臺灣博碩士論文加值系統

肝醣合成酶激酶-3beta (GSK-3beta)，屬於Serine/Threonine kinase並可調控蛋白質生成、細胞生長、分化、凋亡及發炎反應。我們先前的研究指出丙型干擾素 (IFN-gamma) 誘導發炎反應中肝醣合成酶激酶-3beta扮演重要的角色，但其活化的機制仍不清楚。以干擾子及抑制劑的實驗證實抑制肝醣合成酶激酶-3beta的活性能夠降低丙型干擾素所造成的一氧化氮及細胞激素的產生。本篇研究中，我們進一步想探討肝醣合成酶激酶-3beta的活化機制。在丙型干擾素的刺激下，蛋白質去磷酸酶 (phosphatase) 會造成肝醣合成酶激酶-3beta絲胺9酸的位點磷酸化減少而proline-rich tyrosine kinase 2 (Pyk2) 會造成肝醣合成酶激酶-3beta酪氨酸216的位點磷酸化增加，進而活化肝醣合成酶激酶-3beta。神經醯胺 (ceramide) 可能參與活化蛋白質去磷酸酶，因此，我們加以探討神經醯胺扮演的角色。實驗顯示透過中性神經磷質水解酶 (neutral sphingomyelinase) 降解生成的神經醯胺進而調控了肝醣合成酶激酶-3beta的活化。丙型干擾素刺激活化巨噬細胞的訊息傳遞中，phosphatidylcholine-specific phospholipase C (PC-PLC), protein kinase C (PKC)以及Src等調節作用將可活化了Pyk2以及肝醣合成酶激酶-3beta。活化PC-PLC, Pyk2和肝醣合成酶激酶-3beta係由丙型干擾素接受器第二型 (IFNGR2) 活化Jak2所調控。有趣的是，我們的結果也顯示了中性神經磷質水解酶也會調控Jak2, PC-PLC, PKC以及cytosolic PLA2 (cPLA2)。cPLA2也扮演調控活化肝醣合成酶激酶-3的角色。此外，活化nuclear factor kappa B (NF-kB) 的訊號中,是透過肝醣合成酶激酶-3beta調節Jak2進而影響dsRNA-dependent kinase-IkB kinase-inhibitor of NF-kB。並且，肝醣合成酶激酶-3beta透過抑制Src homology-2 domain-containing phosphahase 2而活化Jak2到NF-kB的訊息傳遞。綜合以上的結果顯示，丙型干擾素的刺激下，PC-PLC, cPLA2以及神經醯胺這些生物脂質可活化肝醣合成酶激酶-3beta。

Glycogen synthase kinase-3beta (GSK-3beta), a serine/threonine kinase, regulates protein synthesis, cell growth, differentiation, apoptosis, and inflammation. Our current studies show the key role for GSK-3 in interferon-gamma (IFN-gamma-induced inflammation; however, the activation of GSK-3beta remains unclear. Treating cells with GSK-3beta inhibitor and short interfering RNA showed a decrease on IFN-gamma-induced inflammatory responses, including nitric oxide biosynthesis and cytokine production. In this study, we further investigate the mechanism of GSK-3beta activation. After IFN-gamma stimulation, protein phosphatase (PPase) mediated GSK3beta dephosphorylation at Ser9 and proline-rich tyrosine kinase 2 (Pyk2) mediated GSK-3beta phosphorylation at Tyr216. Since okadaic acid-sensitive PPases were activated by ceramide, results demonstrated that IFN-gamma induced ceramide generation. Furthermore, neutral sphingomyelinase (SMase) was required for GSK-3beta activation. In IFN-gamma-stimulated macrophages, Pyk2 and GSK-3beta were sequentially activated through phosphatidylcholine-specific phospholipase C (PC-PLC)-, protein kinase C (PKC)-, and Src-regulated pathways. Activation of PC-PLC, Pyk2, and GSK-3beta by IFN-gamma was mediated via IFN-gamma receptor 2 (IFNGR2)-associated Jak2-regulated but IFNGR1-independent pathway. Further results demonstrated that IFN-gamma-elicited neutral SMase was also regulated by Jak2, PC-PLC, PKC, and cytosolic PLA2 (cPLA2). cPLA2 was essential for IFN-gamma-induced GSK-3 dephosphorylation (Ser9). In addition, activation of nuclear factor kappa B (NF-kB) via dsRNA-dependent kinase-IkB kinase-inhibitor of NF-kB axis was regulated by Jak2 as well as GSK-3beta Interestingly, GSK-3beta regulated Jak2-NF-kB signaling though inhibiting Src homology-2 domain-containing phosphahase 2. Taken together, these results demonstrate the novel role for GSK-3beta that activated by bioactive lipids, including PC-PLC, cPLA2, and ceramide.

