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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 呂紹俊 | |
| dc.contributor.author | Hui-Ching Yang | en |
| dc.contributor.author | 楊惠晴 | zh_TW |
| dc.date.accessioned | 2021-06-08T05:28:50Z | - |
| dc.date.copyright | 2011-10-05 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-07-27 | |
| dc.identifier.citation | 李曜宏（2008）NF-κB 及Oct-2 在脂多醣透過MEK/ERK 訊息傳遞路徑活化巨噬細胞表現G-CSF 之過程中所扮演的角色。國立台灣大學醫學院生物化學暨分子生物學研究所碩士論文
黃宇澤（2010）探討受LPS刺激的小鼠巨噬細胞中Oct-2在G-CSF表現過程中所扮演的角色。國立台灣大學醫學院生物化學暨分子生物學研究所碩士論文 Adler, B.K., Salzman, D.E., Carabasi, M.H., Vaughan, W.P., Reddy, V.V., and Prchal, J.T. (2001). Fatal sickle cell crisis after granulocyte colony-stimulating factor administration. Blood 97, 3313-3314. Adler, V., Qu, Y., Smith, S.J., Izotova, L., Pestka, S., Kung, H.F., Lin, M., Friedman, F.K., Chie, L., Chung, D., Boutjdir, M., and Pincus, M.R. (2005). Functional interactions of Raf and MEK with Jun-N-terminal kinase (JNK) result in a positive feedback loop on the oncogenic Ras signaling pathway. Biochemistry 44, 10784-10795. Akira, S., and Takeda, K. (2004). Toll-like receptor signalling. Nat Rev Immunol 4, 499-511. Arnosti, D.N., Merino, A., Reinberg, D., and Schaffner, W. (1993). Oct-2 facilitates functional preinitiation complex assembly and is continuously required at the promoter for multiple rounds of transcription. EMBO J 12, 157-166. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/24509 | - |
| dc.description.abstract | 顆粒性白血球群落刺激因子(Granulocyte-colony stimulating factor, G-CSF)是一個造血性醣蛋白，分子量約19.6 kDa。G-CSF最主要的功能，是刺激嗜中性白血球前驅細胞的分化，並促進嗜中性白血球的產生，往發炎部位聚集以吞噬外來病菌，以及降低嗜中性白血球細胞凋亡促進其存活。G-CSF在正常狀況下表現量極低，但當生物體接受外物如：LPS (lipopolysaccharide)、PMA (phorbol 12-myristate 13-acetate)或是其他發炎反應細胞激素TNF-alpha、IL-1beta和IFN-gamma等刺激後，會大幅提高其表現。近年研究顯示，G-CSF也具有其他生理功能，例如：保護神經、調節T淋巴球的耐受性、促進造血幹細胞由骨髓移動至周邊血液循環系統等。除此之外，近年一些研究顯示G-CSF在慢性發炎疾病中也扮演重要角色。ERK已知可調控許多發炎反應細胞激素的表現，如：TNF-alpha、IL-1beta、IL-6、IL-8、IFN-gamma誘導基因，並影響免疫細胞的分化，由此可知ERK對免疫系統的調節非常重要。本實驗室過去研究發現LPS可誘導小鼠巨噬細胞RAW264.7 G-CSF表現，事先處理MEK/ERK抑制劑U0126和PD98059會抑制LPS誘導的G-CSF表現，但ERK調節G-CSF表現的機制目前仍不清楚。因此，我們想更進一步探討ERK如何參與LPS誘導小鼠巨噬細胞表現G-CSF的機制。
