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系統識別號 U0026-2412201213161100
論文名稱(中文) 誘發性發炎轉錄因子CEBPD在阿茲海默症與類風溼性關節炎中的分子病理機制探討
論文名稱(英文) Investigation of inducible inflammatory factor CEBPD in molecular pathogenesis of Alzheimer’s disease and rheumatoid arthritis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 1
出版年 101
研究生(中文) 張玲華
研究生(英文) Ling-hua Chang
學號 S58961450
學位類別 博士
語文別 英文
論文頁數 101頁
口試委員 指導教授-黃暉升
召集委員-王育民
口試委員-湯銘哲
口試委員-何美泠
口試委員-許秉寧
中文關鍵字 發炎  阿茲海默症  類風溼性關節炎 
英文關鍵字 Inflammation  AD  RA  CEBPD 
學科別分類
中文摘要 發炎是身體抵禦外來病菌的重要機制,但過度的活化或不正常的誘發免疫機轉卻會形成一些嚴重的慢性發炎疾病。了解慢性發炎的病理機轉及其所誘發的發炎因子可提供將來治療的策略。由於CEBPD在一些老化相關的疾病中被發現有過度表現的現象,如阿茲海默氏癡呆症(縮寫AD)或類風濕性關節炎(縮寫RA),他們皆是一種慢性發炎的疾病,分別會造成智能的損失及關節的發炎和疼痛。然而CEBPD在AD和RA的病理機轉上扮演甚麼角色卻仍不清楚。CEBPD是一個轉錄因子,調控細胞的生長、分化、代謝,尤其在發炎時扮演很重要的角色。他能促進很多發炎相關因子的表現,包括IL1β和TNFα等。然而,CEBPD在巨噬細胞所調控的下游產物及發炎相關疾病卻仍不清楚。因此,我們使用微陣列與蛋白質陣列分析下游產物。在我們目前AD疾病的研究結果中發現,發炎會促進神經膠細胞(Astrocyte)的CEBPD表現上升,進而抑制巨噬細胞吞噬死亡的神經細胞。並且經由基因表現的檢測,我們找到CEBPD所調控的下游發炎分子PTX3,更進一步證實PTX3參與抑制巨噬細胞吞噬死亡的神經細胞。此結果導致死細胞的堆積,推測於是正回饋促進發炎的反應反而讓AD疾病更加惡化。由於過去研究發現RA病人服用抗發炎藥會減少AD疾病的發生率,因此,我們也有興趣研究在RA的疾病中,發炎會誘發甚麼致病因子,造成周圍組織的過度反應,結果我們在RA疾病的研究發現,使用collagen誘發小鼠關節炎的實驗動物模式中,無法成功誘發CEBPD缺陷的轉殖鼠關節炎且在臨床的數值上也比野生型的小鼠減少嚴重度。另外在組織切片的觀察上也發現CEBPD缺陷的轉殖鼠有比較少的滑液膜組織(pannus)增生,降低了細胞的生長與血管的形成。在免疫組織染色的分析上,我們也發現活化的CEBPD在巨噬細胞中扮演了促進內皮細胞形成血管與促進滑液膜細胞移動與增生的功能。使用染色體免疫沉澱測試及螢光酵素報告測試結果顯示,CEBPD轉錄因子會透過直接接合在CCL20, CXCL1, IL23A及TNFAIP6這些基因的啟動(promoter)區域上,進而調控這些基因的表現。此外,CCL20, IL23A,CXCL1及TNFAIP6共同促進滑液膜細胞的移動與增生,後兩者則促進內皮細胞形成血管。最後,我們利用了兩種藥物,Inotilone及Rosmanol透過抑制了CEBPD 的效力進而抑制了滑液膜增生與血管形成的現象。整體而言,我們的研究發現也許在將來CEBPD及它的下游因子可以做為診斷阿茲海默症及類風濕性關節炎的生物指標和治療標的。
英文摘要 Inflammation is described as the principal response of the body invoked to deal with a defense against foreign pathogens. However, over-activation or abnormal trigger immune machinery will perform many chronic inflammatory diseases. Recognizing the pathogenesis of chronic inflammation and the inflammatory mediators may provide treatment strategies in the future. The up-regulation of CCAAT enhancer binding protein delta (CEBPD) has frequently been observed in age-associated inflammation disorders, including Alzheimer’s disease (AD) or rheumatoid arthritis (RA). However, the role of CEBPD in the pathogenesis of AD and RA is unclear. CEBPD, a transcription factor, participate in cell growth, differentiation, metabolism and especially in immune response. CEBPD is up-regulated by a variety of inflammatory stimuli, such as IL-1β and TNFα. However, CEBPD-mediated gene expressions in macrophages are not well understood, nor are their consequent effects in inflammatory diseases. Therefore, we used microarray and cytokinearray to analyze the downstream targets in CEBPD-regulate macrophage. In our present study of AD, a novel role of CEBPD in attenuating macrophage-mediated phagocytosis of damaged neuron cells was found. By global gene expression profiling, we identified the inflammatory marker pentraxin-3 (PTX3, TNFAIP5, TSG-14) as a CEBPD target in astrocytes. Furthermore, we demonstrate that PTX3 participates in the attenuation of macrophage-mediated phagocytosis of damaged neuron cells. This study provides the first demonstration of a role for astrocytic CEBPD and the CEBPD-regulated molecule PTX3 in the accumulation of damaged neurons, which is a hallmark of AD pathogenesis. The previous studies have found that reduced prevalence of AD in long-using NSAIDs RA patients. We, therefore, have interested to investigate which factors resulting in the over-reaction of the surrounding tissue of RA. Collagen-induced arthritis (CIA) is an animal model of RA that has been studied extensively. The results showed that the CIA score and the number of affected paws in Cebpd-/- mice were significantly decreased compared with the wild-type (WT) mice. The histological analysis revealed an attenuated CIA in Cebpd-/- mice, as shown by reduced pannus formation and greater integrity of joint architecture in affected paws of Cebpd-/- mice compared with WT mice. In addition, immunohistochemistry analysis revealed decreased pannus proliferation and angiogenesis in Cebpd-/- mice compared with WT mice. CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. CCL20, IL23A, CXCL1 and TNFAIP6 contributed to the migration and proliferation of synoviocytes, and the latter two proteins were involved in tube formation of endothelial cells. Finally, two anti-inflammatory chemicals, inotilone and rosmanol, reduced the expression of CEBPD and its downstream targets and mitigated the above phenomena. Collectively, our findings suggest that CEBPD and its downstream effectors could be biomarkers for the diagnosis or serve as therapeutic targets for AD and RA therapy.
論文目次 Contents

