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系統識別號 U0026-2101201416363700
論文名稱(中文) 肝醣合成酶激酶-3 於干擾素-γ 訊息傳遞及其生物功能的角色
論文名稱(英文) Glycogen Synthase Kinase-3 in Interferon-γ Signaling and Biofunction
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 102
學期 1
出版年 103
研究生(中文) 蔡政潔
研究生(英文) Cheng-Chieh Tsai
學號 S58961353
學位類別 博士
語文別 英文
論文頁數 108頁
口試委員 指導教授-林秋烽
召集委員-林以行
口試委員-楊倍昌
口試委員-蔡佩珍
口試委員-胡承波
口試委員-許秉寧
中文關鍵字 干擾素-γ  刀豆素A  訊息傳遞與轉錄活化因子  肝醣合成酶激酶-3  去磷酸酶  訊息傳遞  肝炎 
英文關鍵字 IFN-γ  ConA  STAT1  GSK-3  SHP2  Signal Transduction  Hepatitis 
學科別分類
中文摘要 肝醣合成酶激酶-3 (GSK-3) 是細胞中的一種絲氨酸/酥氨酸激酶,對於細胞分化、增殖及凋亡有重要的調控。肝醣合成酶激酶-3具有調控干擾素-γ (IFN-γ) 訊息傳遞的角色,同時也參與在干擾素-γ所誘導的發炎反應。可誘發急性肝損傷的刀豆素A是從刀豆 (Canavalia ensiformis) 種子分離出來的凝集素 (lectin),為一群醣結合性蛋白質(carbohydrate-binding protein),已被認知是可誘發免疫性肝損傷的實驗性模式。過去的研究已經證實,缺乏干擾素-γ及訊息傳遞與轉錄活化因子 (signal transducer and activator of transcription 1; STAT1) 的老鼠較能抵抗刀豆素A所誘發的免疫性肝炎。然而,刀豆素A刺激之下,肝醣合成酶激酶-3對於干擾素-γ所媒介的免疫性肝炎之角色,目前尚無提出確切的解釋。本論文將探討肝醣合成酶激酶-3在免疫性肝炎中扮演的致病性角色。論文的結果將可釐清肝醣合成酶激酶-3對於干擾素-γ媒介的相關肝疾病其調控發炎及凋亡之機制,並作為抗干擾素-γ所媒介的免疫性肝炎藥物發展之策略。本論文為探討干擾素-γ誘發的發炎反應中,肝醣合成酶激酶-3活化之機制及其活化後造成的影響。結果顯示,以肝醣合成酶激酶-3β抑制劑及干擾子處理細胞後減少了干擾素-γ誘發的發炎反應,包括誘導型一氧化氮合成酶 (iNOS)/一氧化氮 (NO) 的合成及促發炎細胞激素及化學趨化激素生成。在干擾素-γ刺激之下,可藉由兩種不同的機制活化肝醣合成酶激酶-3β,包括活化蛋白質去磷酸酶 (PPase) 並在GSK-3β Ser9位置去磷酸根以及活化富含脯氨酸的酪氨酸激酶2 (Proline-rich tyrosine kinase 2; Pyk2),磷酸化GSK-3β Tyr216位置。抑制肝醣合成酶激酶-3β的訊號之後,同時活化了Src homology region 2 domain-containing phosphatase 2 (SHP2),進而阻止干擾素-γ誘導之後期訊息傳遞與轉錄活化因子1的活化。這樣的研究結果顯示,活化的肝醣合成酶激酶-3β透過抑制SHP2,促使干擾素-γ所誘導的訊息傳遞與轉錄活化因子1 (STAT1) 更加活化。因此,我進一步去證實抑制肝醣合成酶激酶-3是否可影響干擾素-γ所媒介的免疫性肝炎。刀豆素A誘發的免疫性肝炎主要歸因於干擾素-γ媒介之發炎反應,進而造成肝細胞死亡。肝醣合成酶激酶-3扮演著促凋亡及促發炎的角色,亦調控著干擾素-γ的訊息傳遞。在刀豆素A刺激之下,可誘導C57BL/6老鼠肝臟中的肝醣合成酶激酶-3活化。抑制肝醣合成酶激酶-3可降低刀豆素A誘發的肝損傷,包括肝細胞的壞死及凋亡、發炎反應、T細胞及顆粒性白血球的浸潤及細胞黏附因子-1 的表現也都受到抑制。刀豆素A誘發的肝損傷是需要干擾素-γ接受器1。刀豆素A/干擾素-γ誘導訊息傳遞與轉錄活化因子1則是需要肝醣合成酶激酶-3。體外 (in vitro) 實驗結果發現,肝醣合成酶激酶-3可促使干擾素-γ誘發的誘導型一氧化氮合成酶表現,但對於促進CD95的表現及CD95所媒介的肝細胞凋亡作用則是有限的。特別的是,給予肝醣合成酶激酶-3抑制劑,不管是在接受刀豆素A刺激後的正常亦或是缺乏干擾素-γ接受器1的C57BL/6老鼠模式下,產生干擾素-γ的能力都受到抑制。刀豆素A刺激之下活化了自然殺手T細胞 (NKT),同時也活化肝醣合成酶激酶3,並促使干擾素-γ轉錄因子T-box轉錄因子 (Tbx21) 的入核,但肝醣合成酶激酶-3對於CD95配體的表現或活化誘導之細胞死亡是不被需要的。綜合以上敘述,這樣的結果證實了在刀豆素A誘發的肝損傷中,肝醣合成酶激酶-3對於干擾素-γ所媒介之肝臟病變扮演著不可或缺的促發炎及促凋亡角色,同時可針對抑制肝醣合成酶激酶-3的作用來治療干擾素-γ媒介的肝臟疾病。
英文摘要 Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which possesses multiple regulatory roles on cell differentiation, proliferation, and apoptosis. GSK-3 is a regulator in interferon-γ (IFN-γ) signaling and is involved in IFN-γ-induced inflammation. Acute hepatic injury is induced by mitogenic concanavalin A (ConA), a lectin (carbohydrate-binding protein) originally extracted from the jack-bean Canavalia ensiformis, has been established as an experimental model of immune hepatic injury. IFN-γ and signal transducer and activator of transcription 1 (STAT1) deficient mice are resistant to ConA-induced immune hepatitis have been widely demonstrated. However, the