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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 徐立中(Li-Chung Hsu) | |
| dc.contributor.author | Shih-Yi Chuang | en |
| dc.contributor.author | 莊士億 | zh_TW |
| dc.date.accessioned | 2021-06-16T08:38:06Z | - |
| dc.date.available | 2019-02-25 | |
| dc.date.copyright | 2014-02-25 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-10-15 | |
| dc.identifier.citation | References
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58908 | - |
| dc.description.abstract | NLRP3 inflammasome 是一種透過辨識廣泛的外來病原或身體內部損傷因子而活化形成的複合蛋白體，它進而促使半胱氨酸蛋白酶-1的活化及前發炎性細胞激素的介白素-1β 和 -18的產生。 在許多致病性的疾病中，可以發現NLRP3 inflammasome 的功能失調以致過度活化，但是它的調節機制仍舊不是很清楚。 在這裡我們發現在巨噬細胞內剔除一種絲胺酸蛋白酶抑制素，第二型纖溶酶原激活物抑制酶，再活化類鐸受體4和2的訊息傳導過程會造成 NLRP3和 ASC控制的半胱氨酸蛋白酶-1的活化及介白素-1β 的大量產生。然而活化類鐸受體4和2 也會誘導第二型纖溶酶原激活物抑制酶的表現，它會穩定自噬基因蛋白Beclin 1，進而促使自噬作用的增加來降低粒線體的自由基的產生、NLRP3蛋白質的表現及前介白素-1β的生產作用。由我們的實驗確立了一個藉由活化類鐸受體的訊號傳導中來調控NLRP3 inflammasome的活性，並揭示了一種新的細胞自主機制去負調節經由類鐸受體或大腸桿菌所引起的線粒體功能障礙、氧化壓力和介白素-1β 所產生的發炎反應。 | zh_TW |
| dc.description.abstract | The NLRP3 inflammasome, a multiprotein complex, triggers caspase-1 activation and maturation of proinflammatory cytokines IL-1β and IL-18 upon sensing a wide range of pathogen- and damage-associated molecules. Dyregulation of the NLRP3 inflammasome activity contributes to the pathogenesis of many diseases, but its regulation remains poorly defined. Here we show that depletion of Plasminogen activator inhibitor type 2 (PAI-2), a serine protease inhibitor, resulted in NLRP3- and ASC-dependent caspase-1 activation and IL-1β secretion in macrophages upon TLR2 and TLR4 engagement. TLR2 or 4 agonists induced PAI-2 expression, which subsequently stabilized autophagic protein Beclin 1 to promote autophagy resulting in decreased mitochondrial reactive oxygen species (mROS), NLRP3 protein as well as pro-IL-1β processing. Together, our data identify a new tier of TLR signaling in controlling NLRP3 inflammasome activation, and reveal a novel cell-autonomous mechanism which inversely regulates TLRs- or Escherichia coli-induced mitochondrial dysfunction, oxidative stress, and IL-1β-driven inflammation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T08:38:06Z (GMT). No. of bitstreams: 1 ntu-102-D96448009-1.pdf: 10636863 bytes, checksum: 789c5880f55a0ecb9d09fb9d5ccde5f6 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | Contents
中文摘要 1 ABSTRACT 2 CONTENTS 3 1. INTRODUCTION 9 1.1 Innate immunity 9 1.2 Toll-like receptor 4 (TLR4) 12 1.3 Inflammasome 13 1.4 NLRP3 inflammasome 16 1.5 Autophagy 19 1.6 Plasminogen activator inhibitor type 2 (PAI-2) 21 1.7 The purpose and aims of this study 24 2. MATERIALS AND METHODS 26 2.1 Reagents, antibodies, and plasmids 26 2.2 Cell cultures and mice 27 2.3 Macrophage Isolation and Stimulation 28 2.4 Bacterial infection 29 2.5 Transfections and lentivirus infection 29 2.6 shRNA mediated gene silencing 30 2.7 mRNA isolation and RT-quantitative PCR (RT-qPCR) 31 2.8 Immunoblotting 32 2.9 Detection of cytokines and lactate dehydrogenase (LDH) release 33 2.10 ASC pyroptosome cross-linking assay 33 2.11 Immunoprecipitation 34 2.12 Immunofluorescence 35 2.13 ROS detection 35 2.14 Assays for lysosomal integrity and mitochondrial membrane potential 36 2.15 Mitochondrial fractionation 36 2.16 Statistical analysis 37 3. RESULTS 38 3.1 Loss of PAI-2 enhances LPS-induced IL-1β production and caspase-1 activation 38 3.2 Activation of TLR4 and TLR2, but not TLR3 and TLR9, induces IL-1β production in THP-1 macrophages. 39 3.3 LPS-induced activation of IKK, and MAPKs activation, and the expression of proinflammatory cytokines are not altered in PAI-2 expressing THP-1 macrophages. 40 3.4 NLRP3, ASC and caspase-1, but not NLRC4, are required for LPS- and Pam3CSK4-induced IL-1β production and caspase-1 activation in THP-1 macrophages. 