Abstract………………………………………………………………………………..i
Abstract in Chinese……………………………..…………………………………...iii
Acknowledgments………………………………………………………………….....v
Contents…… …………………………………………………………...…………..vii
Figure contents……………………………………………………………………….x
Abbreviations list…………………………………………………………………..xiii


Chapter 1. Introduction
A. The commonality of inflammation-related diseases…………………………1
B. Transcription factors in inflammation-related diseases………………………2
C. CCAAT/enhancer binding protein family…………………………………….4
C-1 CCAAT enhancer binding protein delta (CEBPD)…………………..5
C-2 The role of CEBPD in the chronic and acute-response inflammation 5
C-3 CEBPD in Age- and inflammation-related diseases………………….6
D. Overview of Alzheimer’s disease …….……………………………………....6
D-1 The introduction of CEBPD in Alzheimer’s disease…………………8
D-2 Mechanism of phagocytosis in macrophages……………………..….8
D-3 The role of PTX-3 in inflammation-related diseases……………….10
E. Overview of rheumatoid arthritis ……………………………………………11
E-1 The introduction of CEBPD in rheumatoid arthritis………………..11
E-2 Macrophages in rheumatoid arthritis ……………………………….12
E-3 Cytokines and chemokines in rheumatoid arthritis…………………12
E-4 CEBPD could be a potent target for therapy of inflammatory diseases………………………………………..…………………….13
F. Brief summary………………………………………………………………..15

Chapter 2. Materials and methods……………………………………………..… 17
2-1 Materials……………………………………………………………………17
2-2 Methods……………………………………………………………………..17
Cells culture and primary mouse synovial fibroblasts and macrophages isolation………………………………………………………………17
Conditioned medium collection and Inotilone and Rosmanol treatment….18
Microarray analysis and Reverse Transcription-PCR (RT-PCR)………….19
Short hairpin RNA (shRNA) assay………………………………………..20
Reporter plasmids and luciferase assay……………………………………20
ChIP assay…………………………………………………………………21
Western blotting…………………………………………………………...21
Human protein cytokine array……………………………………………..22
Enzyme Linked Immunosorbent assay (ELISA)………………………………………22
In vitro cell migration and cell proliferation assays………………………23
In vitro endothelial tube formation assay………………………………….23
Phagocytosis assay………………………………………………………...23
Cebpd-deficient mice, collagen-induced arthritis and assessment of arthritis …………………………………………………………...……….25
Histochemistry and immunohistochemical staining………………………26
Statistical analysis…………………………………………………………26

