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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 徐立中 | |
dc.contributor.author | Ting-Yu Lai | en |
dc.contributor.author | 賴亭諭 | zh_TW |
dc.date.accessioned | 2021-05-19T18:01:30Z | - |
dc.date.available | 2025-08-18 | |
dc.date.available | 2021-05-19T18:01:30Z | - |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-18 | |
dc.identifier.citation | 1. Janeway CA, Jr., Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002; 20:197-216.
2. Hansen JD, Vojtech LN, Laing KJ. Sensing disease and danger: a survey of vertebrate PRRs and their origins. Dev Comp Immunol 2011; 35(9):886-97. 3. Reuven EM, Fink A, Shai Y. Regulation of innate immune responses by transmembrane interactions: lessons from the TLR family. Biochim Biophys Acta 2014; 1838(6):1586-93. 4. Takeda K, Akira S. Toll-like receptors. Curr Protoc Immunol 2015; 109:14 12 1-14 12 10. 5. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124(4):783-801. 6. Hasan U, Chaffois C, Gaillard C, et al. Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol 2005; 174(5):2942-50. 7. O'Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors - redefining innate immunity. Nat Rev Immunol 2013; 13(6):453-60. 8. Brodsky I, Medzhitov R. Two modes of ligand recognition by TLRs. Cell 2007; 130(6):979-81. 9. Barton GM, Kagan JC, Medzhitov R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 2006; 7(1):49-56. 10. Gong J, Wei T, Zhang N, et al. TollML: a database of toll-like receptor structural motifs. J Mol Model 2010; 16(7):1283-9. 11. Leulier F, Lemaitre B. Toll-like receptors--taking an evolutionary approach. Nat Rev Genet 2008; 9(3):165-78. 12. O'Neill LAJ, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 2007; 7(5):353-364. 13. Takeuchi O, Takeda K, Hoshino K, et al. Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. Int Immunol 2000; 12(1):113-7. 14. Kawai T, Adachi O, Ogawa T, et al. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999; 11(1):115-22. 15. Horng T, Barton GM, Flavell RA, Medzhitov R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 2002; 420(6913):329-33. 16. Yamamoto M, Sato S, Hemmi H, et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 2002; 420(6913):324-9. 17. Yamamoto M, Sato S, Hemmi H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003; 301(5633):640-3. 18. Fitzgerald KA, Rowe DC, Barnes BJ, et al. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med 2003; 198(7):1043-55. 19. Carty M, Goodbody R, Schroder M, et al. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol 2006; 7(10):1074-81. 20. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348(16):1546-54. 21. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29(7):1303-10. 22. Cavaillon JM, Adib-Conquy M, Fitting C, et al. Cytokine cascade in sepsis. Scand J Infect Dis 2003; 35(9):535-44. 23. Cohen J. The immunopathogenesis of sepsis. Nature 2002; 420(6917):885-891. 24. Hotchkiss RS, Coopersmith Cm Fau - McDunn JE, McDunn Je Fau - Ferguson TA, Ferguson TA. The sepsis seesaw: tilting toward immunosuppression. 2009(1546-170X (Electronic)). 25. Rittirsch D, Hoesel LM, Ward PA. The disconnect between animal models of sepsis and human sepsis. Journal of Leukocyte Biology 2007; 81(1):137-143. 26. Otto GP, Sossdorf M, Claus RA, et al. The late phase of sepsis is characterized by an increased microbiological burden and death rate. Crit Care 2011; 15(4):R183. 27. Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. The sepsis seesaw: tilting toward immunosuppression. Nat Med 2009; 15(5):496-7. 28. Triantafilou M, Miyake K, Golenbock DT, Triantafilou K. Mediators of innate immune recognition of bacteria concentrate in lipid rafts and facilitate lipopolysaccharide-induced cell activation. J Cell Sci 2002; 115(Pt 12):2603-11. 29. Plociennikowska A, Hromada-Judycka A, Borzecka K, Kwiatkowska K. Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling. Cell Mol Life Sci 2015; 72(3):557-81. 30. Kagan JC, Medzhitov R. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 2006; 125(5):943-55. 31. Akira S. Toll-like receptor signaling. J Biol Chem 2003; 278(40):38105-8. 32. Yanagawa Y, Onoe K. Enhanced IL-10 production by TLR4- and TLR2-primed dendritic cells upon TLR restimulation. J Immunol 2007; 178(10):6173-80. 33. Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7(4):261-9. 34. Laird MH, Rhee SH, Perkins DJ, et al. TLR4/MyD88/PI3K interactions regulate TLR4 signaling. J Leukoc Biol 2009; 85(6):966-77. 35. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol; 11(5):373-84. 36. Saccani S, Pantano S, Natoli G. p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol 2002; 3(1):69-75. 37. Park JM, Greten FR, Wong A, et al. Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis--CREB and NF-kappaB as key regulators. Immunity 2005; 23(3):319-29. 38. Basak C, Pathak SK, Bhattacharyya A, et al. NF-kappaB- and C/EBPbeta-driven interleukin-1beta gene expression and PAK1-mediated caspase-1 activation play essential roles in interleukin-1beta release from Helicobacter pylori lipopolysaccharide-stimulated macrophages. J Biol Chem 2005; 280(6):4279-88. 39. Yokota S, Ohnishi T, Muroi M, et al. Highly-purified Helicobacter pylori LPS preparations induce weak inflammatory reactions and utilize Toll-like receptor 2 complex but not Toll-like receptor 4 complex. FEMS Immunol Med Microbiol 2007; 51(1):140-8. 40. Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 2009; 1(4):a000034. 41. Vereecke L, Beyaert R, van Loo G. The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends Immunol 2009; 30(8):383-91. 42. Oeckinghaus A, Ghosh S. The NF-kB Family of Transcription Factors and Its Regulation. Cold Spring Harbor Perspectives in Biology 2009; 1(4):a000034. 43. Berndsen CE, Wolberger CA-O. New insights into ubiquitin E3 ligase mechanism. 2014; 21(4):301–307. 44. Li W, Bengtson Mh Fau - Ulbrich A, Ulbrich A Fau - Matsuda A, et al. Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. 2008(1932-6203 (Electronic)). 45. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998; 67:425-79. 46. Ikeda F, Dikic I. Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series. EMBO Rep 2008; 9(6):536-42. 47. Tokunaga F, Sakata S, Saeki Y, et al. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 2009; 11(2):123-32. 48. Metzger MB, Hristova Va Fau - Weissman AM, Weissman AM. HECT and RING finger families of E3 ubiquitin ligases at a glance. 2012(1477-9137 (Electronic)). 49. Metzger MB, Hristova VA, Weissman AM. HECT and RING finger families of E3 ubiquitin ligases at a glance. Journal of Cell Science 2012; 125(3):531-537. 50. Liu YC, Penninger J, Karin M. Immunity by ubiquitylation: a reversible process of modification. Nat Rev Immunol 2005; 5(12):941-52. 51. Sun SC. Deubiquitylation and regulation of the immune response. Nat Rev Immunol 2008; 8(7):501-11. 