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研究生： 楊璨滋
Yang, Tsan-Tzu
論文名稱： 脂多醣體抑制肝醣合成酶激酶-3β以降低自發性凋亡進而誘導嗜中性球增多症
Lipopolysaccharide causes blood neutrophilia by preventing constitutive apoptosis following glycogen synthase kinase-3β inactivation
指導教授： 林秋烽
Lin, Chiou-Feng
學位類別： 碩士
Master
系所名稱： 醫學院 - 微生物及免疫學研究所
Department of Microbiology & Immunology
論文出版年： 2011
畢業學年度： 99
語文別： 英文
論文頁數： 87
中文關鍵詞： 嗜中性球 、脂多醣體 、肝醣合成酶激酶-3β 、細胞凋亡 、Mcl-1 、活性氧自由基 、PI3K/AKT 、p38 MAPK 、JNK 、p47phox
外文關鍵詞： neutrophilia, LPS, GSK-3, apoptosis, Mcl-1, ROS, PI3K/AKT, p38 MAPK, JNK, p47phox
相關次數： 點閱：116  下載：0 
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    • 當遭受感染時，宿主免疫系統的嗜中性白血球 (neutrophils) 會在第一時間移行到受感染的部位清除病原菌並引起發炎反應。嗜中性白血球為生命週期 (life span) 很短的細胞，離開骨髓的嗜中性白血球會快速的分化至成熟且有功能的白血球。而活化後或老化的嗜中性白血球則會啟動自發性細胞凋亡 (apoptosis) 以維持血液循環中白血球的衡定 (homeostasis)。在感染或發炎等情況下，則可能延長嗜中性白血球的生命週期，進而影響病菌清除、發炎及免疫反應的功能。一旦嗜中性白血球不受自發性凋亡的調控進而破壞了恆定機制，可能導致嗜中性白血球在血液循環中累積，臨床病理上定義為嗜中性球增多症 (neutrophilia)。然而，在感染的模式中，如細菌內毒素脂多醣體 (lipopolysaccharide) 的刺激之下，導致嗜中性球增多症的分子機制仍不清楚。因此，我們假設脂多醣體透過抑制嗜中性白血球的自發性凋亡而導致嗜中性球增多症。首先，我們觀察到有別於野生型 (wild type) C3H/HeN小鼠，在Toll-like receptor (TLR) 4 gene (Tlr4Lps-d) 突變型C3H/HeJ小鼠對於脂多醣體所誘發的嗜中性球增多症有耐受性，說明了其中TLR4訊號存在的重要性。值得注意的是脂多醣體會抑制人類嗜中性球的自發性凋亡發生係透過阻止粒線體凋亡 (mitochondrial apoptosis)、粒線體膜電位損失、myeloid cell leukemia sequence (Mcl) 1的降解及caspase-3的活化。在凋亡的嗜中性球中可觀察到肝醣合成酶激酶-3β (glycogen synthase kinase-3β, GSK-3β) 的活化，而抑制GSK-3β便可避免Mcl-1的降解及粒線體凋亡。全反式視黃酸 (All-trans retinoic acid) 誘發HL-60細胞株分化的多核球發生GSK-3β依賴型細胞凋亡。脂多醣體透過活化phosphatidylinositol-3 kinase/AKT、p38 mitogen-activated protein kinase (MAPK) 及c-Jun N-terminal kinase (JNK) 等激酶而穩定Mcl-1，卻導致GSK-3β的去活化作用。在此也排除介白素-8 的產生直接參與脂多醣體促進的細胞存活中。然而，在in vitro 及in vivo都可證明脂多醣體刺激下產生的活性氧自由基 (reactive oxygen species) 也會調控p38 MAPK/JNK/AKT/GSK-3β/Mcl-1為主軸的訊息路徑、細胞凋亡及嗜中性球增多症。此外，脂多醣體誘發的嗜中性球增多症不會發生在p47phox缺失 (Ncf-/-) 的小鼠或給予抗氧化劑 (antioxidant) 處理的野生型小鼠。與健康的嗜中性球相比較下，伴隨有嗜中性球增多症之菌血症病患的嗜中性球會表現較多活化的AKT、p38 MAPK、JNK、去活化態的GSK-3β及穩定的Mcl-1。綜合以上結果顯示脂多醣在分子層面上直接與嗜中性球作用，透過引起氧活性分子生成來調控使GSK-3β去活化而抑制細胞凋亡，最後造成嗜中性球增多症。