我們的研究發現，不論是在LPS刺激細胞前，或在LPS刺激細胞三到四小時後給予U0126，皆可抑制RAW264.7細胞G-CSF的表現，相同的現象也可在小鼠骨髓分離出的初代巨噬細胞和人類單核球細胞株中觀察到。我們更利用luciferase reporter分析探討ERK是否活化G-CSF啟動子來調節G-CSF表現，結果顯示當細胞表現了constitutive active-ERK (CA-ERK)時，可活化G-CSF啟動子活性，而kinase dead-ERK (KD-ERK)則無此活性，由此可知ERK參與調控G-CSF的表現。文獻指出Oct-2、NF-kappaB和C/EBPbeta在調控G-CSF表現扮演重要角色，因此我們分析ERK是透過活化那一個轉錄因子增強G-CSF啟動子的。由G-CSF promoter luciferase活性分析顯示，同時轉染CA-ERK與C/EBPbeta時，G-CSF啟動子活性明顯提高，且兩者有協同作用；但同時轉染KD-ERK與C/EBPbeta時則無此現象。由於NF-kB具有p50和p65兩個subunits，我們也在細胞中同時表現p65，觀察其對CA-ERK與C/EBPbeta調控G-CSF啟動子活性的影響發現，p65存在時對G-CSF啟動子活性提升並無明顯影響。此外在細胞中表現CA-MEK也可活化G-CSF啟動子活性，而同時表現CA-MEK與C/EBPbeta時可更加提升G-CSF啟動子活性。這些結果顯示MEK/ERK signaling pathway在調控G-CSF表現扮演重要角色。 我們進一步將C/EBPbeta中高度保留的MAPK磷酸化位置(Thr188)進行突變後，由G-CSF promoter luciferase活性分析發現，ERK可藉由磷酸化C/EBPbeta Thr188來影響G-CSF啟動子活性。接著分析細胞受LPS刺激後增加ERK與C/EBPbeta磷酸化，U0126則會減少C/EBPbeta Thr188磷酸化。此外DNA親和力免疫沉澱分析(DAPA)的結果顯示ERK存在於G-CSF啟動子的transcription complex中。然而，若將C/EBPbeta的結合阻斷時，並不影響ERK存在於G-CSF啟動子transcription complex中，因此ERK並不是透過C/EBPbeta存在於transcription complex中。綜合以上結果，ERK確實參與LPS誘導的G-CSF基因表現調控，然而ERK活化G-CSF啟動子活性有部分是透過活化C/EBPbeta。因此，關於ERK在G-CSF啟動子的轉錄活化與G-CSF基因表現所扮演的角色仍需更進一步的研究。 | zh_TW |
| dc.description.abstract | Granulocyte colony-stimulating factor (G-CSF) is a 19.6 kDa hematopoietic glycoprotein growth factor. The main functions of G-CSF are to stimulate differentiation of neutrophilic precursors and promote neutrophil production, migration, and survival. The expression level of G-CSF is very low in healthy individuals, but it is elevated substantially after stimulation with LPS, PMA, or pro-inflammatory cytokines such as TNF-alpha, IL-1beta, and IFN-gamma. Expression of G-CSF after stimulation will promote immune response and is important for host defense during infection. Studies also showed that G-CSF has other physiological roles, such as neuroprotection, regulation of T cell tolerance, and promotion of hematopoietic stem cell migration to peripheral tissues. On the other hand, recent studies also showed that G-CSF plays an important role in chronic inflammatory diseases. ERK1/2 is one of the mitogen activated protein kinases (MAPK). It involves in the expression of many pro-inflammatory cytokines, such as TNF-alpha, IL-1beta, IL-6, IL-8, and IFN-gamma-stimulated gene. Studies also showed that ERK1/2 affect the differentiation of immune cell such as B and T lymphocytes. Above information indicates that ERK plays an important role in regulation of immune system. Our previous studies showed that the expression of G-CSF is upregulated by LPS in RAW264.7 cells; while pretreatment with MEK inhibitors (U0126 and PD98059) inhibited the LPS-induced G-CSF expression. However, it is still unclear how ERK may regulate G-CSF expression in LPS-induced cells. Therefore, the goal of this study is to explore the involvement of ERK1/2 in LPS induced G-CSF expression.