52. Skaug B, Jiang X, Chen ZJ. The role of ubiquitin in NF-kappaB regulatory pathways. Annu Rev Biochem 2009; 78:769-96. 53. Deng L, Wang C, Spencer E, et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 2000; 103(2):351-61. 54. Ea CK, Deng L, Xia ZP, et al. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell 2006; 22(2):245-57. 55. Wang C, Deng L, Hong M, et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 2001; 412(6844):346-51. 56. Wertz IE, O'Rourke KM, Zhou H, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 2004; 430(7000):694-9. 57. Shembade N, Harhaj NS, Parvatiyar K, et al. The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20. Nat Immunol 2008; 9(3):254-62. 58. Kovalenko A, Chable-Bessia C, Cantarella G, et al. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 2003; 424(6950):801-5. 59. Tseng PH, Matsuzawa A, Zhang W, et al. Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol 2010; 11(1):70-5. 60. Shembade N, Ma A, Harhaj EW. Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes. Science 2010; 327(5969):1135-9. 61. Heyninck K, Beyaert R. The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6. FEBS Lett 1999; 442(2-3):147-50. 62. Krikos A, Laherty CD, Dixit VM. Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by kappa B elements. J Biol Chem 1992; 267(25):17971-6. 63. Coornaert B, Carpentier I, Beyaert R. A20: central gatekeeper in inflammation and immunity. J Biol Chem 2009; 284(13):8217-21. 64. Lee EG, Boone DL, Chai S, et al. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 2000; 289(5488):2350-4. 65. He KL, Ting AT. A20 inhibits tumor necrosis factor (TNF) alpha-induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in Jurkat T cells. Mol Cell Biol 2002; 22(17):6034-45. 66. Boone DL, Turer EE, Lee EG, et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 2004; 5(10):1052-60. 67. Wakatsuki S, Saitoh F, Araki T. ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. Nat Cell Biol 2011; 13(12):1415-23. 68. Borden KL. RING fingers and B-boxes: zinc-binding protein-protein interaction domains. Biochem Cell Biol 1998; 76(2-3):351-8. 69. Araki T, Milbrandt J. ZNRF proteins constitute a family of presynaptic E3 ubiquitin ligases. J Neurosci 2003; 23(28):9385-94. 70. Brown DA. Lipid rafts, detergent-resistant membranes, and raft targeting signals. Physiology (Bethesda) 2006; 21:430-9. 71. Smart EJ, Graf GA, McNiven MA, et al. Caveolins, liquid-ordered domains, and signal transduction. Mol Cell Biol 1999; 19(11):7289-304. 72. Couet J, Shengwen L, Okamoto T, et al. Molecular and cellular biology of caveolae paradoxes and plasticities. Trends Cardiovasc Med 1997; 7(4):103-10. 73. Krasteva G, Pfeil U, Drab M, et al. Caveolin-1 and -2 in airway epithelium: expression and in situ association as detected by FRET-CLSM. Respir Res 2006; 7:108. 74. Cohen AW, Hnasko R, Schubert W, Lisanti MP. Role of caveolae and caveolins in health and disease. Physiol Rev 2004; 84(4):1341-79. 75. Song KS, Scherer PE, Tang Z, et al. Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins. J Biol Chem 1996; 271(25):15160-5. 76. Lajoie P, Nabi IR, Kwang WJ. Chapter 3 - Lipid Rafts, Caveolae, and Their Endocytosis. International Review of Cell and Molecular Biology, Vol. Volume 282: Academic Press, 2010. pp. 135-163. 77. Shin JS, Abraham SN. Cell biology. Caveolae--not just craters in the cellular landscape. Science 2001; 293(5534):1447-8. 