LPS. ........... 65
Figure 14. Eps8 knockdown decreases PGN-, polyI:C-, and CpG-induced
macrophage migration. ............ 67
Figure 15. Eps8 induction is iNOS-dependent in macrophages stimulated with
diverse TLR agonists. ............ 69
Figure 16. Ectopic Eps8 rescues the suppressed migration in Src-attenuated
macrophages stimulated with various TLR agonists. ...... 71
Figure 17. Eps8 participates in TLR-activated filopodia and lamellipodia formation
in macrophages. ............. 74
Figure 18. C-terminal Proline 623/626 is important for Eps8 to associate with Src.76
Figure 19. Proline 623/626 alanine mutation in Eps8 decreases LPS, PGN-, polyI:C-,
and CpG-induced macrophage migration. ........ 78
Chapter IV.
Figure 20. The induction of iNOS, COX2 and Src occurs before the enhancement of
x
Eps8 in LPS-exposed macrophages. ......... 93
Figure 21. Attenuation of Src decreases NO production and cytokines secretion in
LPS-mediated macrophage. .......... 95
Figure 22. Eps8 attenuation decreases LPS-mediated NO production and cytokines
secretion in macrophage. ........... 98
Figure 23. PH-truncated 261-p97Eps8 reduces LPS-induced NO production and
cytokines secretion in macrophage. .......... 100
Figure 24. Eps8 restores LPS-induced NO production and cytokines secretion in
Src-attenuated RAW cell. .......... 102
Figure 25. Eps8 promotes LPS-induced NF-κB activition in RAW cells. ... 104
Figure 26. Eps8 and Src promote NF-κB nuclear localization and DNA binding
activity in LPS-engaged macrophage. ......... 105
Figure 27. Viral-mediated Eps8 shRNA reduces cytokines secretion in LPS-induced
sepsis model. ............. 107
Figure 28. A model of Eps8/Src axis in macrophage-mediated innate immunity. 109
Appendix.
Figure 29. Overview of TLR signalling pathways. (from NATURE REVIEWS
IMMUNOLOGY (2014), vol 14, p546, Figure 1) (118) ...... 124
Figure 30. Signal transduction pathways of diverse TLR-mediated macrophage
migration. (from Biochimica et Biophysica Acta (2011), vol 1813, p136, Figure 12)
xi
(22). ............... 125
Figure 31. Eps8 promotes LPS-elicited activation of MAPKs in RAW264.7 cells.
(from THE JOURNAL OF BIOLOGICAL CHEMISTRY (2012), vol 287, p18806,
Figure 8) (17). ............. 126
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