請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/84672完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蘇剛毅(Kang-Yi Su) | |
| dc.contributor.author | Wei-Jia Luo | en |
| dc.contributor.author | 羅偉嘉 | zh_TW |
| dc.date.accessioned | 2023-03-19T22:19:58Z | - |
| dc.date.copyright | 2022-10-13 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-09-13 | |
| dc.identifier.citation | 1. Singer, M., et al., The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 2016. 315(8): p. 801-810. 2. Adhikari, N.K., et al., Critical care and the global burden of critical illness in adults. Lancet, 2010. 376(9749): p. 1339-46. 3. Vincent, J.L., et al., Assessment of the worldwide burden of critical illness: the intensive care over nations (ICON) audit. Lancet Respir Med, 2014. 2(5): p. 380-6. 4. Mayr, F.B., S. Yende, and D.C. Angus, Epidemiology of severe sepsis. Virulence, 2014. 5(1): p. 4-11. 5. Hotchkiss, R.S. and D.W. Nicholson, Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol, 2006. 6(11): p. 813-22. 6. Rivers, E.P., et al., Early and innovative interventions for severe sepsis and septic shock: taking advantage of a window of opportunity. Cmaj, 2005. 173(9): p. 1054-65. 7. Dellinger, R.P., et al., Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med, 2004. 32(3): p. 858-73. 8. Angus, D.C. and T. van der Poll, Severe Sepsis and Septic Shock. New England Journal of Medicine, 2013. 369(9): p. 840-851. 9. Pierrakos, C., et al., Biomarkers of sepsis: time for a reappraisal. Crit Care, 2020. 24(1): p. 287. 10. Breen, G. and A.R. Tunkel, Adjunctive Therapies for Sepsis and Septic Shock. Curr Infect Dis Rep, 1999. 1(3): p. 224-229. 11. Pildal, J. and P.C. Gotzsche, Polyclonal immunoglobulin for treatment of bacterial sepsis: a systematic review. Clin Infect Dis, 2004. 39(1): p. 38-46. 12. Avontuur, J.A., et al., Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study. Crit Care Med, 1998. 26(4): p. 660-7. 13. Alonso de Vega, J.M., et al., Oxidative stress in critically ill patients with systemic inflammatory response syndrome. Crit Care Med, 2002. 30(8): p. 1782-6. 14. Takeuchi, O. and S. Akira, Pattern recognition receptors and inflammation. Cell, 2010. 140(6): p. 805-20. 15. Tang, D., et al., PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev, 2012. 249(1): p. 158-75. 16. Gregory, S.H., L.K. Barczynski, and E.J. Wing, Effector function of hepatocytes and Kupffer cells in the resolution of systemic bacterial infections. J Leukoc Biol, 1992. 51(4): p. 421-4. 17. Steel, D.M. and A.S. Whitehead, The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol Today, 1994. 15(2): p. 81-8. 18. Seki, S., et al., The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag+ T cells in T helper 1 immune responses. Immunol Rev, 2000. 174: p. 35-46. 19. Bierhaus, A. and P.P. Nawroth, Modulation of the vascular endothelium during infection--the role of NF-kappa B activation. Contrib Microbiol, 2003. 10: p. 86-105. 20. Parikh, S.M., Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. Virulence, 2013. 4(6): p. 517-24. 21. Munford, R.S. and J. Pugin, Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med, 2001. 163(2): p. 316-21. 22. Stearns-Kurosawa, D.J., et al., The pathogenesis of sepsis. Annu Rev Pathol, 2011. 6: p. 19-48. 23. Hotchkiss, R.S., et al., Sepsis and septic shock. Nat Rev Dis Primers, 2016. 2: p. 16045. 24. Gentile, L.F., et al., Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg, 2012. 72(6): p. 1491-501. 25. Hu, D., et al., Persistent inflammation-immunosuppression catabolism syndrome, a common manifestation of patients with enterocutaneous fistula in intensive care unit. J Trauma Acute Care Surg, 2014. 76(3): p. 725-9. 26. Vanzant, E.L., et al., Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma. J Trauma Acute Care Surg, 2014. 76(1): p. 21-9; discussion 29-30. 27. Xiao, W., et al., A genomic storm in critically injured humans. J Exp Med, 2011. 208(13): p. 2581-90. 28. Hotchkiss, R.S., G. Monneret, and D. Payen, Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nature Reviews Immunology, 2013. 13(12): p. 862-874. 29. Chiche, L., et al., The role of natural killer cells in sepsis. J Biomed Biotechnol, 2011. 2011: p. 986491. 30. Mencin, A., J. Kluwe, and R.F. Schwabe, Toll-like receptors as targets in chronic liver diseases. Gut, 2009. 58(5): p. 704. 31. Heymann, F. and F. Tacke, Immunology in the liver — from homeostasis to disease. Nature Reviews Gastroenterology & Hepatology, 2016. 13(2): p. 88-110. 