Abstract in Chinese 1
Abstract in English 2
Acknowledgement 3
Abbreviations 4-6
Contents 7-9
List of Figures 10
Chapter I Introduction 11-16
I-1 The biofunction of interferon-gamma (IFN-gamma) 11
I-2 IFN-gamma receptors and its signal transduction 11-12
I-3 Glycogen synthase kinase-3beta (GSK-3beta) in inflammation
12-14
I-4 Relationships between IFN-gamma, inflammation, and GSK-3beta
14
I-5 The regulation of GSK-3beta 14-16
Chapter II Study Objective and Specific Aims 17-18
II-1 Objective 17
II-2 Specific Aims. 17-18
II-3 Study Flowchart 18
Chapter III Materials and Methods. 19-21
III-1 Mice 19
III-2 Cell culture 19
III-3 Western blot 19-20
III-4 Nitrite assay 20
III-5 Immunostaining 20-21
III-6 Sphinogomyelinase assay 21
III-7 PC-PLC assay 21
III-8 Statistics 21
Chapter IV Results 22-28
IV-1 IFN-gammacauses GSK-3beta activation as well as inflammation
22-23
IV-2 IFN-gamma induces PPase/Akt-regulated GSK-3beta activation and inflammation
23
IV-3 Ceramide regulates IFN-gamma-induced inflammation 23-24
IV-4 IFN-gamma-induced PC-PLC/PKC/Src/Pyk2 is required for GSK-3betaactivation
24-25
IV-5 IFNGR2-associated Jak2 is required for PC-PLC, Pyk2, and GSK-3beta activation in IFN-gamma signaling 25-26
IV-6 IFNGR1 KO enhances IKK and NF-kB phosphorylation in IFN-gamma signaling 26
IV-7 Jak2/PC-PLC/PKC/cPLA2 signaling is critical for IFN-gamma-elicited neutral SMase and GSK-3beta as well as inflammation 26-27
IV-8 GSK-3beta is required for IFN-gamma-activated NF-kB signaling as well as inflammation 27-28
Chapter V Discussion 29-33
V-1 The effects of GSK-3beta in IFN-gamma signaling 29
V-2 The regulation of bioactive lipids on IFN-gamma-activated GSK-3beta
29-30
V-3 The role of PPase in IFN-gamma-activated GSK-3beta 30
V-4 The role of cPLA2 in the cross-talk between PC-PLC and ceramide signaling
30-31
V-5 The activation of Pyk2 and its role in IFN-gamma activated GSK-3beta 31
V-6 The role of GSK-3beta in IFN-gamma-activated Jak-STAT signaling
31-32
V-7 The role of GSK-3beta in IFN-gamma-activated NF-kB signaling
32-33
Chapter VI Conclusion 34
Chapter VII References 35-52
Figures and Figure Legends 53-66
Appendix 67-77
A Materials 67-71
A-1 Chemicals 67-69
A-2 Antibodies and Recombinant Proteins 69-70
A-3 Kits 70
A-4 Consumables 70-71
A-5 Apparatus 71
B Methods 72-77
B-1 Cell culture 72-73
B-2 Western blo 73-75
B-3 Griess’s reaction 75
B-4 Immunocytochemistry 75
B-5 Amplex red sphinogomyelinase assay kit 75-77
B-6 Amplex red phosphoatidylcholine-specific phospholipase C assay kit
78-79

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