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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 賴明宗(Ming-Zong Lai) | |
| dc.contributor.author | Yu-Jung Wu | en |
| dc.contributor.author | 吳禹蓉 | zh_TW |
| dc.date.accessioned | 2021-06-15T16:35:32Z | - |
| dc.date.available | 2015-09-24 | |
| dc.date.copyright | 2015-09-24 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-08-12 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52948 | - |
| dc.description.abstract | The caspase-8-specific inhibitor, cellular FLICE inhibitory protein (c-FLIP), inhibits death receptor-induced apoptosis by blocking caspase-8 activation. c-FLIP has also been reported to transmit activation signals, but the exact signals mediated by c-FLIP remain unclear. The aim of this study is to investigate the role of c-FLIP in the development and activation of dendritic cells (DCs) by using c-FLIPf/fCD11c-Cre (DC-specific) conditional knockout mice. We identified a novel function of c-FLIP involving in inhibition of myeloid cell activation through selective innate signaling pathway. We found that conditional knockout of c-FLIP in dendritic cells led to neutrophilia and splenomegaly. Peripheral dendritic cell populations, including CD11b+ conventional DC (cDC), CD8+ cDC, and plasmacytoid DC (pDC), were not affected by c-FLIP absence. Our results also indicated that c-FLIP-knockout cDC, pDC, and bone marrow-derived DC (BMDC) displayed enhanced production of TNF-a, IL-2, or G-CSF in response to stimulation of TLR4, TLR2, and Dectin-1. Splenic DC maturation and T cell priming ability were also increased in c-FLIPf/fCD11c-Cre mice. Consistent with the ability of c-FLIP to inhibit the activation of p38 MAPK, the enhanced activation of c-FLIP-deficient BMDCs could be partly linked to an increased activation of p38 MAPK after engagement of innate receptors. We showed there was an interaction between c-FLIP and p38 MAPK or c-FLIP and ASK1. In addition, the increased activation in c-FLIP-deficient dendritic cells was caspase-8-independent. Our results reveal a novel inhibitory role of c-FLIP in myeloid cell activation through modulating p38 MAPK signaling and demonstrate the unexpected anti-inflammatory activity of c-FLIP. Moreover, our observations suggest that cancer therapy target c-FLIP downregulation may facilitate DC activation and increase T cell immunity. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T16:35:32Z (GMT). No. of bitstreams: 1 ntu-104-D96449006-1.pdf: 10613326 bytes, checksum: 2c7cef91a26c493ee09b34a2e9bad353 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | Table of content
口試委員會審定書 致謝……………………………………………...……………..…i 摘要……………………………………………...…………..…ii Abstract…………………………………………...…….………iii Abbreviation……………………………………...………….….v Chapter I Introduction………………………..……………1 1. Cellular FLICE-like inhibitory protein…………………………………….2 2. Dendritic cells…………………………………………………………..….5 3. Pattern recognition receptors…………………....…………...…………….7 4. Mitogen-activated protein kinases…………………………...…………….8 5. c-FLIP and myeloid cells…………………………………….......……….10 6. Granulocyte-colony stimulating factor and neutrophils……….…….….11 7. Aims…………………………..……………………………………..….12 Chapter II Materials and Methods……………..…..………15 1. Reagents……………………………...…………………..……………….16 2. Mouse………………………………………………………..………..….17 3. Flow cytometry………………………………......…………...………….18 4. Flow antibodies……………………………….……………...………..….18 5. Preparation and purification of splenic DCs…………………………..….20 6. Preparation and purification of BMDCs……….…….………………..….20 7. Preparation of blood and PEC…………………………………….…..….21 8. Immunoprecipitation……………………….…………………..……..….21 9. Western blot………………….....…………...………………...………….22 10. Anti-G-CSF treatment……………………………………...…………….23 11. Knockdown of caspase-8 in dendritic cells…………………...………….24 12. Antigen presentation in DC-T cell cocultures……….…….………….….24 13. Quantitative PCR……………………………………………...………….25 14. Cell viability analysis……………………………..…………………..….26 15. Determination of caspase-8 activity………………………..…………….26 16. Analysis of murine T cell activation………………………..…………….27 17. Single cell calcium imaging………………………………..…………….27 18. NFAT nuclear translocation and IL-2 production……………………….28 19. Statistical analysis……………………………………...…...…………….28 Chapter III Results………….…………………….…...……29 1. Conditional knockout of c-FLIP in dendritic cells leads to increase of neutrophils in bone marrow…………….….…………………..……...….30 2. c-FLIP-deficiency in dendritic cells results in splenomegaly and peripheral neutrophilia.…………………………..…………..……………….…..….32 3. Increased expression of MHC II, CD80 and CD86 in c-FLIP-deficient DCs…………………………………………….……...………………….35 4. Increased production of TNF-and IL-2 in c-FLIP-deficient bone marrow- derived DCs.………………………………………………...…...……….36 5. Enhanced p38 MAPK activation in c-FLIP-deficient BMDCs…….…….38 6. Differential production of G-CSF may account for neutrophilia in c-FLIP condition knockout mice…………………………………..…...…..…….40 7. The suppressive activity of c-FLIP is caspase-8 independent……...…….41 8. Calcium influx, NFATc activation and proliferation in T cells are defected in c-FLIPL CKO T cells……………..…………………..……………….43 Chapter VI Discussion…………………………….……...…45 1. DCs are different from macrophages in their sensitivity to deletion of c-FLIP………………………….……….….…………………..……...….46 2. The generation of neutrophilia in c-FLIPf/fCD11c-Cre mice.…….……...47 3. Linkage between in vivo and in vitro…………………………….……….48 4. The innate receptor signaling affected by c-FLIP in DCs.............……….49 5. The molecular processes affected by c-FLIP in p38 MAPK activation……………………………………………………………....... 51 6. Novel biological activity of c-FLIP in myeloid cells through the suppression of activation signals.……………………………....…..…….52 7. The role of c-FLIP in cancer therapy.................................................…….53 References…………………………………………..…….……55 Figures………………………………………………...…..……71 Appendix…………………………………………….......……110 | |
| dc.language.iso | en | |
| dc.title | c-FLIP 在樹突細胞的發育與活化中扮演的角色 | zh_TW |
| dc.title | The role of c-FLIP in the development and activation of dendritic cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 許秉寧(Ping-Ning Hsu),謝世良(Shie-Liang Hsieh),繆希椿(Shi-Chuen Miaw),羅傅倫(Steve R. Roffler) | |
| dc.subject.keyword | 樹突細胞, | zh_TW |
| dc.subject.keyword | c-FLIP,dendritic cells,p38 MAPK, | en |
| dc.relation.page | 114 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-08-12 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 免疫學研究所 | zh_TW |
| 顯示於系所單位： | 免疫學研究所 | |
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