Chapter 3. Results…………………………………………………………………..28
CEBPD expression is induced by proinflammatory cytokines in U373MG and THP-1 cells………………………………………………………………..28
Indentification and verification of CEBPD regulated downstream targets in U373MG and THP-1 cells…………………………………………………29
Conditioned medium from U373MG cells overexpressing CEBPD inhibits the phagocytosis of apoptotic neuron cells……………………………………29
Overexpression of CEBPD increases PTX3 transcripts in U373MG cells……..30
PTX3 inhibits phagocytosis of apoptotic cells by macrophages and enhances the apoptosis of SH-SY5Y cells……………………………………………….30
CEBPD plays an important role in CIA induction in mice…………………..…31
Loss of CEBPD is coincident with less cell growth and angiogenesis…………32
Macrophage CEBPD contributes to the proliferation and migration of synoviocytes……………………………………………………………….33
Endothelial cell tube formation responds to CEBPD-modulated conditioned medium………………………………………………………………..…...34
Identification of CEBPD downstream targets in macrophages…………………35
The effects of CCL20, CXCL1, IL23A and TNFAIP6 on the migration and proliferation of rFLS and the tube formation ability of HUVECs………..36
The anti-inflammatory chemicals inotilone and rosmanol inhibit the proliferation and migration of rFLS and the angiogenesis of HUVECs………………..37

Chapter 4. Discussion……………………………………………………………….38
References…...………………………………………………………………………47
Figures and legends…………………………………………………………………59
Appendixes…………………………………………………………………………..98
Curriculum vitae…………………………………………………………………..100

Figure contents

Figure 1. CCAAT/enhancer binding protein delta (CEBPD) expression is induced by proinflammatory cytokines.……………………………………………………………………..59
Figure 2. Identification of CEBPD regulated genes in U373MG cells.……………...60
Figure 3. Phagocytosis of apoptotic SH-SY5Y neuronal cells by THP-1 derived macrophages……………………………………………………………………………………………61
Figure 4. Conditioned medium from U373MG cells overexpressing CEBPD inhibits the phagocytosis of apoptotic SH-SY5Y cells or primary neurons by macrophage……………………………………………………………….………………….………..62
Figure 5. Overexpression of CEBPD increases PTX3 transcripts.………………….……….63
Figure 6. PTX3 inhibits phagocytosis of apoptotic cells by macrophages……….………64
Figure 7. PTX3 enhances the acculmulation of dying SH-SY5Y cells.…………………...65
Figure 8. Cebpd plays an important role in CIA mice……………………………….66
Figure 9. Pannus, destruction of the articular surface and ankylosis are decreased in CIA Cebpd–/– mice……………………………….....................................67
Figure 10. Synoviocytes growth decreased in CIA Cebpd–/– mice……………….….68
Figure 11. Angiogenesis decreased in CIA Cebpd–/– mice…………………………..69
Figure 12. The accumulation and distribution of macrophages has no difference in CIA wt and Cebpd–/– mice………………………………………………..70
Figure 13. Macrophage CEBPD elevations in proinflammatory cytokines treatment………………………………………………………………….71
Figure 14. Verification and identification of transient transfection CEBPD in THP-1 cells and cytokinearray detecting the potential targets from overexpression CEBPD conditioned medium…………………………………………….72
Figure 15. Verification of lentiviral knockdown CEBPD system and profiling of genes modulated by CEBPD in THP-1 cells…………………………………...73
Figure 16. CEBPD promotes rFLS proliferation in vitro……………………………74
Figure 17. CEBPD downstream targets mediated the effect of proliferation on HUVEC…………………………………………………………………..75
Figure 18. CEBPD promotes rFLS migration in vitro……………………………….76
Figure 19. Conditioned medium harvested from overexpression CEBPD promotes endothelial cell tube formation…………………………………………..77
Figure 20. Conditioned medium harvested from knockdown CEBPD inhibits endothelial cell tube formation…………………………………………..78
Figure 21. Verification of CEBPD-modulated downstream targets, CCL20, CXCL1, IL23A and TNFAIP6 in THP-1 and primary mice macrophages…………………………………………………….……….79
Figure 22. CCL20, CXCL1, IL23A and TNFAIP6 genes are responsive to CEBPD activation in THP-1 and u937 cells………………………………………80
Figure 23. CCL20, CXCL1, IL23A and TNFAIP6 genes are responsive to CEBPD activation in THP-1 cells…………………………………………………81
Figure 24. CEBPD directly bind to the CCL20, CXCL1, IL23A and TNFAIP6 promoters…………………………………………………………………82
Figure 25. Verification of lentiviral shRNAs against CCL20, CXCL1, IL23A and TNFAIP6 in THP-1 cells…………………………………………………83
Figure 26. CCL20, CXCL1, IL23A and TNFAIP6 contribute to the proliferation of rFLS cells………………………………………………………………...84
Figure 27. CCL20, CXCL1, IL23A and TNFAIP6 contribute to the migration of rFLS cells………………………………………………………………………85
Figure 28. CXCL1 and TNFAIP6 increase endothelial cell tube formation………..86
Figure 29. Inotilone and rosmanol inhibit CEBPD, CCL20, CXCL1, IL23A and TNFAIP6 transcription in THP-1 cells.…………………………………..87
Figure 30. Inotilone and rosmanol inhibit the proliferation of rFLS.………………...88
Figure 31. Inotilone and rosmanol inhibit the migration of rFLS……………………89
Figure 32. Inotilone and rosmanol inhibit the endothelial tube formation of HUVECs……………………………………............................................90
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