First, U0126 and PD98059 were used to inhibit MEK1/2 activity induced by LPS. The expression of G-CSF was down-regulated by ERK inhibitors at 3-4h after the cells were stimulated by LPS in Raw264.7 cells. Similar phenomena were observed in mouse bone-marrow derived macrophages and in human monocytic cell line THP-1. We then studied how ERK interacts with transcription factors that regulate G-CSF expression by co-transfecting a G-CSF promoter-Luciferase reporter with a constitutive active- or kinase dead-ERK expression plasmid in Raw264.7 cells. Results show that G-CSF promoter activity is activated when forced expression of CA-ERK, but is not activated when forced expression of KD-ERK. These results support that ERK is involved in the regulation of G-CSF expression. We then studied which transcription factor interacts with ERK by transfection of NF-kappaB p50, p65, Oct-2, C/EBPbeta and/or CA-ERK with the G-CSF promoter-Luciferase construct. Results show that G-CSF promoter activity is induced synergistically only when C/EBPbeta and CA-ERK were co-transfected. Transfection of CA-MEK also results in elevation of G-CSF promoter activity. Moreover, co-transfection of C/EBPbeta and CA-MEK further elevates G-CSF promoter activity. These results further support that activation of MEK/ERK signaling pathway is essential for the expression of G-CSF in macrophages. To further study whether ERK activates G-CSF promoter activity through promoting C/EBPbeta phosphorylation, we constructed two C/EBPbeta mutants (C/EBPbeta T188A and S64A) and transfected cells with these mutants with CA-ERK separately. Results show that transfection with C/EBPbeta T188A resulted in about 50 % decrease of G-CSF promoter activity, but transfection with C/EBPbeta S64A has no effect on promoter activity. Western blot analyses also show that C/EBPbeta Thr188 phosphorylation is partially inhibited by U0126 in LPS-treated cells. Moreover, ERK can be precipitated by a DNA affinity precipitation assay. These results suggest that ERK is in the transcriptional complex that binds to G-CSF promoter. However, ERK still bound to G-CSF promoter when the binding of C/EBPbeta was competed out by C/EBPbeta consensus sequence. These results suggest that ERK does not bind to the transcriptional complex through interaction with C/EBPbeta. Taken together, our results show that activation of ERK is essential for G-CSF expression induced by LPS; however, the functional role of ERK in the transcriptional activation of G-CSF is still unclear and requires further investigation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T05:28:50Z (GMT). No. of bitstreams: 1 ntu-100-R98442011-1.pdf: 3262469 bytes, checksum: 5e575578b0d42ea790cebb0a14244eb1 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 摘 要 xi
Abstract xiii 名詞縮寫對照表 xvi 第一章 緒論 1 第一節 文獻回顧 2 研究動機與實驗目的 14 第二章 材料與方法 15 第一節 實驗材料 16 第二節 細胞培養 17 第三節 細胞mRNA表現分析 18 第四節 分泌性蛋白質G-CSF表現量分析：Enzyme-Linked ImmunoSorbent Assay (ELISA) 21 第五節 以西方點墨法分析細胞內蛋白質之表現 22 第六節 3XFLAG mC/EBPbeta S64A表現質體之建構 26 第七節 以luciferase assay進行小鼠之G-CSF promoter活性分析 30 第八節 DNA親和力沉澱分析法(DNA affinity precipitation assay, DAPA)分析ERK與RAW264.7細胞中G-CSF promoter的結合情形 33 第九節 以MTT assay測定U0126和PD98059對RAW264.7細胞的毒殺性 34 第十節 資料統計分析 35 第三章 實驗結果 36 第一節 探討MEK/ERKpathway的持續活化與LPS誘導G-CSF基因表現之關係 37 第二節 MEK/ERK pathway的活化以及與轉錄因子C/EBPbeta的影響G-CSF啟動子活性具有協同作用 39 第三節 ERK對於C/EBPbeta threonine 188的磷酸化與否影響G-CSF啟動子活性 41 第四節 探討U0126抑制ERK的活化對C/EBPbeta threonine 188磷酸化的影響 42 第五節 探討在LPS刺激後，ERK進入細胞核調控G-CSF基因轉錄的機制 42 第四章 討論 45 第一節 MEK/ERK pathway的活化影響LPS誘導的巨噬細胞G-CSF的表現 46 第二節 MEK/ERK pathway與轉錄因子C/EBPbeta影響G-CSF啟動子活性具有協同作用 47 第三節 ERK活化促進G-CSF基因轉錄活性並非完全透過影響C/EBPbeta的轉錄因子活性 48 第四節 ERK對於G-CSF基因轉錄的調控機制探討 50 第五節 MEK/ERK抑制劑應用於臨床治療慢性發炎疾病之評估 51 第六節 總結 53 第五章 圖表 55 參考文獻 84 附錄 101 圖 目 錄 Figure 1. LPS-induced G-CSF mRNA expression is inhibited by MEK1/2 inhibitor U0126 before or after LPS stimulation in RAW264.7 macrophages. 56 Figure 2. U0126, MEK1/2 inhibitor, inhibits G-CSF mRNA expression after LPS stimulation in a time-dependent manner in RAW264.7 macrophages. 