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系統識別號 U0026-2008201217520800
論文名稱(中文) 登革病毒感染誘導肝醣合成酶激酶3調控單核球介白素10之生成
論文名稱(英文) Infection of Dengue Virus Causes Glycogen Synthase Kinase-3-regulated IL-10 Production in Monocytes
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 100
學期 2
出版年 101
研究生(中文) 莊宜叡
研究生(英文) Yi-Jui Chuang
學號 S46991075
學位類別 碩士
語文別 英文
論文頁數 60頁
口試委員 指導教授-林秋烽
口試委員-林以行
口試委員-伍安怡
中文關鍵字 登革病毒  介白素10  蛋白質激酶A  蛋白質激酶B  環磷酸腺苷反應元件結合蛋白  肝醣合成酶激酶3 
英文關鍵字 Dengue  Interleukin-10  PKA  PKB  CREB  GSK-3β 
學科別分類
中文摘要 登革病毒 (DV) 感染造成的臨床症狀包含輕微的登革熱以及嚴重的登革出血熱與登革休克症候群。臨床研究證實登革重症病患血清中所表現的抗發炎細胞激素介白素10 (IL-10) 較登革輕症病患高;然而,登革病毒調控介白素10表現之確切分子機制以及其在病理上的意義目前尚未明瞭。本研究論文證實登革病毒感染人類單核球細胞株THP-1可誘導介白素10以及其下游訊息分子細胞激素訊號抑制分子3 (SOCS3) 的表現。進一步發現登革病毒可藉由蛋白質激酶A (PKA) 活化磷脂酰肌醇3激酶 (PI3K)/蛋白質激酶B (PKB) 進而促使轉錄因子環磷酸腺苷反應元件結合蛋白 (CREB) 磷酸化並且入核轉錄誘導介白素10的產生。實驗室先前研究證實肝醣合成酶激酶3 (GSK-3) 可藉由抑制環磷酸腺苷反應元件结合蛋白活性,以降低介白素10生成。而登革病毒感染後確實可藉由蛋白質激酶A/磷脂酰肌醇3激酶訊息路徑抑制肝醣合成酶激酶3的活性;且利用肝醣合成酶激酶3抑制劑可增加登革病毒所誘導之環磷酸腺苷反應元件結合蛋白磷酸化以及介白素10表現量。然而不僅僅是TLR3非依賴性作用,抑制已知的登革病毒受器包括CD209 (DC-SIGN)、CD29 (integrin β1) 以及CD61 (integrin β3) 並不會影響介白素10生成。除此之外,登革病毒所誘導之介白素10亦可促成登革病毒之複製作用及破壞干擾素γ (IFN-γ) 的訊息傳遞。由上述結果指出,登革病毒感染單核球後可藉由調控蛋白質激酶A/磷脂酰肌醇3激酶/蛋白質激酶B/肝醣合成酶激酶3/環磷酸腺苷反應元件結合蛋白的活性誘導介白素10生成,並可能促成介白素10/細胞激素訊號抑制分子3所媒介之免疫逃脫現象。
英文摘要 Dengue virus (DV)-caused anti-inflammatory cytokine interleukin (IL)-10 production is much higher in patients with severe dengue hemorrhagic fever and dengue shock syndrome than those with mild dengue fever; however, the mechanism underlying IL-10 regulation and its pathological significance remain unclear. Here we show that DV infection significantly increases IL-10-mediated expression of suppressor of cytokine signaling 3 in human monocytic THP-1 cells. In DV-infected cells, activation of cyclic adenosine monophosphate (cAMP) response element-binding (CREB), largely through protein kinase A (PKA)- and phosphoinositide (PI) 3-kinase-regulated manners, determines IL-10 increase. Furthermore, sequential activation of PKA facilitates PI3K/PKB signaling. Notably, DV infection causes glycogen synthase kinase (GSK)-3 inactivation in a PKA/PI3K-regulated manner and inhibiting GSK-3 considerably increases DV-induced IL-10 following CREB activation. However, not only TLR3 independently, blocking the well-known DV receptors, including heparan sulfate, CD209 (DC-SIGN), CD29 (integrin β1), and CD61 (integrin β3), do not inhibit DV-induced IL-10. This study also explore the effects of IL-10 signaling on facilitation of viral replication. These results show a molecular basis of PKA/PI3K/PKB/GSK-3/CREB for DV infection-induced IL-10 production followed by IL-10/SOCS3-mediated advantages for viral replication in monocytes.