78. Gargalovic P, Dory L. Caveolin-1 and Caveolin-2 Expression in Mouse Macrophages: HIGH DENSITY LIPOPROTEIN 3-STIMULATED SECRETION AND A LACK OF SIGNIFICANT SUBCELLULAR CO-LOCALIZATION. Journal of Biological Chemistry 2001; 276(28):26164-26170. 79. Shin JS, Gao Z, Abraham SN. Involvement of cellular caveolae in bacterial entry into mast cells. Science 2000; 289(5480):785-8. 80. Werling D, Hope JC, Chaplin P, et al. Involvement of caveolae in the uptake of respiratory syncytial virus antigen by dendritic cells. J Leukoc Biol 1999; 66(1):50-8. 81. Gadjeva M, Paradis-Bleau C, Priebe GP, et al. Caveolin-1 modifies the immunity to Pseudomonas aeruginosa. J Immunol 2010; 184(1):296-302. 82. Medina FA, de Almeida CJ, Dew E, et al. Caveolin-1-Deficient Mice Show Defects in Innate Immunity and Inflammatory Immune Response during Salmonella enterica Serovar Typhimurium Infection. Infection and Immunity 2006; 74(12):6665-6674. 83. Wang XM, Kim HP, Song R, Choi AM. Caveolin-1 confers antiinflammatory effects in murine macrophages via the MKK3/p38 MAPK pathway. Am J Respir Cell Mol Biol 2006; 34(4):434-42. 84. Ruocco MG, Maeda S, Park JM, et al. IkB kinase (IKK)beta, but not IKKalpha, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. The Journal of Experimental Medicine 2005; 201(10):1677-1687. 85. Brazma A, Hingamp P, Quackenbush J, et al. Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet 2001; 29(4):365-71. 86. Hsu LC, Park JM, Zhang K, et al. The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 2004; 428(6980):341-5. 87. Mundy DI, Li WP, Luby-Phelps K, Anderson RG. Caveolin targeting to late endosome/lysosomal membranes is induced by perturbations of lysosomal pH and cholesterol content. Mol Biol Cell 2012; 23(5):864-80. 88. Kirchner P, Bug M, Meyer H. Ubiquitination of the N-terminal region of caveolin-1 regulates endosomal sorting by the VCP/p97 AAA-ATPase. J Biol Chem 2013; 288(10):7363-72. 89. Hayer A, Stoeber M, Ritz D, et al. Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation. J Cell Biol 2010; 191(3):615-29. 90. Li L, Ren CH, Tahir SA, et al. Caveolin-1 Maintains Activated Akt in Prostate Cancer Cells through Scaffolding Domain Binding Site Interactions with and Inhibition of Serine/Threonine Protein Phosphatases PP1 and PP2A. Molecular and Cellular Biology 2003; 23(24):9389-9404. 91. Cross DA, Alessi DR, Cohen P, et al. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378(6559):785-9. 92. Hu X, Paik PK, Chen J, et al. IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity 2006; 24(5):563-74. 93. Wang H, Brown J, Gu Z, et al. Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-beta-signaling pathways regulates the innate inflammatory response. J Immunol 2006; 186(9):5217-26. 94. Woodgett JR, Ohashi PS. GSK3: an in-Toll-erant protein kinase? Nat Immunol 2005; 6(8):751-2. 95. Martin M, Rehani K, Jope RS, Michalek SM. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol 2005; 6(8):777-84. 96. Platzer C, Fritsch E, Elsner T, et al. Cyclic adenosine monophosphate-responsive elements are involved in the transcriptional activation of the human IL-10 gene in monocytic cells. Eur J Immunol 1999; 29(10):3098-104. 97. Cheng Y-L, Wang C-Y, Huang W-C, et al. Staphylococcus aureus Induces Microglial Inflammation via a Glycogen Synthase Kinase 3β-Regulated Pathway. Infection and Immunity 2009; 77(9):4002-4008. 