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系統識別號 U0026-1308201011163300
論文名稱(中文) 研究A群鏈球菌引發中樞NF-κB活化所媒介之發炎反應
論文名稱(英文) Study of group A streptococcus-induced central NF-κB activation and inflammation
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 98
學期 2
出版年 99
研究生(中文) 吳佩樺
研究生(英文) Pei-Hua Wu
學號 s4697410
學位類別 碩士
語文別 英文
論文頁數 51頁
口試委員 指導教授-蔡佩珍
共同指導教授-余俊強
口試委員-林以行
口試委員-郭志峰
中文關鍵字 A群鏈球菌  細胞激素風暴  核轉錄因子κB  中樞發炎現象  腫瘤壞死因子α 
英文關鍵字 Group A streptococcus  nuclear factor κB  tumor necrosis factor α  reactive oxygen species  central inflammation 
學科別分類
中文摘要 A群鏈球菌(Group A streptococcus)在人類感染中引發強烈的發炎反應,並與細胞激素風暴息息相關,而細胞激素風暴則已知會造成多重器官衰竭並被定為鏈球菌毒性休克症候群。核轉錄因子κB (NF-κB)已知是先天免疫與發炎反應的關鍵調節者。為了研究A群鏈球菌感染中NF-κB的動態變化,我們在小鼠建立了一個活體內冷光報導NF-κB活化模式。皮下感染A群鏈球菌後,在初級感染的皮膚位置,以具時間依賴性的方式發出亮光。意外地,在皮下感染A群鏈球菌四十八小時後,由NF-κB調控的冷光和iNOS基因表現都顯著地在腦部增加,而其他器官則否。此外,也發現腦中特化免疫細胞的小膠質細胞(microglia)、發炎細胞激素與活性氧相關基因的表現、還有蛋白質的氧化程度,在鏈球菌感染後四十八小時的腦內均有顯著的活化增加。為了進一步分析細菌感染後,此細胞激素風暴在中樞NF-κB調控的發炎現象,我們分析了在鏈球菌感染後細胞激素與趨化激素在循環系統中的量。腫瘤壞死因子α (TNFα)在細菌感染二十四小時後急遽增加,可能扮演造成腦部發炎的關鍵角色。因此經由腹腔給予顯性失活TNF (dominant negative TNF)成功地降低在腦部由NF-κB所調控的冷光,還有發炎細胞激素的表現。我們的結果證實了,細菌感染時所引發的周邊發炎細胞激素,特別是TNFα,會促使中樞NF-κB活化及發炎現象。此研究對於在細菌感染周邊組織時,循環系統中的TNFα所引發的中樞NF-κB活化,及其隨之而來的中樞發炎現象的角色提供了寶貴的瞭解。
英文摘要 Group A streptococcus (GAS) infection in human causes a strong inflammatory response associated with cytokine storm which lead to multi-organ failure characterized as streptococcal toxic shock syndrome (STSS). Nuclear factor κB (NF-κB) is a critical regulator of innate immunity and inflammatory responses. To study the kinetics of NF-κB activation upon streptococcal infection, we established an in vivo luminescence reporting system for NF-κB activation in mice. After subcutaneous GAS infection, the site of primary infection, skin, was illuminated in a time-dependent manner. Surprisingly, NF-κB-mediated luminescence and iNOS expression were dramatically increased in the brain, but not notably in the peripheral organs such as liver and spleen, at 48 hr post infection (hpi). Moreover, activation of microglia, the specialized immune cell in CNS, as well as expression of inflammatory cytokines, reactive oxygen species (ROS) related genes, and protein oxidation were significantly induced in the brain at 48 hpi. To further dissect this effects of cytokine storm on central NF-κB mediated central inflammation after bacterial infection, we analyzed circulating levels of cytokines and chemokines after streptococcal infection. Tumor necrosis factor α (TNFα), which has been shown to play a pivotal role during the bacteria-induced brain abscesses, was rapidly increased at 24 hpi. Intraperitoneal administration of dominant negative TNF (DN-TNF) effectively decreased brain NF-κB mediated luminescence and expression of inflammatory cytokines. Our results demonstrated bacterial infection induced peripheral inflammatory cytokines, particularly TNFα, in turn contributing to central NF-κB activation and inflammation. This study provides valuable insight into the role of circulating TNFα-induced central NF-κB activation and the consequent central inflammation upon the bacterial infection in the peripheral.