32. Jirillo, E., et al., The role of the liver in the response to LPS: experimental and clinical findings. J Endotoxin Res, 2002. 8(5): p. 319-27. 33. Rivera, C.A., et al., Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. Journal of Hepatology, 2007. 47(4): p. 571-579. 34. Levels, J.H., et al., Distribution and kinetics of lipoprotein-bound endotoxin. Infect Immun, 2001. 69(5): p. 2821-8. 35. Yao, Z., et al., Blood-Borne Lipopolysaccharide Is Rapidly Eliminated by Liver Sinusoidal Endothelial Cells via High-Density Lipoprotein. J Immunol, 2016. 197(6): p. 2390-9. 36. Kim, S.J. and H.M. Kim, Dynamic lipopolysaccharide transfer cascade to TLR4/MD2 complex via LBP and CD14. BMB Rep, 2017. 50(2): p. 55-57. 37. Yang, H., et al., Cellular events mediated by lipopolysaccharide-stimulated toll-like receptor 4. MD-2 is required for activation of mitogen-activated protein kinases and Elk-1. J Biol Chem, 2000. 275(27): p. 20861-6. 38. Fajgenbaum, D.C. and C.H. June, Cytokine Storm. New England Journal of Medicine, 2020. 383(23): p. 2255-2273. 39. Otani, T., et al., Identification of IFN-gamma-producing cells in IL-12/IL-18-treated mice. Cell Immunol, 1999. 198(2): p. 111-9. 40. Schenten, D. and R. Medzhitov, The control of adaptive immune responses by the innate immune system. Adv Immunol, 2011. 109: p. 87-124. 41. Salazar-Mather, T.P., T.A. Hamilton, and C.A. Biron, A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense. J Clin Invest, 2000. 105(7): p. 985-93. 42. Trinchieri, G., Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol, 1995. 13: p. 251-76. 43. Bancroft, G.J., R.D. Schreiber, and E.R. Unanue, Natural immunity: a T-cell-independent pathway of macrophage activation, defined in the scid mouse. Immunol Rev, 1991. 124: p. 5-24. 44. Takahashi, M., et al., LPS induces NK1.1+ alpha beta T cells with potent cytotoxicity in the liver of mice via production of IL-12 from Kupffer cells. J Immunol, 1996. 156(7): p. 2436-42. 45. Grohmann, U., et al., Positive Regulatory Role of IL-12 in Macrophages and Modulation by IFN-γ. The Journal of Immunology, 2001. 167(1): p. 221. 46. Wysocka, M., et al., Interleukin-12 is required for interferon-gamma production and lethality in lipopolysaccharide-induced shock in mice. Eur J Immunol, 1995. 25(3): p. 672-6. 47. Doherty, G.M., et al., Evidence for IFN-gamma as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha. The Journal of Immunology, 1992. 149(5): p. 1666-1670. 48. Ramirez-Alejo, N. and L. Santos-Argumedo, Innate defects of the IL-12/IFN-γ axis in susceptibility to infections by mycobacteria and salmonella. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2014. 34(5): p. 307-317. 49. Kunze, F.A., et al., ARTD1 in Myeloid Cells Controls the IL-12/18-IFN-gamma Axis in a Model of Sterile Sepsis, Chronic Bacterial Infection, and Cancer. J Immunol, 2019. 202(5): p. 1406-1416. 50. Romero, C.R., et al., The role of interferon-γ in the pathogenesis of acute intra-abdominal sepsis. J Leukoc Biol, 2010. 88(4): p. 725-35. 51. Yin, K., E. Gribbin, and H. Wang, Interferon-gamma inhibition attenuates lethality after cecal ligation and puncture in rats: implication of high mobility group box-1. Shock, 2005. 24(4): p. 396-401. 52. Deitch, E.A., Rodent models of intra-abdominal infection. Shock, 2005. 24 Suppl 1: p. 19-23. 53. Hamesch, K., et al., Lipopolysaccharide-induced inflammatory liver injury in mice. Lab Anim, 2015. 49(1 Suppl): p. 37-46. 54. Silva, J.F., et al., Acute Increase in O-GlcNAc Improves Survival in Mice With LPS-Induced Systemic Inflammatory Response Syndrome. Front Physiol, 2019. 10: p. 1614. 55. Starr, M.E., et al., Age-dependent vulnerability to endotoxemia is associated with reduction of anticoagulant factors activated protein C and thrombomodulin. Blood, 2010. 115(23): p. 4886-93. 56. Netea, M.G., et al., Lethal Escherichia coli and Salmonella typhimurium endotoxemia is mediated through different pathways. Eur J Immunol, 2001. 31(9): p. 2529-38. 57. Silva, J.F., et al., Acute Increase in O-GlcNAc Improves Survival in Mice With LPS-Induced Systemic Inflammatory Response Syndrome. Frontiers in Physiology, 2020. 10(1614). 58. Samie, M., et al., Selective autophagy of the adaptor TRIF regulates innate inflammatory signaling. Nature Immunology, 2018. 19(3): p. 246-254. 59. Cauwels, A., B. Vandendriessche, and P. Brouckaert, Of mice, men, and inflammation. Proceedings of the National Academy of Sciences, 2013. 110(34): p. E3150. 60. Fink, M.P., Animal models of sepsis. Virulence, 2014. 5(1): p. 143-53. 