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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 徐立中(Li-Chung Hsu) | |
| dc.contributor.author | Chih-Hsiang Yang | en |
| dc.contributor.author | 楊志祥 | zh_TW |
| dc.date.accessioned | 2021-06-16T10:49:34Z | - |
| dc.date.available | 2018-09-24 | |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-08-12 | |
| dc.identifier.citation | Andrejeva, J., Childs, K., Young, D., Carlos, T., Stock, N., Goodbourn, S., and Randall, R.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/61151 | - |
| dc.description.abstract | 先天性免疫系統是人體中面對外來病菌入侵或是自身危險因子攻擊的第一道防線。近幾年，發炎體(the inflammasomes)這種新興蛋白質複合體在先天免疫學界中迅速竄起，被證實其是多細胞生物體內用以對抗病原體重要的一環。發炎體主要功能為，將第一型半胱天冬酶(caspase-1)活化並因此催化第一型介白素β (IL-1β)與第十八型介白素(IL-18)熟成的能力，以協助宿主對抗病原體。但發炎體究竟是如何被調控的至今尚未明瞭。
過去研究中，指出第二型纖溶酶原激活物抑制酶(PAI-2)在受LPS刺激的IKKβ缺陷巨噬細胞中能夠抑制過多的第一型介白素β的熟成，但其抑制機制目前並不清楚。而本研究便進一步利用轉殖小鼠來研究第二型纖溶酶原激活物抑制酶的生理功能。我們在IKKβ缺陷小鼠骨髓分化巨噬細胞(bone marrow derived macrophages)與中性球(neutrophils)中證實第二型纖溶酶原激活物抑制酶，皆能抑制LPS引發第一型介白素β的分泌。另外，第二型纖溶酶原激活物抑制酶也能降低LPS引發血清第一型介白素β的表現。正常小鼠受到大腸桿菌(DH5α)感染所引發的血清第一型介白素β，也可以被第二型纖溶酶原激活物抑制酶所抑制其表現。以上的實驗結果顯示:第二型纖溶酶原激活物抑制酶是重要的第一型介白素β熟成的負調控因子。 除此之外，我們實驗室進行了酵母雙雜交實驗發現一核醣核酸解旋脢為第二型纖溶酶原激活物抑制酶的結合蛋白。本篇研究也進一步探討此核醣核酸解旋脢與調節第一型介白素β的熟成關係。我們在人類胚腎細胞株HEK293T內證實該核醣核酸解旋脢是NLRP3發炎體的結合蛋白。當我們進一步利用RNA干擾技術(RNA interference)抑制該核醣核酸解旋脢的基因表現後，不管是在單純施以LPS刺激的小鼠巨噬細胞J774A.1細胞株或是小鼠骨巨噬細胞中都能提高成熟型第一型半胱天冬酶(mature caspase-1) 活性以及成熟型第一型介白素β (mature IL-1β)的釋放，卻不影響上游前第一型介白素β核醣核酸 (pro-IL-1β mRNA)的合成；反之，當我們在小鼠巨噬細胞J774A.1細胞株中過度表現其核醣核酸解旋脢的時候，可以抑制LPS加ATP所造成的成熟型第一型半胱天冬酶(mature caspase-1) 活性以及成熟型第一型介白素β (mature IL-1β)的釋放，這指出該核醣核酸解旋脢可能調控發炎體活化。另外我們也發現受LPS刺激的核醣核酸解旋脢會從細胞核往細胞質移動並且和NLRP3 蛋白有重和的情形。從以上的實驗，我們認為該核醣核酸解旋脢能夠負調控NLRP3發炎體的活性。 | zh_TW |
| dc.description.abstract | The innate immunity is the first defense when hosts encounter pathogens or sense danger signals released from stressed or damaged tissues. Recently, a novel system named the inflammasome, a multiple protein complex for caspase-1 activation, has been characterized and has been proved to play a critical role in host defense against bacterial and viral infection. Activation of the inflammasome leads to cleavage of pro- inflammatory cytokines, IL-1β and IL-18 into their active forms.