role of GSK-3 in ConA-induced IFN-γ-mediated immune hepatic injury is not well understood. The aim of this thesis is to examine the pathogenic role of GSK-3 in immune hepatic injury. Results may shed light on the mechanisms by which GSK-3 regulates inflammation and apoptosis in IFN-γ-related liver diseases and serve as an anti-inflammatory therapeutic strategy. In this thesis, the mechanism that activates GSK-3 and the effects of activation on IFN-γ-induced inflammation were investigated. Results showed that treating cells with GSK-3β inhibitor and short interfering RNA showed a decrease on IFN-γ-induced inflammatory responses, including inducible nitric oxide synthase (iNOS)/nitric oxide (NO) biosynthesis and proinflammatory cytokine and chemokine production. Following IFN-γ stimulation, activation of GSK-3β was regulated by two distinct mechanisms, which included okadaic acid (OA)-sensitive phosphatase (PPase)-mediated dephosphorylation at Ser9 and proline-rich tyrosine kinase (Pyk2)-mediated phosphorylation at Tyr216. Inhibiting GSK-3β activated SH2 domain-containing tyrosine phosphatase (SHP2), thereby preventing STAT1 activation in the late stage of IFN-γ stimulation. These results demonstrate that activated GSK-3β synergistically affected IFN-γ-induced STAT1 activation by inhibiting SHP2. Therefore, I further examined the effects of GSK-3 inhibition on IFN-γ mediated immune hepatitis. Immune hepatic injury induced by ConA results primarily from IFN-γ-mediated inflammation, followed by hepatic cell death. GSK-3, which acts proapoptotically and is proinflammatory, is also important for facilitating IFN-γ signaling. ConA stimulation caused GSK-3 activation in the livers of C57BL/6 mice. GSK-3 inhibition reduced ConA hepatic injury, including hepatic necrosis and apoptosis, inflammation, infiltration of T cells and granulocytes, and deregulated expression of intercellular adhesion molecule-1 (ICAM-1). ConA induced hepatic injury in an IFN-γ receptor 1 (IFNGR1)-dependent manner. ConA/IFN-γ induced activation and expression of STAT1 in a GSK-3-dependent manner. GSK-3 facilitated IFN-γ-induced iNOS, but had limited effects on CD95 upregulation and CD95-mediated hepatocyte apoptosis in vitro. Notably, inhibiting GSK-3 decreased ConA-induced IFN-γ production in both wild-type and IFNGR1-deficient C57BL/6 mice. In ConA-activated natural killer T (NKT) cells, GSK-3 was also activated and was required for nuclear translocation of T-box transcription factor Tbx21 (T-bet), a transcription factor of IFN-γ, but it was not required for CD95 ligand expression or activation-induced cell death. Taken together, these data demonstrate the proinflammatory and proapoptotic roles of GSK-3 are indispensable in the pathogenesis of immune hepatic injury, and targeting GSK-3 can be used for the treatment of IFN-γ-related liver diseases.