57 Figure 3. LPS-induced increase in G-CSF mRNA expression was inhibited by MEK1 inhibitor PD98059 in a dose-dependent manner in RAW264.7 macrophages. 58 Figure 4. MEK1 inhibitor PD98059 inhibits LPS-induced G-CSF protein secretion in a dose-dependent manner in RAW264.7 macrophages. 59 Figure 5. MEK1 inhibitor PD98059 inhibits G-CSF mRNA expression after LPS stimulation in a time-dependent manner in RAW264.7 macrophages. 60 Figure 6. Cytotoxicity of U0126 and PD98059 on LPS-induced RAW264.7 macrophages. 62 Figure 7. MEK1/2 inhibitor U0126 inhibits LPS-induced G-CSF mRNA expression in a dose-dependent manner in mouse bone marrow-derived macrophages (BMDMs). 63 Figure 8. MEK1 inhibitor PD98059 inhibits LPS-induced G-CSF mRNA expression in a dose-dependent manner in mouse bone marrow-derived macrophages (BMDMs). 64 Figure 9. LPS-induced G-CSF mRNA expression is inhibited by MEK1/2 inhibitor U0126 before or after LPS stimulation in human monocytic cell line THP-1. 65 Figure 10. MEK1/2 inhibitor U0126 but not p38 inhibitor SB203580 inhibits LPS-induced G-CSF mRNA expression after LPS stimulation in THP-1. 66 Figure 11. Constitutive active ERK activates G-CSF promoter activity in a dose-dependent manner. 67 Figure 12. Co-transfection with CA-ERK and C/EBPbeta increase G-CSF promoter activity. 68 Figure 13. CA-ERK but not KD-ERK cotransfection with p50, Oct-2, and C/EBPbeta activates G-CSF promoter activity in a dose-dependent manner. 69 Figure 14. p65 cotransfection with CA-ERK, C/EBPbeta, p50, and Oct-2 doesn’t further activate G-CSF promoter activity. 70 Figure 15. MEK activates G-CSF promoter activity in a dose-dependent manner. 71 Figure 16. CA-MEK cotransfection with C/EBPbeta activates G-CSF promoter activity in a dose-dependent manner. 72 Figure 17. The wild type and different mutant forms of C/EBPbeta coding sequence were cloned into the p3XFLAG-Myc-CMV expression vector. 73 Figure 18. C/EBPbeta threonine 188 is important in the interaction with ERK to activate G-CSF promoter activity. 74 Figure 19. MEK1/2 inhibitor U0126 inhibits LPS-induced phosphorylation of ERK in RAW264.7 macrophages. 76 Figure 20. MEK1/2 inhibitor U0126 decreases LPS-induced phosphorylation of C/EBPbeta in RAW264.7 macrophages. 77 Figure 21. LPS treatment increases the level of phosphor-ERK and U0126 decreases level of phosphor-ERK in nucleus in RAW264.7 macrophages. 78 Figure 22. Binding of ERK and C/EBPbeta to the biotin-labeled G-CSF promoter probe containing NF-kB and C/EBPb element. 79 Figure 23. The binding of ERK on G-CSF promoter is influenced by the existence of G-CSF promoter (-202 to -163) competitor. 81 表 目 錄 Table 1. RT-PCR之primers. 82 Table 2. 建構mouse C/EBPbeta serine 64單點突變表現質體之primers. 82 Table 3. Biotinylated probe and G-CSF promoter competitor oligonucleotides. 83 Table 4. C/EBPbeta, NF-kappaB, Sp1 consensus sequences. 83 | |
| dc.language.iso | zh-TW | |
| dc.subject | 顆粒性白血球群落刺激因子 | zh_TW |
| dc.subject | 基因轉錄調控 | zh_TW |
| dc.subject | ERK | zh_TW |
| dc.subject | C/EBPbeta | zh_TW |
| dc.subject | MEK/ERK抑制劑U0126和PD98059 | zh_TW |
| dc.subject | 巨噬細胞 | zh_TW |
| dc.subject | G-CSF | en |
| dc.subject | U0126 | en |
| dc.subject | PD98059 | en |
| dc.subject | Macrophage | en |
| dc.subject | C/EBPbeta | en |
| dc.subject | ERK | en |
| dc.subject | gene transcription regulation | en |
| dc.title | MEK-ERK-C/EBPbeta在巨噬細胞中對脂多醣誘導G-CSF表現的必要角色 | zh_TW |
| dc.title | Essential Role of MEK-ERK-C/EBPbeta in LPS-induced G-CSF Expression in Macrophages | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 余明俊,繆希椿,張淑芬 | |
| dc.subject.keyword | 顆粒性白血球群落刺激因子,巨噬細胞,ERK,C/EBPbeta,基因轉錄調控,MEK/ERK抑制劑U0126和PD98059, | zh_TW |
| dc.subject.keyword | C/EBPbeta,ERK,G-CSF,gene transcription regulation,Macrophage,PD98059,U0126, | en |
| dc.relation.page | 109 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2011-07-27 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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