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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 莊立民(Lee-Ming Chuang) | |
| dc.contributor.author | Lynn Su | en |
| dc.contributor.author | 蘇寧 | zh_TW |
| dc.date.accessioned | 2021-06-17T03:19:35Z | - |
| dc.date.available | 2021-08-01 | |
| dc.date.copyright | 2018-08-01 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-06-26 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69568 | - |
| dc.description.abstract | 發炎反應可以透過許多促炎分子與抗發炎分子來調控訊息傳遞路徑，核因子NF-κB pathway為一經典的促炎信號傳導路徑，已有許多以此為標靶的抗發炎藥物被研究。NF-κB pathway可被多種誘導物刺激，包括促炎因子如IL-6，MCP-1和TNF-α，並隨後活化發炎因子。前列腺素也是參與發炎反應的分子之一，在先天性發炎反應中前列腺素及其代謝物的調節作用也已被廣泛研究也了解其重要性。 在本篇研究中，我們探討了前列腺素代謝物15-keto-PGE2的抗發炎性質。我們發現，於RAW 264.7細胞中在LPS刺激下15-keto-PGE2會透過抑制NF-κB pathway達到抗發炎的效果。15-keto-PGE2會抑制促炎因子的表達並且降低NF-κB調控基因表現量。我們也進一步證實15-keto-PGE2可造成 NF-κB轉錄因子的轉譯後修飾，其包括分別在p50及其先驅體p105第59位點的Cysteine以及 RelA，又稱p65第120位點的Cysteine。最後，我們證明了15-keto-PGE2加速了p105的降解，可能是透過泛素所調節的，而不影響其入核的機制。 最後，本篇研究證實了15-keto-PGE2對於調節發炎反應的重要性，也提供了一個未來可以使用15-keto-PGE2的抗發炎治療方法。 | zh_TW |
| dc.description.abstract | The inflammatory response can be depicted as coordinated activation of a myriad of signaling pathways that come together to regulate the expressions of both pro- and anti-inflammatory mediators. One of the most classic pro-inflammatory signaling pathway, the nuclear factor NF-κB pathway has long been studied as a target for new anti-inflammatory drugs. NF-κB pathway can be stimulated by several inducers, including pro-inflammatory cytokines such as IL-6, MCP-1, and TNF-α. Subsequently, pro-inflammatory genes will be activated. A class of molecules that also play a part in the inflammatory pathways are the prostaglandins. The regulatory roles that prostaglandins and their metabolites play in innate inflammation have also been extensively studied.
In this study, we investigate the anti-inflammatory property of a prostaglandin metabolite 15-keto-PGE2. We saw that 15-keto-PGE2 have anti-inflammatory effects in LPS-stimulated RAW 264.7 cells by inhibiting the NF-κB inflammatory pathway. The treatment of 15-keto-PGE2 led to a reduction of the pro-inflammatory cytokine expressions and Igκ-mediated reporter activities. 15-keto-PGE2 further demonstrated post-translational modification to NF-κB transcription factors, NF-κB1, which include the p50 subunit and its precursor p105, and RelA, or p65, at Cysteine 59 and Cysteine 120 sites, respectively. Finally, we demonstrated that the treatment of 15-keto-PGE2 accelerated the degradation of p105, potentially ubiquitin-mediated yet it did not affect nuclear translocation of p50. Taken together, our study affirms the significance of 15-keto-PGE2 in attenuating inflammatory responses and suggests a novel anti-inflammatory therapy for LPS-induced inflammation through administering 15-keto-PGE2. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T03:19:35Z (GMT). No. of bitstreams: 1 ntu-107-R04448025-1.pdf: 2361216 bytes, checksum: 3ce80f2cf2c796d355c39851d41af26f (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 口試委員會審定書 ........................................................................................................... I
謝誌 .................................................................................................................................. II Abstract ......................................................................................................................... III 中文摘要 ........................................................................................................................ IV Table of contents ............................................................................................................. V Introduction ..................................................................................................................... 1 1.1 Inflammation .............................................................................................................. 2 1.1.1 The progression and regulation of inflammation: onset to resolution ........................ 2 1.1.2 The role of macrophages in the face of inflammation .............................................. 4 1.2 The NF-κB inflammatory pathway .............................................................................. 6 1.2.1 Proteasomal processing and degradation of p105 .................................................... 7 1.3 Prostaglandins (PGs) ................................................................................................. 10 1.3.1 Prostaglandin E2 and its metabolite, 15-keto-PGE2 ................................................ 10 1.4 Experimental rationale ............................................................................................... 14 2. Materials and Methods ............................................................................................. 15 2.1 Cell Culture and Reagents.......................................................................................... 15 2.2 RNA Extraction and Quantitative PCR ................................................................. 15 2.3 Western Blot Analysis ........................................................................................... 15 2.4 Luciferase Reporter Assay ..................................................................................... 16 2.5 Immunoprecipitation and Proteomic Analysis ....................................................... 