61. Seemann, S., F. Zohles, and A. Lupp, Comprehensive comparison of three different animal models for systemic inflammation. Journal of Biomedical Science, 2017. 24(1): p. 60. 62. Malgorzata-Miller, G., et al., Bartonella quintana lipopolysaccharide (LPS): structure and characteristics of a potent TLR4 antagonist for in-vitro and in-vivo applications. Sci Rep, 2016. 6: p. 34221. 63. Lewis, A.J., C.W. Seymour, and M.R. Rosengart, Current Murine Models of Sepsis. Surg Infect (Larchmt), 2016. 17(4): p. 385-93. 64. Au - Toscano, M.G., D. Au - Ganea, and A.M. Au - Gamero, Cecal Ligation Puncture Procedure. JoVE, 2011(51): p. e2860. 65. Dejager, L., et al., Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol, 2011. 19(4): p. 198-208. 66. Turnbull, I.R., et al., Antibiotics improve survival in sepsis independent of injury severity but do not change mortality in mice with markedly elevated interleukin 6 levels. Shock, 2004. 21(2): p. 121-5. 67. Lindquist, S. and E.A. Craig, The heat-shock proteins. Annu Rev Genet, 1988. 22: p. 631-77. 68. Cotto, J.J. and R.I. Morimoto, Stress-induced activation of the heat-shock response: cell and molecular biology of heat-shock factors. Biochem Soc Symp, 1999. 64: p. 105-18. 69. Khalil, A.A., et al., Heat shock proteins in oncology: diagnostic biomarkers or therapeutic targets? Biochim Biophys Acta, 2011. 1816(2): p. 89-104. 70. Georgopoulos, C. and W.J. Welch, Role of the major heat shock proteins as molecular chaperones. Annu Rev Cell Biol, 1993. 9: p. 601-34. 71. Rosenzweig, R., et al., The Hsp70 chaperone network. Nat Rev Mol Cell Biol, 2019. 20(11): p. 665-680. 72. Vabulas, R.M., et al., Protein folding in the cytoplasm and the heat shock response. Cold Spring Harb Perspect Biol, 2010. 2(12): p. a004390. 73. Richter, K., M. Haslbeck, and J. Buchner, The heat shock response: life on the verge of death. Mol Cell, 2010. 40(2): p. 253-66. 74. Kampinga, H.H., et al., Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones, 2009. 14(1): p. 105-11. 75. Zorzi, E. and P. Bonvini, Inducible hsp70 in the regulation of cancer cell survival: analysis of chaperone induction, expression and activity. Cancers (Basel), 2011. 3(4): p. 3921-56. 76. Cruzat, V.F., et al., Oral supplementations with free and dipeptide forms of L-glutamine in endotoxemic mice: effects on muscle glutamine-glutathione axis and heat shock proteins. J Nutr Biochem, 2014. 25(3): p. 345-52. 77. Andreasen, A.S., et al., The effect of glutamine infusion on the inflammatory response and HSP70 during human experimental endotoxaemia. Critical care (London, England), 2009. 13(1): p. R7-R7. 78. Silva, L.S., et al., Curcumin suppresses inflammatory cytokines and heat shock protein 70 release and improves metabolic parameters during experimental sepsis. Pharm Biol, 2017. 55(1): p. 269-276. 79. Oehler, R., et al., Glutamine depletion impairs cellular stress response in human leucocytes. British Journal of Nutrition, 2002. 87(S1): p. S17-S21. 80. Ribeiro, S.P., et al., Sodium arsenite induces heat shock protein-72 kilodalton expression in the lungs and protects rats against sepsis. Crit Care Med, 1994. 22(6): p. 922-9. 81. Zininga, T., L. Ramatsui, and A. Shonhai, Heat Shock Proteins as Immunomodulants. Molecules, 2018. 23(11). 82. Chen, Y., et al., Heat shock paradox and a new role of heat shock proteins and their receptors as anti-inflammation targets. Inflamm Allergy Drug Targets, 2007. 6(2): p. 91-100. 83. Spierings, J. and W. van Eden, Heat shock proteins and their immunomodulatory role in inflammatory arthritis. Rheumatology (Oxford), 2017. 56(2): p. 198-208. 84. Schmitt, E., et al., Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol, 2007. 81(1): p. 15-27. 85. Lechner, P., et al., Serum heat shock protein 70 levels as a biomarker for inflammatory processes in multiple sclerosis. Multiple sclerosis journal - experimental, translational and clinical, 2018. 4(2): p. 2055217318767192-2055217318767192. 86. Gelain, D.P., et al., Serum heat shock protein 70 levels, oxidant status, and mortality in sepsis. Shock, 2011. 35(5): p. 466-70. 87. Wu, Y., et al., Pneumococcal DnaJ modulates dendritic cell-mediated Th1 and Th17 immune responses through Toll-like receptor 4 signaling pathway. Immunobiology, 2017. 222(2): p. 384-393. 88. Cui, J., et al., DnaJ (hsp40) of Streptococcus pneumoniae is involved in bacterial virulence and elicits a strong natural immune reaction via PI3K/JNK. Molecular Immunology, 2017. 83: p. 137-146. 89. Tukaj, S., et al., Hsp40 proteins modulate humoral and cellular immune response in rheumatoid arthritis patients. Cell stress & chaperones, 2010. 