論文目次 中文摘要 I
ABSTRACT II
致謝 III
CONTENTS V
INDEX OF TABLES AND FIGURES VIII
INTRODUCTION 1
MATERIALS AND METHODS 6
Bacteria strain 6
Animal 6
Reagents 7
Bacterial culture 7
GAS infection in vivo 8
DN-TNF administration 8
In vivo imaging 8
Tissue RNA extraction 9
Reverse transcription and real-time PCR 10
Tissue protein extraction 10
Western blotting 11
Immunofluorescent staining 11
Detection of carbonylation 12
Dot blotting 12
Luminex assay 12
Data analysis 13
RESULTS 14
In vivo imaging of activated NF-κB after streptococcal infection 14
Central NF-κB activation in the brain after streptococcal infection 14
Expression pattern of suppressor of cytokine signaling proteins 15
Microglia activation after subcutaneous GAS infection 16
Central inflammation after subcutaneous GAS infection 16
Increased central reactive oxygen species (ROS) after streptococcal infection 17
Increased central expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase (MMP)-9 after subcutaneous GAS infection 18
No correlation between bacteria presented in the brain and central NF-κB activation 19
Circulating inflammatory cytokines after subcutaneous GAS infection 20
Attenuated central NF-κB mediated central inflammation by blocking TNFα 20
DISCUSSION 22
REFERENCES 25
APPENDIX 48
Avertin 48
Homemade lysis buffer 48
Reagents list 49


INDEX OF TABLES AND FIGURES
Table 1. Mouse primer pairs. 33
Figure 1. Real time simultaneous visualization of streptococcal infection (Lux, A) and associated NF-kB activation (luc, B) after subcutaneously infected with GAS. 35
Figure 2. Activated NF-κB loci after streptococcal infection. 36
Figure 3. Relative expression level of SOCS1 and SOCS3 in the skin, brain, spleen, and liver of mice. 37
Figure 4. Immunofluorescent staining for CD11b in hippocampus of control and GAS-infected mice at 48 hpi. 38
Figure 5. Gene expression profile and protein level of components related to inflammation in brain of mice 48 hr post streptococcal infection. 39
Figure 6. Gene expression profile of components related to ROS production and protein carbonyl level in brain at 48 hpi. 40
Figure 7. Gene expression profile of COX-2 and MMP9 in brain of mice 48 hr post streptococcal infection. 41
Figure 8. Presence of bacteria in the brain and the association of luminescence after subcutaneous GAS infection. 42
Figure 9. Serum levels of TNFα, IL-1β, IL-6, KC, MCP-1, and RANTES in mice. 43
Figure 10. Gene expression level of TNFR1 and TNFR2 in the brain of mice 48 hr post streptococcal infection. 44
Figure 11. Attenuated NF-κB activation and neuroinflammation by blocking TNFα. 45
Figure 12. Gene expression profile in the brain at 48 hr post infection. 46
Figure 13. Postulated mechanism of GAS-induced central NF-κB activation and inflammation. 47
參考文獻 1 Cunningham, M.W., Pathogenesis of group A streptococcal infections and their sequelae. Adv Exp Med Biol 609, 29-42 (2008).
2 Stevens, D.L., Invasive group A streptococcus infections. Clin Infect Dis 14 (1), 2-11 (1992).
3 Cunningham, M.W., Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 13 (3), 470-511 (2000).
4 Dale, R.C., Post-streptococcal autoimmune disorders of the central nervous system. Dev Med Child Neurol 47 (11), 785-791 (2005).