論文目次 中文摘要 I
Abstract II
誌謝 III
Abbreviations IV
Contents VII
I. Introduction 1
I-1. Characteristics of DV 1
I-2. Epidemiology of DV 4
I-3. Clinical symptoms and laboratory findings of DV infection 5
I-4. Mechanisms of DHF/DSS pathogenesis 5
I-5. IL-10 7
I-6. The role of IL-10 in dengue disease 8
I-7. Interferon 10
I-8. Glycogen synthase kinase-3β 11
II. Study Objective and Specific Aims 13
II-1. Objective 13
II-2. Specific aims 13
1. To check the expression and function of IL-10 in DV-infected monocytes. 13
2. To investigate the role of CREB in DV-induced IL-10 production. 13
3. To clarify the activity of GSK-3β in DV-induced IL-10 production. 13
4. To test the involvement of cell surface molecules in DV-induced IL-10 production. 13
5. To investigate the role of IL-10 during DV infection. 13
III. Materials and Methods 14
III-1. Cell lines, reagents, and antibodies 14
III-2. Virus culture 15
III-3. Plaque assay 15
III-4. DV infection 15
III-5. UV inactivation 16
III-6. Western blotting 16
III-7. ELISA 16
III-8. PKA activity assay 16
III-9. PIP3 generation assay 16
III-10. Immunostaining 17
III-11. RNA interference 17
III-12. Cytotoxicity assay 18
III-13. Statistical analysis 18
IV. Results 19
IV-1. Infection of DV causes IL-10 production and its downstream SOCS3 expression in human monocytic THP-1 cells 19
IV-2. DV infection induces PKA- and PI3K-regulated CREB activation followed by CREB-mediated IL-10 production 19
IV-3. DV infection induces PKA activation leading to PI3K/PKB activation 20
IV-4. PKA/PKB-regulated GSK-3 inactivation is also involved for DV-facilitated CREB-mediated IL-10 production 21
IV-5. Signaling of TLR3, DC-SIGN, β1- and β3-integrins, and heparan sulfate is not involved for DV-induced IL-10 production 22
IV-6. DV-induced IL-10 production mediates IFN-γ/STAT1 signaling inhibition 23
V. Discussion 24
VI. Conclusion and Implication 28
References 29
Figures and Figure Legends 39
Figure 1. DV infection induces IL-10 production and activation in human monocytic THP-1 cells. 39
Figure 2. DV infection induces CREB-mediated IL-10 production through PKA- and PI3K-regulated pathways. 40
Figure 3. DV infection activates PKA followed by PKA-regulated PI3K/PKB. 42
Figure 4. DV infection induces PKA/PI3K-regulated GSK-3β inactivation, which facilitates CREB-mediated IL-10 production. 43
Figure 5. DV infection induces IL-10 production independent of heparan sulfate, DC-SIGN, β1- and β3-integrins, and TLR3 signaling. 45
Figure 6. DV-induced IL-10 facilitates virus escape from IFN-γ/STAT1-mediated antiviral immunosurveillance. 47
Figure 7. A model of IL-10 induction in DV-infected monocytes. 48
Appendix 49
A. Materials 49
A-1 Chemicals 49
A-2 Antibodies 50
A-3 Kits 51
A-4 Consumables 52
A-5 Apparatus 52
B. Methods 53
B-1 Cell culture 53
B-2 Western blot 55
B-3 Lentiviral-based shRNA knockdown 57
Curriculum Vitae 60
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