論文目次 Abstract...................................................I
摘要.....................................................III
誌謝.......................................................V
Contents..................................................VI
Figure Lists...............................................X
Abbreviations.............................................XI
1 Introduction.......................................1
1-1 Glycogen Synthase Kinase-3 (GSK-3).....................1
1-1-1 Regulation of GSK-3..................................1
1-1-2 GSK-3 in apoptosis...................................2
1-1-3 GSK-3 and inflammation...............................3
1-2 IFNs and their receptors...............................3
1-2-1 IFNs bioactivities...................................4
1-2-1-1 The IFNs-induced antiviral state...................4
1-2-1-2 Cell growth and apoptosis..........................5
1-2-1-3 MHC antigen presentation pathways..................6
1-2-1-4 Development of Th1 response........................7
1-2-1-5 IFN-γ priming of the macrophage LPS response......7
1-2-1-6 Immunomodulation and leukocyte trafficking.........7
1-2-1-7 Activation of microbial effector functions.........8
1-2-2 IFN-γ signaling.....................................8
1-2-3 The negative-feedback regulation of IFN-γ signaling..................................................9
1-2-3-1 The suppressors of cytokine signaling (SOCSs)......9
1-2-3-2 The SH2-containing phosphatase (SHP)...............9
1-2-4 GSK-3 involves in IFN-γ bioactivities..............10
1-2-5 Molecular mechanisms of GSK-3β activation in IFN-γ signaling.................................................10
1-2-5-1 PC-PLC/DAG/PKC/Src/Pyk2 pathway...................10
1-2-5-2 nSMase/PPase pathway..............................11
1-3 IFN-γ and immune-mediated diseases...................12
1-3-1 Characterization of liver...........................12
1-3-2 Immune-mediated hepatic injury......................13
1-3-3 ConA-induced T cells-mediated hepatic injury........13
1-3-4 Pathogenesis of ConA-induced IFN-γ-mediated hepatic injury....................................................14
1-3-4-1 Cellular effectors................................14
1-3-4-2 Molecular effectors...............................15
1-3-5 IFN-γ producing cells and T-box transcription factor Tbx21 (T-bet).............................................16
1-3-6 GSK-3 in ConA-induced IFN-γ-mediated hepatic injury....................................................16
2 Objectives and Specific Aims......................18
3 Materials and Methods.............................20
3-1 Mice..................................................20
3-2 Cell line and cell culture............................20
3-3 Antibodies............................................20
3-4 Reagents..............................................21
3-5 Protein silencing.....................................21
3-5-1 Transcient transfection.............................21
3-5-2 Stable knockdown using lentiviral-based shRNA.......22
3-6 Reverse transcription polymerase chain reaction (RT-PCR)..................................................22
3-7 Western blot analysis.................................23
3-8 Nitrite assay.........................................23
3-9 Protein tyrosine phosphatase (PTPase) assay...........23
3-10 Sphinogomyelinase assay..............................24
3-11 Induction of ConA-induced hepatic injury.............24
3-12 Isolation of primary cells...........................24
3-13 Isolation of liver MNCs..............................24
3-14 FACS analysis........................................25
3-15 Pathological examination.............................25
3-15-1 Blood analysis.....................................25
3-15-2 Liver histology....................................25
3-16 Immunohistochemistry and immunostaining..............26
3-17 Luciferase reporter assay............................26
3-18 Apoptosis assay......................................27
3-19 Cytotoxicity assay...................................27
3-20 Enzyme-linked immunosorbent assay (ELISA)............27
3-21 Statistical analysis.................................28
4 Results...........................................29