98. Cremer TJ, Shah P, Cormet-Boyaka E, et al. Akt-mediated proinflammatory response of mononuclear phagocytes infected with Burkholderia cenocepacia occurs by a novel GSK3beta-dependent, IkappaB kinase-independent mechanism. J Immunol 2011; 187(2):635-43. 99. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011; 34(5):637-50. 100. Siegemund S, Sauer K. Balancing pro- and anti-inflammatory TLR4 signaling. Nat Immunol; 13(11):1031-3. 101. Fielding CJ, Fielding PE. Intracellular cholesterol transport. J Lipid Res 1997; 38(8):1503-21. 102. Anderson RG. The caveolae membrane system. Annu Rev Biochem 1998; 67:199-225. 103. Mirza MK, Yuan J, Gao XP, et al. Caveolin-1 deficiency dampens Toll-like receptor 4 signaling through eNOS activation. Am J Pathol 2010; 176(5):2344-51. 104. Garrean S, Gao XP, Brovkovych V, et al. Caveolin-1 regulates NF-kappaB activation and lung inflammatory response to sepsis induced by lipopolysaccharide. J Immunol 2006; 177(7):4853-60. 105. Jiao H, Zhang Y, Yan Z, et al. Caveolin-1 Tyr14 phosphorylation induces interaction with TLR4 in endothelial cells and mediates MyD88-dependent signaling and sepsis-induced lung inflammation. J Immunol 2013; 191(12):6191-9. 106. Jiao H, Zhang Y, Yan Z, et al. Caveolin-1 Tyr14 phosphorylation induces interaction with TLR4 in endothelial cells and mediates MyD88-dependent signaling and sepsis-induced lung inflammation. J Immunol 2013; 191(12):6191-9. 107. Feng H, Guo L, Song Z, et al. Caveolin-1 protects against sepsis by modulating inflammatory response, alleviating bacterial burden, and suppressing thymocyte apoptosis. J Biol Chem; 285(33):25154-60. 108. Feng H, Guo W, Han J, Li XA. Role of caveolin-1 and caveolae signaling in endotoxemia and sepsis. Life Sci 2013; 93(1):1-6. 109. Park WY, Park JS, Cho KA, et al. Up-regulation of caveolin attenuates epidermal growth factor signaling in senescent cells. J Biol Chem 2000; 275(27):20847-52. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7985 | - |
dc.description.abstract | 哺乳類動物中,先天性免疫系統(Innate immunity)是防禦病原菌侵入生物體內的首道防線。先天性免疫反應的防禦機制在於藉由pattern-recognition receptors,如Toll-like receptors (TLRs) , 以非特異性方式辨識病菌特有的分子特徵(pathogen-associated molecular patterns)而保護生物體不受感染威脅。巨噬細胞是一種有吞噬能力的大型白血球,它可以移動到組織之間去獵取入侵的病源菌,並產生細胞激素以及將抗原表現給其他細胞以活化適應性免疫反應(adaptive immunity),進行毒殺病原體的動作。
TLR訊息傳導途徑在生物體內通常受到了嚴密精細的調控。失控的全身性發炎反應可能造成全身性發炎反應症候群 (Systemic inflammatory response syndrome,SIRS)、動脈硬化,或是自體免疫性疾病,這些疾病多由體內持續性的發炎反應所造成,進而使內臟器官嚴重受損甚至死亡。在受到病原體刺激之後,TLR透過許多不同的分子經由訊息傳導引發巨噬細胞免疫反應,而這些分子在免疫系統上將可有效的防止免疫反應過量及不足的情況。因此透過這些免疫反應調控因子深入的研究以及了解,臨床上將有助於治療各種發炎引起的疾病。 我們從微陣列資料庫分析中發現了兩種新型調控TLR4訊息傳導的機制。TLR4受到LPS刺激活化後會藉由NF-κB及p38調控之轉錄因子C/EBPβ轉錄出一個重要基因,稱為Tnfaip3,Tnfaip3轉譯出的蛋白質稱為A20。免疫系統中A20可作為廣泛負向調控TLR下游的訊息傳遞,達到關閉發炎反應的作用。另一種機制是藉由一個新型E3連接酶蛋白,ZNRF1所調控。我們發現一旦TLR4受活化後,ZNRF1會藉由和小凹蛋白(Caveolin-1)的結合進而泛素化並降解小凹蛋白的量。ZNRF1和小凹蛋白之間的互動,影響了Akt-GSK3β-CREB路徑,最終使得發炎性細胞激素大量產生同時抑制了抗發炎細胞激素,如IL10,的分泌,進而有效控制發炎過程的平衡。我們揭開了兩種新型態的TLR4調控機制也為發炎性疾病的治療帶來曙光。 | zh_TW |