15(5): p. 555-566. 90. Bork, P., et al., A module of the DnaJ heat shock proteins found in malaria parasites. Trends Biochem Sci, 1992. 17(4): p. 129. 91. Langer, T., et al., Successive action of DnaK, DnaJ and GroEL along the pathway of chaperone-mediated protein folding. Nature, 1992. 356(6371): p. 683-9. 92. Caplan, A.J., D.M. Cyr, and M.G. Douglas, Eukaryotic homologues of Escherichia coli dnaJ: a diverse protein family that functions with hsp70 stress proteins. Mol Biol Cell, 1993. 4(6): p. 555-63. 93. Frydman, J., et al., Folding of nascent polypeptide chains in a high molecular mass assembly with molecular chaperones. Nature, 1994. 370(6485): p. 111-7. 94. Qian, Y.Q., et al., Nuclear magnetic resonance solution structure of the human Hsp40 (HDJ-1) J-domain. J Mol Biol, 1996. 260(2): p. 224-35. 95. Hoe, K.L., et al., Isolation of a new member of DnaJ-like heat shock protein 40 (Hsp40) from human liver. Biochim Biophys Acta, 1998. 1383(1): p. 4-8. 96. Freeman, B.C., et al., Identification of a regulatory motif in Hsp70 that affects ATPase activity, substrate binding and interaction with HDJ-1. Embo j, 1995. 14(10): p. 2281-92. 97. Hsu, M.C., et al., Genetic Deletion of HLJ1 Does Not Affect Blood Coagulation in Mice. Int J Mol Sci, 2022. 23(4). 98. Liu, Y., et al., HLJ1 is a novel biomarker for colorectal carcinoma progression and overall patient survival. Int J Clin Exp Pathol, 2014. 7(3): p. 969-77. 99. Tsai, M.F., et al., A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma. J Natl Cancer Inst, 2006. 98(12): p. 825-38. 100. Wang, C.C., et al., The transcriptional factor YY1 upregulates the novel invasion suppressor HLJ1 expression and inhibits cancer cell invasion. Oncogene, 2005. 24(25): p. 4081-93. 101. Wang, C.C., et al., Synergistic activation of the tumor suppressor, HLJ1, by the transcription factors YY1 and activator protein 1. Cancer Res, 2007. 67(10): p. 4816-26. 102. Chang, T.P., et al., Tumor suppressor HLJ1 binds and functionally alters nucleophosmin via activating enhancer binding protein 2alpha complex formation. Cancer Res, 2010. 70(4): p. 1656-67. 103. Chen, C.H., et al., Acidic stress facilitates tyrosine phosphorylation of HLJ1 to associate with actin cytoskeleton in lung cancer cells. Exp Cell Res, 2010. 316(17): p. 2910-21. 104. Lin, S.Y., et al., HLJ1 is a novel caspase-3 substrate and its expression enhances UV-induced apoptosis in non-small cell lung carcinoma. Nucleic Acids Res, 2010. 38(18): p. 6148-58. 105. Chen, C.H., et al., HLJ1 is an endogenous Src inhibitor suppressing cancer progression through dual mechanisms. Oncogene, 2016. 35(43): p. 5674-5685. 106. Miao, W., L. Li, and Y. Wang, A Targeted Proteomic Approach for Heat Shock Proteins Reveals DNAJB4 as a Suppressor for Melanoma Metastasis. Anal Chem, 2018. 90(11): p. 6835-6842. 107. Uretmen Kagiali, Z.C., et al., Systems-level Analysis Reveals Multiple Modulators of Epithelial-mesenchymal Transition and Identifies DNAJB4 and CD81 as Novel Metastasis Inducers in Breast Cancer. Molecular & Cellular Proteomics, 2019. 18(9): p. 1756. 108. Chen, H.W., et al., Curcumin inhibits lung cancer cell invasion and metastasis through the tumor suppressor HLJ1. Cancer Res, 2008. 68(18): p. 7428-38. 109. Lai, Y.H., et al., The HLJ1-targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer. Carcinogenesis, 2013. 34(5): p. 1069-80. 110. Miao, W., et al., HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N(6)-methyladenosine. Nat Commun, 2019. 10(1): p. 3613. 111. Vignali, D.A. and V.K. Kuchroo, IL-12 family cytokines: immunological playmakers. Nat Immunol, 2012. 13(8): p. 722-8. 112. Hasegawa, H., et al., Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family. Front Immunol, 2016. 7: p. 479. 113. Yoon, C., et al., Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12. The EMBO Journal, 2000. 19(14): p. 3530-3541. 114. Gearing, D.P. and D. Cosman, Homology of the p40 subunit of natural killer cell stimulatory factor (NKSF) with the extracellular domain of the interleukin-6 receptor. Cell, 1991. 66(1): p. 9-10. 115. Oppmann, B., et al., Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity, 2000. 13(5): p. 715-25. 116. Bazan, J.F., Emerging families of cytokines and receptors. Curr Biol, 1993. 3(9): p. 603-6. 117. Walter, M.J., INTERLEUKINS | IL-12, in Encyclopedia of Respiratory Medicine, G.J. Laurent and S.D. Shapiro, Editors. 2006, Academic Press: Oxford. p. 377-382. 118. Liu, J., et al., Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-gamma-primed IL-12 production by IFN regulatory factor 1. J Exp Med, 2003. 