5 Shulman, S.T., Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS): update. Curr Opin Pediatr 21 (1), 127-130 (2009).
6 O'Brien, K.L., Beall, B., Barrett, N.L., Cieslak, P.R., Reingold, A., Farley, M.M., Danila, R., Zell, E.R., Facklam, R., Schwartz, B., & Schuchat, A., Epidemiology of invasive group a streptococcus disease in the United States, 1995-1999. Clin Infect Dis 35 (3), 268-276 (2002).
7 Carapetis, J.R., Steer, A.C., Mulholland, E.K., & Weber, M., The global burden of group A streptococcal diseases. Lancet Infect Dis 5 (11), 685-694 (2005).
8 Centers for Disease Control, R.O.C.T., Cases of Notifiable Diseases, Taiwan, R.O.C. Taiwan Epidemiology Bulletin (2003).
9 Centers for Disease Control, R.O.C.T., Cases of Notifiable Diseases, Taiwan, R.O.C. Taiwan Epidemiology Bulletin (2006).
10 Yan, M.Y., 噬肉菌-A 群鏈球菌感染性壞疽-在台灣之現況分析 Taiwan Epidemiology Bulletin 7, 201-211 (1996).
11 Wang, S.M., Lu, I.H., Lin, Y.L., Lin, Y.S., Wu, J.J., Chuang, W.J., Lin, M.T., & Liu, C.C., The severity of Streptococcus pyogenes infections in children is significantly associated with plasma levels of inflammatory cytokines. Diagn Microbiol Infect Dis 61 (2), 165-169 (2008).
12 Johansson, L., Thulin, P., Low, D.E., & Norrby-Teglund, A., Getting under the skin: the immunopathogenesis of Streptococcus pyogenes deep tissue infections. Clin Infect Dis 51 (1), 58-65.
13 Hasty, D.L., Ofek, I., Courtney, H.S., & Doyle, R.J., Multiple adhesins of streptococci. Infect Immun 60 (6), 2147-2152 (1992).
14 Courtney, H.S., von Hunolstein, C., Dale, J.B., Bronze, M.S., Beachey, E.H., & Hasty, D.L., Lipoteichoic acid and M protein: dual adhesins of group A streptococci. Microb Pathog 12 (3), 199-208 (1992).
15 Kreikemeyer, B., Talay, S.R., & Chhatwal, G.S., Characterization of a novel fibronectin-binding surface protein in group A streptococci. Mol Microbiol 17 (1), 137-145 (1995).
16 Talay, S.R., Valentin-Weigand, P., Jerlstrom, P.G., Timmis, K.N., & Chhatwal, G.S., Fibronectin-binding protein of Streptococcus pyogenes: sequence of the binding domain involved in adherence of streptococci to epithelial cells. Infect Immun 60 (9), 3837-3844 (1992).
17 Hanski, E., Horwitz, P.A., & Caparon, M.G., Expression of protein F, the fibronectin-binding protein of Streptococcus pyogenes JRS4, in heterologous streptococcal and enterococcal strains promotes their adherence to respiratory epithelial cells. Infect Immun 60 (12), 5119-5125 (1992).
18 Courtney, H.S., Dale, J.B., & Hasty, D.I., Differential effects of the streptococcal fibronectin-binding protein, FBP54, on adhesion of group A streptococci to human buccal cells and HEp-2 tissue culture cells. Infect Immun 64 (7), 2415-2419 (1996).
19 Jaffe, J., Natanson-Yaron, S., Caparon, M.G., & Hanski, E., Protein F2, a novel fibronectin-binding protein from Streptococcus pyogenes, possesses two binding domains. Mol Microbiol 21 (2), 373-384 (1996).
