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研究生(外文):Ting-Yu Lai
論文名稱(外文):The novel regulation of Toll-Like Receptor 4
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哺乳類動物中,先天性免疫系統(Innate immunity)是防禦病原菌侵入生物體內的首道防線。先天性免疫反應的防禦機制在於藉由pattern-recognition receptors,如Toll-like receptors (TLRs) , 以非特異性方式辨識病菌特有的分子特徵(pathogen-associated molecular patterns)而保護生物體不受感染威脅。巨噬細胞是一種有吞噬能力的大型白血球,它可以移動到組織之間去獵取入侵的病源菌,並產生細胞激素以及將抗原表現給其他細胞以活化適應性免疫反應(adaptive immunity),進行毒殺病原體的動作。
TLR訊息傳導途徑在生物體內通常受到了嚴密精細的調控。失控的全身性發炎反應可能造成全身性發炎反應症候群 (Systemic inflammatory response syndrome,SIRS)、動脈硬化,或是自體免疫性疾病,這些疾病多由體內持續性的發炎反應所造成,進而使內臟器官嚴重受損甚至死亡。在受到病原體刺激之後,TLR透過許多不同的分子經由訊息傳導引發巨噬細胞免疫反應,而這些分子在免疫系統上將可有效的防止免疫反應過量及不足的情況。因此透過這些免疫反應調控因子深入的研究以及了解,臨床上將有助於治療各種發炎引起的疾病。

In mammals, innate immunity is the first line of defense against pathogenic infection, and is mainly mediated by pattern-recognition receptors, including Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns derived from microbes or endogenous molecules termed damage-associated molecular patterns. Macrophages, a type of phagocytic leukocytes, play a crucial role in innate immunity by producing various cytokines and chemokines and presenting antigens to lymphocytes, both of which are also involved in the activation of adaptive immunity. However, dysregulation of TLRs-mediated inflammatory response can impair host immune homeostasis, and is associated with many autoimmune and inflammatory diseases, such as systemic inflammatory response syndrome (SIRS) and atherosclerosis. Thus, the molecular mechanisms of how TLRs signaling is regulated have been intensively investigated, but the detailed mechanism still remains fragmentary. In this study, we discovered two novel regulatory mechanisms in TLR4-mediated immune response by exploring microarray analysis. We found that TLR4 engagement induced a transcription factor C/EBPβ through p38 MAPK, which subsequently increased A20 expression in conjunction with NF-κB. A20, in turn, negatively regulated TLR4 signaling to terminate inflammatory response. In addition, we identified a novel E3 ubiquitin ligase, ZNRF1, which mediated caveolin-1 (CAV1) ubiquitination and degradation in response to lipopolysaccharide (LPS). Mechanistically, the ZNRF1-CAV1 axis influences Akt-GSK3β activity upon TLR4 activation, eventually resulting in enhanced production of pro-inflammatory cytokines and inhibiting anti-inflammatory cytokine IL-10 expression. Our findings unravel two new regulatory mechanisms of TLR4 signaling pathway and may shed light on treatments for inflammation-related diseases.

Table of contents 1
中文摘要 4
Abstract 5
Introduction 6
1. Innate immunity 6
2. Toll-like receptors 6
3. Structure of TLRs 7
4. Toll-Like Receptor 4 8
5. TLR4 signaling 9
6. p38 MAPK 10
7. NF-κB 10
8. Mechanism of Ubiquitination 11
9. A20 12
10. ZNRF1 13
11. Caveolin-1 14
Materials and Methods 16
PART 1 23
Specific Aim 23
Results 24
PART 2 34
Specific Aim 34
Result 35
Discussion 42
Conclusion 45
References 46
Table 1. Top 10 enriched canonical pathways of the NF-κB and p38-dependent genes 58
Table 2. Prediction of transcription factor binding sites of NF-κB and p38-dependent genes using oPOSSUM 59
Table 3. Summary of E3 Ubiquitin ligases regulated by LPS in macrophages from the analysis of Microarray datasets 60
Table 4. Primer pairs for real-time RT-QPCR 61
Figure 1. Depletion of IKKβ expression and inhibition of p38 signaling pathway in IkkβΔ and SB202190-treated bone marrow-derived macrophages (BMDMs). 62
Figure 3. C/EBPβ and A20 (TNFAIP3) were suppressed in IkkβΔ and p38-inhibited macrophages. 65
Figure 4. LPS-induced expression of A20 (TNFAIP3) was decreased in C/EBPβ-depleted RAW264.7 cells. 66
Figure 5. Proposed model of NF-

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