198(8): p. 1265-76. 119. Gubler, U., et al., Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci U S A, 1991. 88(10): p. 4143-7. 120. Wolf, S.F., et al., Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol, 1991. 146(9): p. 3074-81. 121. Carra, G., F. Gerosa, and G. Trinchieri, Biosynthesis and posttranslational regulation of human IL-12. J Immunol, 2000. 164(9): p. 4752-61. 122. Ling, P., et al., Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity. J Immunol, 1995. 154(1): p. 116-27. 123. Stern, A.S., et al., Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A, 1990. 87(17): p. 6808-12. 124. Meier, S., et al., The molecular basis of chaperone-mediated interleukin 23 assembly control. Nature Communications, 2019. 10(1): p. 4121. 125. Reitberger, S., et al., Assembly-induced folding regulates interleukin 12 biogenesis and secretion. The Journal of biological chemistry, 2017. 292(19): p. 8073-8081. 126. Tait Wojno, E.D., C.A. Hunter, and J.S. Stumhofer, The Immunobiology of the Interleukin-12 Family: Room for Discovery. Immunity, 2019. 50(4): p. 851-870. 127. Trinchieri, G., Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol, 2003. 3(2): p. 133-46. 128. Gazzinelli, R.T., et al., Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci U S A, 1993. 90(13): p. 6115-9. 129. de Jong, R., et al., Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science, 1998. 280(5368): p. 1435-8. 130. Luger, D., et al., Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J Exp Med, 2008. 205(4): p. 799-810. 131. Yen, D., et al., IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest, 2006. 116(5): p. 1310-6. 132. Uhlig, H.H., et al., Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity, 2006. 25(2): p. 309-18. 133. Murphy, C.A., et al., Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med, 2003. 198(12): p. 1951-7. 134. Cua, D.J., et al., Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature, 2003. 421(6924): p. 744-8. 135. Teng, M.W.L., et al., IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nature Medicine, 2015. 21(7): p. 719-729. 136. Savage, L.J., et al., Ustekinumab in the Treatment of Psoriasis and Psoriatic Arthritis. Rheumatology and therapy, 2015. 2(1): p. 1-16. 137. Chen, N., et al., Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet, 2020. 395(10223): p. 507-513. 138. Huang, C., et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 2020. 395(10223): p. 497-506. 139. Chen, C., et al., [Advances in the research of mechanism and related immunotherapy on the cytokine storm induced by coronavirus disease 2019]. Zhonghua Shao Shang Za Zhi, 2020. 36(6): p. 471-475. 140. Ushioda, R., et al., ERdj5 is required as a disulfide reductase for degradation of misfolded proteins in the ER. Science, 2008. 321(5888): p. 569-72. 141. Samie, M., et al., Selective autophagy of the adaptor TRIF regulates innate inflammatory signaling. Nat Immunol, 2018. 19(3): p. 246-254. 142. Au - Weisser, S.B., N. Au - van Rooijen, and L.M. Au - Sly, Depletion and Reconstitution of Macrophages in Mice. JoVE, 2012(66): p. e4105. 143. Stuart, T., et al., Comprehensive Integration of Single-Cell Data. Cell, 2019. 177(7): p. 1888-1902.e21. 144. Xiong, X., et al., Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis. Mol Cell, 2019. 75(3): p. 644-660.e5. 145. Zhao, L., et al., Tissue Repair in the Mouse Liver Following Acute Carbon Tetrachloride Depends on Injury-Induced Wnt/β-Catenin Signaling. Hepatology, 2019. 69(6): p. 2623-2635. 146. Pflanz, S., et al., IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity, 2002. 16(6): p. 779-90. 147. Collison, L.W., et al., The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature, 2007. 450(7169): p. 566-9. 148. Jalah, R., et al., The p40 subunit of interleukin (IL)-12 promotes stabilization and export of the p35 subunit: implications for improved IL-12 cytokine production. The Journal of biological chemistry, 2013. 288(9): p. 6763-6776. 149. Trouplin, V., et al., Bone marrow-derived macrophage production. J Vis Exp, 2013(81): p. e50966. 150. Ma, X., et al., The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. J Exp Med, 1996. 183(1): p. 147-57. 151. Fu, J., et al., A novel triptolide derivative ZT01 exerts anti-inflammatory effects by targeting TAK1 to prevent macrophage polarization into pro-inflammatory phenotype. Biomed Pharmacother, 2020. 126: p. 110084. 