20 Rocha, C.L. & Fischetti, V.A., Identification and characterization of a novel fibronectin-binding protein on the surface of group A streptococci. Infect Immun 67 (6), 2720-2728 (1999).
21 Okada, N., Liszewski, M.K., Atkinson, J.P., & Caparon, M., Membrane cofactor protein (CD46) is a keratinocyte receptor for the M protein of the group A streptococcus. Proc Natl Acad Sci U S A 92 (7), 2489-2493 (1995).
22 Nitsche-Schmitz, D.P., Rohde, M., & Chhatwal, G.S., Invasion mechanisms of Gram-positive pathogenic cocci. Thromb Haemost 98 (3), 488-496 (2007).
23 Zhou, M.J. & Brown, E.J., CR3 (Mac-1, alpha M beta 2, CD11b/CD18) and Fc gamma RIII cooperate in generation of a neutrophil respiratory burst: requirement for Fc gamma RIII and tyrosine phosphorylation. J Cell Biol 125 (6), 1407-1416 (1994).
24 Mitchell, T.J., The pathogenesis of streptococcal infections: from tooth decay to meningitis. Nat Rev Microbiol 1 (3), 219-230 (2003).
25 Collin, M. & Olsen, A., Effect of SpeB and EndoS from Streptococcus pyogenes on human immunoglobulins. Infect Immun 69 (11), 7187-7189 (2001).
26 Kapur, V., Topouzis, S., Majesky, M.W., Li, L.L., Hamrick, M.R., Hamill, R.J., Patti, J.M., & Musser, J.M., A conserved Streptococcus pyogenes extracellular cysteine protease cleaves human fibronectin and degrades vitronectin. Microb Pathog 15 (5), 327-346 (1993).
27 Kapur, V., Majesky, M.W., Li, L.L., Black, R.A., & Musser, J.M., Cleavage of interleukin 1 beta (IL-1 beta) precursor to produce active IL-1 beta by a conserved extracellular cysteine protease from Streptococcus pyogenes. Proc Natl Acad Sci U S A 90 (16), 7676-7680 (1993).
28 Burns, E.H., Jr., Marciel, A.M., & Musser, J.M., Activation of a 66-kilodalton human endothelial cell matrix metalloprotease by Streptococcus pyogenes extracellular cysteine protease. Infect Immun 64 (11), 4744-4750 (1996).
29 Herwald, H., Collin, M., Muller-Esterl, W., & Bjorck, L., Streptococcal cysteine proteinase releases kinins: a virulence mechanism. J Exp Med 184 (2), 665-673 (1996).
30 Herman, A., Kappler, J.W., Marrack, P., & Pullen, A.M., Superantigens: mechanism of T-cell stimulation and role in immune responses. Annu Rev Immunol 9, 745-772 (1991).
31 Kotzin, B.L., Leung, D.Y., Kappler, J., & Marrack, P., Superantigens and their potential role in human disease. Adv Immunol 54, 99-166 (1993).
32 Kotb, M., Bacterial pyrogenic exotoxins as superantigens. Clin Microbiol Rev 8 (3), 411-426 (1995).
33 Llewelyn, M. & Cohen, J., Superantigens: microbial agents that corrupt immunity. Lancet Infect Dis 2 (3), 156-162 (2002).
34 Sriskandan, S., Faulkner, L., & Hopkins, P., Streptococcus pyogenes: Insight into the function of the streptococcal superantigens. Int J Biochem Cell Biol 39 (1), 12-19 (2007).
35 Lappin, E. & Ferguson, A.J., Gram-positive toxic shock syndromes. Lancet Infect Dis 9 (5), 281-290 (2009).
36 Hackett, S.P. & Stevens, D.L., Streptococcal toxic shock syndrome: synthesis of tumor necrosis factor and interleukin-1 by monocytes stimulated with pyrogenic exotoxin A and streptolysin O. J Infect Dis 165 (5), 879-885 (1992).