dc.description.abstract | In mammals, innate immunity is the first line of defense against pathogenic infection, and is mainly mediated by pattern-recognition receptors, including Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns derived from microbes or endogenous molecules termed damage-associated molecular patterns. Macrophages, a type of phagocytic leukocytes, play a crucial role in innate immunity by producing various cytokines and chemokines and presenting antigens to lymphocytes, both of which are also involved in the activation of adaptive immunity. However, dysregulation of TLRs-mediated inflammatory response can impair host immune homeostasis, and is associated with many autoimmune and inflammatory diseases, such as systemic inflammatory response syndrome (SIRS) and atherosclerosis. Thus, the molecular mechanisms of how TLRs signaling is regulated have been intensively investigated, but the detailed mechanism still remains fragmentary. In this study, we discovered two novel regulatory mechanisms in TLR4-mediated immune response by exploring microarray analysis. We found that TLR4 engagement induced a transcription factor C/EBPβ through p38 MAPK, which subsequently increased A20 expression in conjunction with NF-κB. A20, in turn, negatively regulated TLR4 signaling to terminate inflammatory response. In addition, we identified a novel E3 ubiquitin ligase, ZNRF1, which mediated caveolin-1 (CAV1) ubiquitination and degradation in response to lipopolysaccharide (LPS). Mechanistically, the ZNRF1-CAV1 axis influences Akt-GSK3β activity upon TLR4 activation, eventually resulting in enhanced production of pro-inflammatory cytokines and inhibiting anti-inflammatory cytokine IL-10 expression. Our findings unravel two new regulatory mechanisms of TLR4 signaling pathway and may shed light on treatments for inflammation-related diseases. | en |
dc.description.provenance | Made available in DSpace on 2021-05-19T18:01:30Z (GMT). No. of bitstreams: 1 ntu-104-D97448006-1.pdf: 5780416 bytes, checksum: 17e1359132366d5451c8724ca9188b68 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | Table of contents 1
中文摘要 4 Abstract 5 Introduction 6 1. Innate immunity 6 2. Toll-like receptors 6 3. Structure of TLRs 7 4. Toll-Like Receptor 4 8 5. TLR4 signaling 9 6. p38 MAPK 10 7. NF-κB 10 8. Mechanism of Ubiquitination 11 9. A20 12 10. ZNRF1 13 11. Caveolin-1 14 Materials and Methods 16 PART 1 23 Specific Aim 23 Results 24 PART 2 34 Specific Aim 34 Result 35 Discussion 42 Conclusion 45 References 46 Table 1. Top 10 enriched canonical pathways of the NF-κB and p38-dependent genes 58 Table 2. Prediction of transcription factor binding sites of NF-κB and p38-dependent genes using oPOSSUM 59 Table 3. Summary of E3 Ubiquitin ligases regulated by LPS in macrophages from the analysis of Microarray datasets 60 Table 4. Primer pairs for real-time RT-QPCR 61 Figure 1. Depletion of IKKβ expression and inhibition of p38 signaling pathway in IkkβΔ and SB202190-treated bone marrow-derived macrophages (BMDMs). 62 Figure 3. C/EBPβ and A20 (TNFAIP3) were suppressed in IkkβΔ and p38-inhibited macrophages. 65 Figure 4. LPS-induced expression of A20 (TNFAIP3) was decreased in C/EBPβ-depleted RAW264.7 cells. 66 Figure 5. Proposed model of NF- | |
dc.language.iso | en | |
dc.title | 第四型類鐸受體之新型調控機制 | zh_TW |
dc.title | The novel regulation of Toll-Like Receptor 4 | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 陳瑞華,陳俊任,李建國,增炳輝 | |
dc.subject.keyword | 巨噬細胞,小凹蛋白,第四型類鐸受體, | zh_TW |
dc.subject.keyword | Macrophage,Caveolin1,TLR4, | en |
dc.relation.page | 84 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2015-08-18 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
dc.date.embargo-lift | 2025-08-18 | - |
顯示於系所單位: | 分子醫學研究所 |
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