152. Bartneck, M., et al., Roles of CCR2 and CCR5 for Hepatic Macrophage Polarization in Mice With Liver Parenchymal Cell-Specific NEMO Deletion. Cellular and Molecular Gastroenterology and Hepatology, 2021. 11(2): p. 327-347. 153. Nishiwaki, S., et al., In vivo tracking of transplanted macrophages with near infrared fluorescent dye reveals temporal distribution and specific homing in the liver that can be perturbed by clodronate liposomes. PLOS ONE, 2020. 15(12): p. e0242488. 154. Oka, O.B., et al., ERdj5 is the ER reductase that catalyzes the removal of non-native disulfides and correct folding of the LDL receptor. Mol Cell, 2013. 50(6): p. 793-804. 155. Huang, M., S. Cai, and J. Su, The Pathogenesis of Sepsis and Potential Therapeutic Targets. International Journal of Molecular Sciences, 2019. 20(21): p. 5376. 156. Angus, D.C. and T. van der Poll, Severe sepsis and septic shock. N Engl J Med, 2013. 369(9): p. 840-51. 157. Polat, G., et al., Sepsis and Septic Shock: Current Treatment Strategies and New Approaches. Eurasian J Med, 2017. 49(1): p. 53-58. 158. Chousterman, B.G., F.K. Swirski, and G.F. Weber, Cytokine storm and sepsis disease pathogenesis. Seminars in Immunopathology, 2017. 39(5): p. 517-528. 159. London, N.R., et al., Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci Transl Med, 2010. 2(23): p. 23ra19. 160. Maceyka, M., et al., Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol, 2012. 22(1): p. 50-60. 161. Leentjens, J., et al., Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med, 2012. 186(9): p. 838-45. 162. Payen, D., et al., Multicentric experience with interferon gamma therapy in sepsis induced immunosuppression. A case series. BMC Infectious Diseases, 2019. 19(1): p. 931. 163. Nalos, M., et al., Immune effects of interferon gamma in persistent staphylococcal sepsis. Am J Respir Crit Care Med, 2012. 185(1): p. 110-2. 164. Kim, E.Y., et al., Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN-γ in NK cells. J Clin Invest, 2020. 130(6): p. 3238-3252. 165. Quintana, F.J. and I.R. Cohen, The HSP60 immune system network. Trends Immunol, 2011. 32(2): p. 89-95. 166. Henderson, B. and A.G. Pockley, Molecular chaperones and protein-folding catalysts as intercellular signaling regulators in immunity and inflammation. J Leukoc Biol, 2010. 88(3): p. 445-62. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/84672 | - |
| dc.description.abstract | 敗血症被定義為由宿主對感染的反應失調引起的危及生命的器官功能障礙，在重症監護患者中敗血症是最常見的死因，而全身性的細菌感染常是造成敗血性休克的主因，當細菌感染時，其膜上的脂多醣(LPS)主要透過活化TLR4受器，導致大量多種細胞激素分泌進而活化免疫系統。其中IL-12釋放後可透過活化自然殺手細胞，進而促進γ干擾素(IFN-γ) 釋放，先前研究指出IL-12與IFN-γ激素與器官衰竭及敗血性休克息息相關，因此針對阻斷IL-12與IFN-γ路徑是否可用以治療敗血症為一重要課題。HLJ1為熱休克蛋白40家族中成員之一，大量研究指出HLJ1蛋白在人類肺癌中為抑癌基因，我們利用HLJ1基因剔除小鼠探討HLJ1蛋白的生理功能，並發現其具有內質網壓力引發之脂質代謝異常與脂肪肝，除此之外HLJ1缺失導致小鼠對致肝癌劑較敏感，顯示其在維持肝臟功能恆定中扮演重要角色，然而HLJ1如何在肝臟中調控細菌脂多糖引發之發炎與敗血性休克仍不清楚。 本研究中我們初步給予小鼠不同劑量LPS刺激，發現HLJ1基因剔除小鼠存活顯著較野生型小鼠佳，且肝腎受損程度較低。利用細胞激素微陣列分析與中和抗體抑制細胞激素，發現此現象是由於HLJ1基因剔除小鼠體內IFN-γ減少所致，利用單細胞定序分析肝臟免疫細胞轉錄組，發現IFN-γ缺失小鼠自然殺手細胞、巨噬細胞、及樹突細胞內的IFN-γ相關訊息路徑活化異常，進一步利用流式細胞儀分析脾臟免疫細胞，我們確認了HLJ1缺失導致自然殺手細胞分泌較少IFN-γ。若是以CLP手術模擬活菌感染，仍可發現HLJ1基因剔除小鼠的IFN-γ表現量下降且器官受損較少，並且給予抗生素可使其活得較野生型小鼠佳。接下來利用中和抗體抑制細胞激素，發現IFN-γ減少是導因於IL-12表現量下降，因此我們將HLJ1缺失的巨噬細胞移植到野生型小鼠體內，發現其可降低IL-12及 IFN-γ表現並且小鼠存活明顯改善，顯示HLJ1在巨噬細胞中調控活體內IL-12生成與敗血性死亡。若分離巨噬細胞進行體外培養後給予LPS刺激，可發現HLJ1缺失細胞內與細胞外之IL-12蛋白量皆較對照組低。為了探討此分子機制，我們在293T細胞中過表達人類IL-12次單元IL-12p35，同時降低HLJ1表現量，結果發現HLJ1的減少導致錯誤折疊的IL-12p35蛋白同二聚體(homodimer)堆積，使得自然折疊的IL-12p35單體所佔的比例下降，IL-12p35單體的缺乏可能導致其與IL-12p40的異二聚化(heterodimerization)程度下降，最後使有正常功能的IL-12p70異二聚體 (heterodimer)無法合成與分泌。 總結來說， HLJ1在巨噬細胞中幫助IL-12蛋白折疊與釋放，使得自然殺手細胞表達過量IFN-γ，進而引發敗血症導致的器官受損與死亡。此研究結果說明未來針對HLJ1可以發展新穎的敗血症的治療策略，例如抑制HLJ1的藥物可搭配抗生素以減緩敗血症導致的死亡，而除了敗血症外，以HLJ1為治療標的的策略同樣可應用於治療存在IL-12與IFN-γ活化的免疫與發炎疾病。 | zh_TW |
| dc.description.abstract | Sepsis is described as life-threatening organ dysfunction owing to a dysregulated host response to infection, and is a growing health problem remains to be solved since it is the single most encountered cause of mortality in intensive care patients. When infection occurs, LPS as an endotoxin initiates immune response and multiple cytokine production. Recently, HSP40 has emerged as a key factor in both innate and adaptive immunity, whereas the role of HLJ1, a molecular chaperone in HSP40 family, in modulating endotoxin–induced sepsis severity is still unclear. In the study, we investigate the impact of HLJ1 on LPS-induced sepsis with HLJ1 whole-body knockout mice. During LPS-induced endotoxemia, HLJ1 knockout mice display significantly alleviated vital organ damage and mortality when compared with wild-type mice. With cytokine array analysis and cytokine neutralization experiments, we