4-1 IFN-γ induces inflammation in RAW264.7 murine macrophage................................................29
4-2 Inhibiting GSK-3β reduces IFN-γ-induced iNOS/NO biosynthesis and TNF-α and RANTES production.............29
4-3 IFN-γ induces neutral SMase-, PPase-, and Pyk2-regulated GSK-3β activation and inflammation........29
4-4 IFN-γ induces PC-PLC-, PKC-, and Src-regulated Pyk2 and GSK-3β activation and inflammation...................30
4-5 Signaling of Jak2, PC-PLC, PKC, and cPLA2 are critical for IFN-γ-induced activation of neutral SMase and GSK-3β as well as inflammation...................................31
4-6 Bioactive lipids sustaines IFN-γ-induced STAT1activation...........................................31
4-7 GSK-3β facilitates IFN-γ-induced STAT1 activation...31
4-8 GSK-3β is critical for IFN-γ-activated STAT1 and inflammation independent of tyrosine kinases and MAPKs-regulated pathway.........................................31
4-9 GSK-3β negative regulates SHP2 phosphorylation and its kinase activity...........................................32
4-10 GSK-3β facilitates IFN-γ-induced STAT1 activation and inflammation through SHP2 inhibition..................32
4-11 A schematic diagram for GSK-3β facilitated IFN-γ-induced persistent STAT1 activation and inflammation......32
4-12 ConA treatment activates GSK-3 in liver..............33
4-13 GSK-3 inhibition prevents ConA-induced hepatic injury....................................................34
4-14 ConA-induced STAT1 activation is reduced in IFNGR1 deficient mice............................................34
4-15 ConA-induced hepatic injury is attenuated in IFNGR1-deficient mice............................................34
4-16 GSK-3 mediates ConA/IFN-γ-activated STAT1 signaling.................................................35
4-17 GSK-3 facilitates IFN-γ-induced iNOS expression in vitro.....................................................35
4-18 GSK-3 has limited effects on either CD95 upregulation or CD95-mediated hepatocyte apoptosis in vitro............35
4-19 Inhibiting GSK-3 reduces ConA-induced IFN-γ production................................................36
4-20 GSK-3 mediates ConA-induced cytokine production......36
4-21 ConA induces activation-induced cell death and CD95 ligand expression in NKT cells is independent of GSK-3....36
4-22 GSK-3 facilitates IFN-γ production in ConA-activated hepatic NKT cells.........................................37
4-23 Activated GSK-3 facilitates IFN-γ production in ConA-activated hepatic NKT cells through a mechanism involving T-bet activation................................37
4-24 Schematic model for GSK-3-facilitated ConA hepatic injury....................................................37
5 Discussion........................................38
GSK-3β facilitated IFN-γ-induced STAT1 activation by inhibiting SHP2...........................................38
Regulation of IFN-γ signaling............................38
The role of GSK-3β in IFN-γ-activated Jak-STAT1 signaling.................................................38
Mechanism of STAT1 inactivation...........................39
Mechanism of GSK-3β negatively regulated SHP2............39
GSK-3 facilitates ConA-activated NKT cells to secrete IFN-γ through activating T-bet...........................40
Mechanism of IFN-γ-, ConA-induced GSK-3 activation.......40
The role of GSK-3 in ConA-induced cytokine production.....41
The role of GSK-3 in ConA-induced cytokine-mediated immune hepatic injury............................................41
Glycogen metabolism effect of GSK-3 in ConA-induced hepatic injury....................................................42
Apoptotic action of GSK-3 in ConA-induced hepatic injury..42
The role of IFN-γ in ConA-induced hepatic injury.........43
The potential role of SHP2 in ConA-induced hepatic injury.44
The role of GSK-3 in ConA-activated NKT cells.............44
References................................................46
Figures...................................................74
Appendix..................................................98
Curriculum vitae.........................................105
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