41 3.5 PAI-2-inhibited LPS-stimulated IL-1β production, caspase-1 activation and ASC oligomerization, requires its protease inhibition function. 41 3.6 LPS-induced cellular ROS generation is required for IL-1β production and caspase-1 activation, which is abrogated by PAI-2 43 3.7 PAI-2 prevents LPS-induced loss of mitochondrial integrity and mitochondrial ROS (mROS) production 44 3.8 PAI-2 attenuates LPS-induced lysosomal destabilization and cathepsin B activation 45 3.9 PAI-2 enhances autophagy by increasing the level of the autophagic protein Beclin 1 46 3.10 PAI-2 associates with HSP90 and Beclin 1, and protects Beclin 1 from proteasome degradation 47 3.11 PAI-2 augments NLRP3 degradation through autophagy upon LPS stimulation 49 3.12 E. coli-induced IL-1β secretion and cell death are blocked by PAI-2 50 4. DISCUSSION 52 5. FIGURES 61 Fig. 1. Loss of PAI-2 enhances LPS-induced IL-1β production and caspase-1 activation in human and mouse macrophages. 62 Fig. 2. Activation of TLR4 and TLR2, but not TLR3 and TLR9, induces PAI-2 expression to suppress IL-1β production. 64 Fig. 3. LPS-induced activation of IKK, and MAPKs activation, and the mRNA expression of proinflammatory cytokines are not altered in PAI-2 expressing THP-1 macrophages. 66 Fig. 4. NLRP3, ASC and caspase-1, but not NLRC4, are required for LPS- and Pam3CSK4-induced IL-1β production in THP-1 macrophages. 68 Fig. 5. PAI-2-inhibited LPS-stimulated IL-1β production, caspase-1 activation and ASC oligomerization, requires its protease inhibition function. 70 Fig. 6. LPS-induced cellular ROS generation is required for IL-1β production and caspase-1 activation, which is abrogated by PAI-2. 72 Fig. 7. PAI-2 prevents LPS-induced loss of mitochondrial integrity and mitochondrial ROS (mROS) production 74 Fig. 8. PAI-2 abrogates relocation of NLRP3 to mitochondria after LPS stimulation. 76 Fig. 9. LPS triggers lysosomal destabilization and cathepsin B activation in an ROS-dependent manner leading to IL-1β maturation, and PAI-2 reverses these effects. 78 Fig. 10. Potassium efflux is required for LPS-induced cathepsin B activation and IL-1β secretion, but not ROS production. 80 Fig. 11. PAI-2 increases the expression of Beclin 1 and LC3 lipidation. 82 Fig. 12. PAI-2 enhances autophagy. 84 Fig. 13. PAI-2 complexes with HSP90 and Beclin 1 86 Fig. 14. PAI-2 associates with Beclin 1 and HSP90, and protects Beclin 1 from proteosome-mediated degradation. 88 Fig. 15. Autophagy negatively regulates LPS-induced IL-1β secretion and NLRP3 expression. 90 Fig. 16. PAI-2 augments NLRP3 degradation through autophagy upon LPS stimulation 92 Fig. 17. PAI-2 increases colocalization of NLRP3 with autophagosome after LPS treatment. 94 Fig. 18. PAI-2 decreases IL-1β, but not TNF, and NLRP3 production in response to E. coli infection. 96 Fig. 19. PAI-2 protects macrophages from cell death after E. coli infection. 98 Fig. 20. A proposed model summarizes the control of TLR-triggered NLRP3 activation and IL-1β secretion by PAI-2. 100 6. REFERENCES 101 | |
| dc.language.iso | en | |
| dc.subject | 第二型纖溶?原激活物抑制? | zh_TW |
| dc.subject | 自噬作用 | zh_TW |
| dc.subject | 介白素-1β | zh_TW |
| dc.subject | PAI-2 | en |
| dc.subject | autophagy | en |
| dc.subject | NLRP3 | en |
| dc.subject | IL-1β | en |
| dc.title | 第二型纖溶酶原激活物抑制酶經由引發自噬作用和NLRP3降解作用以抑制類鐸受體引發之介白素-1β產生 | zh_TW |
| dc.title | TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 伍安怡(B. A. Wu-Hsieh),林琬琬(Wan-Wan Lin),莊宗顯(Tsung-Hsien Chuang),曾炳輝(Ping-Hui Tseng) | |
| dc.subject.keyword | 第二型纖溶?原激活物抑制?,自噬作用,介白素-1β, | zh_TW |
| dc.subject.keyword | PAI-2,autophagy,NLRP3,IL-1β, | en |
| dc.relation.page | 117 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-10-15 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-102-1.pdf 未授權公開取用 | 10.39 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。