16 2.6 Plasmid mutagenesis .............................................................................................. 17 2.7 Nuclear-Cytoplasmic Fractionation ....................................................................... 18 3. Results ......................................................................................................................... 19 3.1 15-keto-PGE2 reduces pro-inflammatory gene expression in LPS-stimulated RAW264.7 cells ........................................................................................................... 19 3.2 Treatment of 15-keto-PGE2 inhibits NF-κB promoter activity in LPS-stimulated RAW264.7 cells ........................................................................................................... 19 3.3 15-keto-PGE2 attenuates the phosphorylation of IKKα/β and IkBα ..................... 20 3.4 15-keto-PGE2 modifies components of the NF-κB pathway ................................. 20 3.5 15-keto-PGE2 mediated anti-inflammatory responses in RAW264.7 cells via modification of RelA (p65) at Cysteine 120 ............................................................... 21 3.6 15-keto-PGE2 mediated anti-inflammatory responses in RAW264.7 cells via modification of NF-κB (p105/p50) at Cysteine 59 ..................................................... 22 3.7 15-keto-PGE2 promotes signal-induced degradation of NF-κB but not nuclear translocation ................................................................................................................. 23 4. Conclusion .................................................................................................................. 24 5. Discussion ................................................................................................................... 25 5.1 15-keto-PGE2 was once viewed as an inactive metabolite of PGE2 ...................... 25 5.2 The treatment with 15-keto-PGE2 increased ubiquitination in RAW264.7 cells .. 25 5.3 The modification by 15-keto-PGE2 on NF-κB (p105/p50) accelerates p105’s degradation ..................................................................................................................26 5.4 The modification of the C59 site of NF-κB (p105/p50) by 15-keto-PGE2 affects DNA binding activity of p50 ....................................................................................... 27 5.5 15-keto-PGE2 binds to the C120 site of RelA (p65) and potentially affects the functions of the Rel homology domain (RHD) of Rel A (p65) .................................. 28 Figures ............................................................................................................................ 29 Tables .............................................................................................................................. 46 References ....................................................................................................................... 47 List of Figures 1 15-keto-PGE2 reduces pro-inflammatory gene expression in LPS-stimulated RAW264.7 cells .......................................................................................................... 29 2 Treatment of 15-keto-PGE2 inhibits NF-κB promoter activity in LPS-stimulated RAW264.7 cells .......................................................................................................... 31 3 15-keto-PGE2 attenuates the phosphorylation of IKKα/β and IkBα ........................ 32 4 15-keto-PGE2 modifies components of the NF-κB pathway ................................... 33 5 15-keto-PGE2 mediated anti-inflammatory responses in RAW264.7 cells via modification of RelA (p65) at Cysteine 120 ............................................................... 36 6 15-keto-PGE2 mediated anti-inflammatory responses in RAW264.7 cells via modification of NF-κB (p105/p50) at Cysteine 59 ..................................................... 38 7 15-keto-PGE2 promotes signal-induced degradation of NF-κB but not nuclear translocation ................................................................................................................. 41 8 Schematic model of 15-keto-PGE2 regulates inflammation by modification of NF-κB ...................................................................................................................................... 44 | |
| dc.language.iso | en | |
| dc.subject | 轉譯後修 | zh_TW |
| dc.subject | 前列腺素 | zh_TW |
| dc.subject | 發炎反應 | zh_TW |
| dc.subject | inflammation | en |
| dc.subject | Prostaglandin | en |
| dc.subject | 15-keto-PGE2 | en |
| dc.subject | anti-inflammatory | en |
| dc.subject | PTM | en |
| dc.subject | post-translational modification | en |
| dc.title | 前列腺素15-keto-PGE2經由轉譯後修飾NF-κB pathway調控發炎反應 | zh_TW |
| dc.title | 15-keto-PGE2 exhibited anti-inflammatory properties through post-translationally modifying the NF-κB pathway | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 張以承(Yi-Cheng Chang),徐立中(Li-Chung Hsu),蔡欣祐(Hsin-Yue Tsai) | |
| dc.subject.keyword | 前列腺素,轉譯後修,發炎反應, | zh_TW |
| dc.subject.keyword | Prostaglandin,15-keto-PGE2,inflammation,anti-inflammatory,PTM,post-translational modification, | en |
| dc.relation.page | 53 | |
| dc.identifier.doi | 10.6342/NTU201801102 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-06-27 | |
| 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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