Previous studies demonstrated that mice with Ikkβ deletion in myeloid cells (Ikkβ) are more susceptible to LPS-induced septic shock in a IL-1β-dependent manner. In addition, PAI-2, a NF-κB mediated gene, suppressed IL-1β production in Ikkβ bone marrow-derived macrophages (BMDMs) after LPS treatment, indicating that PAI-2 inhibits LPS-induced IL-1β in macrophages. However, the physiological role of PAI-2 remains unknown. To this end, we generated transgenic mice that specifically expressed PAI-2 in myeloid cells, then crossed this transgenic mice with Ikkβ mutant mice to examine whether the restoration of PAI-2 in Ikkβ mice can resist LPS-induced septic shock. We found that increased IL-1β production in IKKβ deficient mice was suppressed by PAI-2 in BMDMs and neutrophils, wherein they are caspase-1-dependent and independent, respectively. In addition, PAI-2 expression decreased plasma IL-1β in Ikkβ mice after LPS challenge. We also demonstrated that transgenic PAI-2 mice had lower levels of plasma IL-1β and delayed median survival rate upon E. coli infection. Together, our results confirm that PAI-2 is a negative regulator in physiological inflammation. We previously showed that DDX27, a DEAD box-containing protein, was obtained from a yeast two-hybrid screening using PAI-2 as bait. Ablation of DDX27 in THP-1 macrophages largely enhanced caspase-1 activity and IL-1β production solely upon LPS challenge, suggesting that DDX27 is involved in negative regulation of the inflammasome activation. Here, we demonstrated that DDX27 suppressed IL-1β maturation and caspase-1 activation after LPS+ATP challenge in J774A.1 macrophages whose PAI-2 gene is functional. In addition, enhanced IL-1β production was observed in DDX27-deficient J774A.1 cells and BMDMs in response to LPS. Furthermore, we found that DDX27 associated with NLRP3 in co-immunoprecipitation assays. We further confirmed wild type, but not nuclear export-defective DDX27 mutant, translocated from the nucleus to the cytosol and co-localized with NLRP3 upon LPS treatment in J774A.1 cells. These results suggest that DDX27 plays a negative regulator of NLRP3 inflammasome activation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T10:49:34Z (GMT). No. of bitstreams: 1 ntu-102-R00448001-1.pdf: 3355120 bytes, checksum: a12649b42a93901efc5cab907ce66f7b (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 誌謝 1
摘要 2 Abstract 4 Contents 6 Introduction 9 Inflammasomes 9 Structure of the inflammasomes 10 Regulation of the inflammasomes 11 NF-κB signaling 13 NF-κB signaling and the inflammasomes 14 Sepsis 14 Sepsis and inflammasomes 15 PAI-2 16 Overview of the DEAD RNA Helicase family 17 The helicase core 18 The DEAD-box proteins and the immune system 19 DDX27 19 Specific aims 21 Materials and Methods 22 Reagents 22 Plasmids 23 Mice 23 Cell culture and transfection 25 Preparation of pseudotyped lentiviruses 25 Isolation of peritoneal macrophages and neutrophils 26 Preparation of Bone Marrow Derived Macrophages 26 Enzyme-linked immunosorbent assay (ELISA) 27 Total RNA extraction and Reverse Transcription Quantitative PCR 28 Preparation of whole cell lysate 29 Measurement of secreted cytokines and caspase-1 30 Preparation of nuclear and cytosolic extracts 30 Immunoblotting 31 Immunoprecipitation 32 Immunofluorescence staining 32 Results 34 Part 1. The physiological role of PAI-2 in LPS-induced sepsis 34 Generation of transgenic mice that specifically express PAI-2 in myeloid cells 34 PAI-2 suppresses IL-1β secretion in IkkβΔ macrophages after LPS challenge 35 PAI-2 suppresses IL-1β secretion in LPS-stimulated IkkβΔ neutrophils 36 PAI-2 inhibits plasma IL-1β production in IkkβΔ mice challenged with LPS 37 PAI-2 blunts the plasma IL-1β secretion in E.coli-infected mice 38 PAI-2 improves the survival of IkkβF/F mice after E. coli infection but this effect is still not significant 38 Part2. The role of DDX27 in NLRP3 inflammasome activation 39 Knockdown of DDX27 enhanced LPS-induced inflammasome activity in J774A.1 macrophages 39 Depletion of DDX27 in BMDMs induces IL-1β production after LPS stimulation 41 Overexpression of DDX27 reduced NLRP3 inflammasome activity in J774A.1 macrophages in response to LPS+ATP 42 DDX27 associates with NLRP3 when overexpressed in HEK293T 43 DDX27 translocates to the cytosol and colocalizes with NLRP3 in J774A.1 macrophages in response to LPS 44 Discussion 47 Part 1. The physiologicl role of PAI-2 in LPS-induced sepsis 47 Part2. The role of DDX27 in NLRP3 inflammasome activation 50 Figures 55 Figure 1. PAI-2 specific expresses in peritoneal macropgages, neutrophils and BMDMs in transgenic mice. 55 Figure 2. Overexpression of PAI-2 suppressed IL-1β secretion in IkkβΔ BMDMs after LPS treatment. 56 Figure3. Transgenic PAI-2 suppresses IL-1β secretion in LPS-stimulated IkkβΔ neutrophils. 57 Figure 4. PAI-2 suppresses plasma IL-1β production in IkkβΔ mice after LPS challenge. 58 Figure 5. PAI-2 suppresses plasma IL-1β secretion in vivo after E. coli infection. 59 Figure6. PAI-2 can improve the survival of mice after E.coli infection but this effect is not significant. 60 Figure 7. LPS enhances IL-1β maturation in DDX27 knockdown J774A.1 cells. 61 Figure 8. Knockdown of DDX27 induces IL-1β production in BMDMs after LPS stimulation. 62 Figure 9. LPS+ATP-induced IL-1β maturation is suppressed in DDX27 overexpressing J774A.1 macrophages. 63 Figure 10. DDX27 associates with NLRP3 when overexpressed in HEK293T cells. 64 Figure 11. LPS induces wild type DDX27, but not NES mutant, translocation from the nucleus to the cytosol in J774A.1 macrophages. 66 Figure 12. LPS induces wild type DDX27, but not DDX27-NES mutant, translocation to the cytosol and co-localizates with NLRP3 in J774A.1 macrophages. 67 Appendices 68 Appendix A. Molecular compositions of the inflammasomes. 68 Appendix B. Two signals are required for NLRP3 inflammasome activation and IL-1β production in macrophages. 69 Appendix C. Schematic diagram of DDX27. 70 Appendix D. Microinjection procedure of transgenic PAI-2 mice . 71 References 72 | |
| dc.language.iso | en | |
| dc.subject | 發炎體 | zh_TW |
| dc.subject | inflammasome | en |
| dc.title | 第二型纖溶酶原激活物抑制酶在發炎體負調控的角色 | zh_TW |
| dc.title | The role of PAI-2 in negative regulation of inflammasome | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 楊性芳(Hsin-Fang Yang-Yen),顧家綺 | |
| dc.subject.keyword | 發炎體, | zh_TW |
| dc.subject.keyword | inflammasome, | en |
| dc.relation.page | 76 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-08-12 | |
| 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 | |
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