    While pathogens invade host, neutrophils immediately transmigrate to the sites of infection for microbial elimination as well as inflammatory activation. Neutrophilia, characterized by accumulative circulating neutrophils, is caused by the increased differentiation from bone marrow and/or by neutrophil survival from activation- as well as aging-induced cell death. Regulation of cell apoptosis is essential for the homeostasis of neutrophils; however, the molecular signaling remains unclear. In this study, we exclusively investigated lipopolysaccharide (LPS)-induced cell death-associated neutrophilia in vivo and in vitro. Unlike C3H/HeN (wild type), C3H/HeJ mice (mutation in Toll-like receptor (TLR) 4 gene, Tlr4Lps-d) were insusceptible to LPS-induced neutrophilia, indicating a critical role of TLR4 signaling. Notably, LPS prevented human primary neutrophils undergoing constitutive apoptosis partly involving a blockade of mitochondrial pathway, including the loss of mitochondria transmembrane potential, myeloid cell leukemia sequence (Mcl) 1 degradation, and caspase-3 activation. In apoptotic neutrophils, glycogen synthase kinase (GSK)-3β was activated and inhibiting GSK-3β blocks Mcl-1 degradation as well as mitochondrial apoptosis. All-trans retinoic acid-induced polymorphonuclear differentiation of HL-60 cells underwent a GSK-3β-dependent apoptosis. LPS in vitro caused phosphatidylinositol-3 kinase (PI3K)/AKT-, p38 mitogen-activated protein kinase (MAPK)-, and c-Jun N-terminal kinase (JNK)-mediated Mcl-1 stabilization but induces GSK-3β inactivation mainly through PI3K/AKT and p38 MAPK. However, IL-8 secretion was precluded from LPS-induced survival indirectly. Notably, LPS induced reactive oxygen species (ROS) generation to regulate p38 MAPK/JNK/AKT/GSK-3β/Mcl-1 axis signaling, apoptosis, and neutrophilia in vitro and in vivo. Furthermore, LPS-induced neutrophilia was lacking in either p47phox deficient mice or wild type mice pretreated with antioxidant. In comparison with healthy neutrophils, septic neutophils express high levels of activated AKT, p38 MAPK, and JNK, inactivated GSK-3β, and stabilized Mcl-1. These results demonstrate the molecular basis for LPS-induced neutrophilia partly and directly on neutrophils through a mechanism involving ROS-regulated GSK-3β inactivation and Mcl-1 stabilization to prevent constitutive apoptosis and mitochondrial apoptosis through AKT/p38 MAPK/JNK signaling.

    Abstract in Chinese 2 Abstract in English 3 Acknowledgment 4 Abbreviations 5 Contents 7 I. Introduction 10 II. Hypothesis and specific aims 18 III. Materials and Methods 20 III-1. Animal treatment 20 III-2. Antibodies and reagents 20 III-3. Histological observation and complete blood counter (CBC) test 21 III-4. Isolation of peripheral blood neutrohils 21 III-5. Cell culture 21 III-6. Viability assay 22 III-7. Cytotoxicity assay 22 III-8. Nitroblue tetrazolium (NBT) assay 22 III-9. Myeloperoxidase (MPO) assay 22 III-10. Immunostaining 22 III-11. Western blot analysis 23 III-12. Apoptosis assay 23 III-13. Mitochondria transmembrane potential assay 23 III-14. RNA interference 24 III-15. ELISA 24 III-16. Intracellular ROS assay 24 III-17. Statistical analysis 24 IV. Results 26 IV-1. TLR4 mediates LPS-induced blood neutrophilia that facilitates endotoxemic mortality in mice 26 IV-2. LPS prevents Mcl-1 destabilization, mitochondria injury, and constitutive apoptosis in human neutrophils 26 IV-3. Deregulated GSK-3β in neutrophils determines constitutive apoptosis by modulating Mcl-1 stabilization and correlates to neutrophilia 27 IV-4. An inducible neutrophilic differentiation causes GSK-3β-regulated apoptosis 27 IV-5. Activation of p38 MAPK, JNK, and AKT determines LPS-induced GSK-3β inactivation, Mcl-1 stabilization, and neutrophil survival and correlates to neutrophilia 28 IV-6. CD95 induces GSK-3β-independent apoptosis 29 IV-7. The independent role of IL-8 in LPS-induced neutrophil survival 30 IV-8. Intracellular ROS mediates LPS-activated p38 MAPK, JNK, and AKT which regulate GSK-3β inactivation, Mcl-1 stabilization, and neutrophil survival and neutrophilia in mice 30 V. Conclusion 32 VI. Discussion 33 VII. References 39 VIII. Figure 51 IX. Appendix 72 A. Materials 72 A-1 Chemicals 72 A-2 Antibodies 74 A-3 Consumables 75 A-4 Apparatus 75 B. Methods 76 B-1 Cell culture 76 B-1.1 Cell culture medium 76 B-1.2 Cell passage 77 B-1.3 Cell freeze 77 B-1.4 Cell defreeze 77 B-1.5 Isolation of primary neutrophils (PMNs) 78 B-2 Western blot 78 B-2.1 Lysis buffer 78 B-2.2 loading dye and TBS-T 78 B-2.3 Running gel preparation 79 B-2.4 Stacking gel preparation 79 B-2.5 Cell lysate preparation 80 B-2.6 SDS-PAGE 80 B-2.7 Western blot buffer 81 B-3 Immunocytofluorescent (IF) 82 B-4 Myeloperoxidase (MPO) assay 82 B-4.1 Reagents 82 B-4.2 Measurement of MPO activity 83 B-5 Histology 83 B-5.1 Reagents 83 B-5.2 Deparaffinization 84 B-5.3 Immunohistochemistry (IHC) 84 B-5.4 In Situ Cell Death (Apoptosis) Detection by TUNEL assay 85 B-6 Liu’s stain 85 B-7 Propidium iodide (PI) staining and flow cytometric assay 86 B-8 Rhodaminutese 123 staining and flow cytometric assay 86 X. Curriculum Vitae 87

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