found HLJ1 amplifies IFN-γ-dependent mortality in vivo. We take adventage of single-cell RNA sequencing and characterize liver nonparenchymal cell transcriptome under LPS stimulation, and show that HLJ1 deletion affected IFN-γ-related gene signatures in macrophages, dendritic cells and NK cells. Splenocytes analyzed with intracellular staining validate diminished production of IFN-γ in HLJ1-deficient NK cells instead of CD4+ or CD8+ T cells. In addition, during CLP-induced sepsis with live bacterial infection, HLJ1-deleted mice show reduced IFN-γ expression and alleviated organ injury. CLP-associated mortality rate decreases as well when HLJ1 knockout mice receive systemic antibiotics. By using ELISA analysis, we found LPS-treated mice exhibit reduced serum levels of IL-12 after HLJ1 deletion. IL-12 neutralization experiment demonstrates that diminished IL-12 contributing to dampened production of IFN-γ and subsequent improved survival. Transplantation of wild-type macrophages into HLJ1 knockout mice significantly elevates serum levels of IL-12 as well as IFN-γ and confers lethality, indicating HLJ1 functions mainly in macrophages upon LPS stimulation. On the other hand, adoptive transfer of HLJ1-deleted macrophages into LPS-treated mice results in reduced IL-12 as well as IFN-γ levels and protects the mice from IFN-γ–dependent mortality. In the context of molecular mechanisms, HLJ1 protein is significantly induced in macrophages, where it converts misfolded IL-12p35 homodimers to monomers, maintaining bioactive IL-12p70 heterodimerization and secretion. Finally, we found HLJ1 can be detected in serum and its amount is positively correlated to serum IL-12 when LPS-induced sepsis occurs. In summary, HLJ1 in macrophages causes IFN-γ–dependent septic lethality by promoting IL-12 heterodimerization, suggesting HLJ1-targeting agent has therapeutic potential and provides novel strategy for inflammatory diseases involving activated IL-12/IFN-γ-axis. In addition, HLJ1 deletion results in reduced CLP-induced mortality when mice are treated with antibiotics, implying combined therapy provides novel treatment regimens for sepsis. Finally, HLJ1 might be a serum biomarker for patient selection as its expression correlated to serum levels of IL-12. | en |
| dc.description.provenance | Made available in DSpace on 2023-03-19T22:19:58Z (GMT). No. of bitstreams: 1 U0001-1309202210100700.pdf: 72367399 bytes, checksum: d6a305960fdcd88959de6e66a0382cd5 (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | 口試委員審定書 i 誌謝 ii 摘要 iii Abstract v Abbreviation viii List of Figures xiv List of Appendixes xvii Chapter 1. Introduction 1 1.1.1. Sepsis and septic shock 1 1.1.2. Dysregulated host immune response to infection 2 1.1.3. LPS-induced cellular and molecular response 4 1.1.4. IL-12/IFN-γ axis in sepsis 5 1.2. Mouse models of sepsis 6 1.2.1. Mouse model of LPS-induced endotoxic shock 6 1.2.2. CLP model for polymicrobial sepsis 8 1.3. Heat shock proteins 9 1.3.1. HSPs 9 1.3.2. HSPs in inflammatory response and sepsis 10 1.4. HLJ1 11 1.4.1. HSP40 family 11 1.4.2. HLJ1 gene and protein 12 1.4.3. Physiological functions of HLJ1 13 1.5. IL-12 14 1.5.1. IL-12 gene and protein structure 14 1.5.2. IL-12 biogenesis 15 1.5.3. Biological function of IL-12 16 1.5.4. HSPs in IL-12 protein folding 17 1.6. Research motivation and strategy 19 Chapter 2. Materials and Methods 20 2.1. Mice experiments 20 2.1.1. HLJ1-knockout mice generation and maintenance 20 2.1.2. LPS administration 20 2.1.3. CBC and biochemical analysis 21 2.1.4. Immunofluorescence staining 21 2.1.5. Cytokine neutralization 22 2.1.6. Cecal ligation and puncture 23 2.1.7. Macrophage depletion and reconstitution 23 2.2. Single-cell RNA sequencing 24 2.2.1. Single cell isolation, cDNA library preparation and next generation sequencing 24 2.2.2. scRNA-seq data analysis 25 2.3. Quantitative real-time PCR analysis 26 2.3.1. RNA extraction 26 2.3.2. Reverse transcription and qRT-PCR 27 2.4. Cytokine analysis 28 2.4.1. Multiplex bead array 28 2.4.2. ELISA analysis 29 2.5. Flow cytometry analysis 30 2.5.1. Sample preparation for surface staining 30 2.5.2. Intracellular staining 31 2.6. Cell culture 32 2.6.1. Cell culture and transfection 32 2.6.2. Primary NK cell isolation and stimulation 32 2.6.3. BMDM isolation and activation 33 2.7. Immunoblotting experiments 34 2.7.1. Protein extraction and quantification 34 2.7.2. Sample preparation for non-reducing SDS-PAGE 34 2.7.3. Serum sample preparation for SDS-PAGE 34 2.7.4. SDS-PAGE 35 2.8. Statistical analysis 35 Chapter 3. Results 37 3.1. HLJ1 deficiency protected against endotoxemia 37 3.1.1. Dnajb4−/− mice showed better survival than wild-type mice administrated with lethal dosage of LPS 37 3.1.2. Vital organ injury was alleviated in Dnajb4−/− mice with non-lethal endotoxemia 37 3.2. HLJ1 amplified IFN-γ–dependent septic death 38 3.2.1. CBC analysis for immune cell profile in peripheral blood 38 3.2.2. Proinflammatory cytokines mRNA expression in livers 38 3.2.3. Cytokine array analysis for proinflammatory cytokines in serum 39 3.2.4. IFN-γ neutralization improved survival in wild-type mice rather than in Dnajb4−/− mice 40 3.3. HLJ1 deficiency changed IFN-γ-related gene signature in distinct cell clusters in the liver after LPS challenge 41 3.3.1. Signaling pathways affected by IFN-γ were altered in HLJ1-deleted macrophages and dendritic cells 41 3.3.2. IFN-γ signaling was down-regulated in hepatic Dnajb4−/− NK cells 42 3.4. HLJ1 deficiency resulted in reduced IFN-γ production in NK cells 44 3.4.1. NK and T cell populations in the spleen of Dnajb4−/− mice 44 3.4.2. Intracellular IFN-γ decreased in splenic NK cells after HLJ1 deletion 44 3.5. HLJ1 deletion protect against CLP-induced organ dysfunction and death 45 3.5.1. Dnajb4−/− mice showed dampened organ injury in CLP model 45 3.5.2. Dnajb4−/− mice has lower IFN-γ expression during CLP-induced sepsis 46 3.5.3. HLJ1 deletion improved survival rate when mice received immediate systemic antibiotics immediately after CLP surgery 46 3.6. HLJ1 functions in macrophages to maintain IL-12/IFN-γ-axis in vivo and promote septic death 47 3.6.1. HLJ1 contributes to IL-12–dependent IFN-γ production and lethality 47 3.6.2. Numbers of macrophages in livers of LPS-treated Dnajb4−/− mice 48 3.6.3. HLJ1 in macrophages regulated IL-12/IFN-γ axis-related death 49 3.7. LPS-induced HLJ1 helped IL-12p70 production via reducing accumulated IL-12p35 homodimer 50 3.7.1. Supernatant and intracellular IL-12p70 decreased in Dnajb4−/− macrophages 51 3.7.2. Transcriptional levels of IL-12 subunit remained unchanged between Dnajb4−/− and Dnajb4+/+ BMDM 51 3.7.3. LPS induced time-dependent expression of HLJ1 in macrophages 53 3.7.4. HLJ1 helps IL-12p35 folding and heterodimeric IL-12p70 production 53 3.8. Serum levels of HLJ positively correlated to serum IL-12 54 3.8.1. Serum HLJ1 was positively correlated to IL-12p70 in sepsis mice 54 Chapter 4. Discussion 56 4.1. HLJ1 play an important role in mild endotoxemia and live-infection model which resemble human sepsis 56 4.2. The t-SNE plots were similar across genotypes in scRNA-seq data 57 4.3. In vivo IL-12 transcription was lower in Dnajb4−/− whereas that in vitro was similar between genotypes 58 4.4. IL-12-producing macrophages may function in the liver microenvironment during high-dose endotoxemia 59 4.5. HLJ1-mediated IL-12 protein folding and assembly 61 4.6. HLJ1-targeting strategies for sepsis treatment 62 4.7. HLJ1-targeting therapy may be applied before immunoparalysis occurs because of the dual role of IFN-γ in sepsis 64 4.8. Serum HLJ1 as a potential biomarker for sepsis 65 Chapter 5. Conclusion and Prospective 67 Figure 69 Bibliography 119 Appendix 130 | |
| dc.language.iso | en | |
| dc.subject | 介白素12 | zh_TW |
| dc.subject | 敗血症 | zh_TW |
| dc.subject | 異二聚化 | zh_TW |
| dc.subject | 脂多醣 | zh_TW |
| dc.subject | 熱休克蛋白 | zh_TW |
| dc.subject | 單細胞定序 | zh_TW |
| dc.subject | heterodimerization | en |
| dc.subject | Sepsis | en |
| dc.subject | Lipopolysaccharide | en |
| dc.subject | Heat shock protein | en |
| dc.subject | Single-cell RNA sequencing | en |
| dc.subject | IL-12 | en |
| dc.title | 動物模式闡明HLJ1缺失對內毒素引發敗血症之影響 | zh_TW |
| dc.title | Mouse model elucidates the impact of HLJ1 deficiency on immunomodulation during endotoxin-induced sepsis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.advisor-orcid | 蘇剛毅(0000-0002-6538-9526) | |
| dc.contributor.oralexamcommittee | 楊泮池(Pan-Chyr Yang),鐘桂彬(Kuei-Pin Chung),莊雅惠(Ya-Hui Chuang),郭靜穎(Ching-Ying Kuo) | |
| dc.subject.keyword | 敗血症,脂多醣,熱休克蛋白,單細胞定序,介白素12,異二聚化, | zh_TW |
| dc.subject.keyword | Sepsis,Lipopolysaccharide,Heat shock protein,Single-cell RNA sequencing,IL-12,heterodimerization, | en |
| dc.relation.page | 132 | |
| dc.identifier.doi | 10.6342/NTU202203334 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2022-09-13 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| dc.date.embargo-lift | 2022-10-13 | - |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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