37 Nadal, D., Lauener, R.P., Braegger, C.P., Kaufhold, A., Simma, B., Lutticken, R., & Seger, R.A., T cell activation and cytokine release in streptococcal toxic shock-like syndrome. J Pediatr 122 (5 Pt 1), 727-729 (1993).
38 Bonizzi, G. & Karin, M., The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25 (6), 280-288 (2004).
39 Medina, E., Anders, D., & Chhatwal, G.S., Induction of NF-kappaB nuclear translocation in human respiratory epithelial cells by group A streptococci. Microb Pathog 33 (6), 307-313 (2002).
40 Tsai, P.J., Chen, Y.H., Hsueh, C.H., Hsieh, H.C., Liu, Y.H., Wu, J.J., & Tsou, C.C., Streptococcus pyogenes induces epithelial inflammatory responses through NF-kappaB/MAPK signaling pathways. Microbes Infect 8 (6), 1440-1449 (2006).
41 Basak, S. & Hoffmann, A., Crosstalk via the NF-kappaB signaling system. Cytokine Growth Factor Rev 19 (3-4), 187-197 (2008).
42 Karin, M. & Ben-Neriah, Y., Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18, 621-663 (2000).
43 Chen, L.F. & Greene, W.C., Shaping the nuclear action of NF-kappaB. Nat Rev Mol Cell Biol 5 (5), 392-401 (2004).
44 Trede, N.S., Castigli, E., Geha, R.S., & Chatila, T., Microbial superantigens induce NF-kappa B in the human monocytic cell line THP-1. J Immunol 150 (12), 5604-5613 (1993).
45 Cohen, J., Shock factor shed by microbe. Nat Med 10 (4), 342-343 (2004).
46 Gu, A., Zhang, Z., Zhang, N., Tsark, W., & Shively, J.E., Generation of human CEACAM1 transgenic mice and binding of Neisseria Opa protein to their neutrophils. PLoS One 5 (4), e10067.
47 Nejak-Bowen, K.N., Thompson, M.D., Singh, S., Bowen, W.C., Jr., Dar, M.J., Khillan, J., Dai, C., & Monga, S.P., Accelerated liver regeneration and hepatocarcinogenesis in mice overexpressing serine-45 mutant beta-catenin. Hepatology 51 (5), 1603-1613.
48 Steed, P.M., Tansey, M.G., Zalevsky, J., Zhukovsky, E.A., Desjarlais, J.R., Szymkowski, D.E., Abbott, C., Carmichael, D., Chan, C., Cherry, L., Cheung, P., Chirino, A.J., Chung, H.H., Doberstein, S.K., Eivazi, A., Filikov, A.V., Gao, S.X., Hubert, R.S., Hwang, M., Hyun, L., Kashi, S., Kim, A., Kim, E., Kung, J., Martinez, S.P., Muchhal, U.S., Nguyen, D.H., O'Brien, C., O'Keefe, D., Singer, K., Vafa, O., Vielmetter, J., Yoder, S.C., & Dahiyat, B.I., Inactivation of TNF signaling by rationally designed dominant-negative TNF variants. Science 301 (5641), 1895-1898 (2003).
49 Yang, M.S., Min, K.J., & Joe, E., Multiple mechanisms that prevent excessive brain inflammation. J Neurosci Res 85 (11), 2298-2305 (2007).
50 Ryo, A., Suizu, F., Yoshida, Y., Perrem, K., Liou, Y.C., Wulf, G., Rottapel, R., Yamaoka, S., & Lu, K.P., Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol Cell 12 (6), 1413-1426 (2003).
51 Shrikant, P. & Benveniste, E.N., The central nervous system as an immunocompetent organ: role of glial cells in antigen presentation. J Immunol 157 (5), 1819-1822 (1996).
52 Block, M.L., Zecca, L., & Hong, J.S., Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8 (1), 57-69 (2007).
53 Mattson, M.P. & Camandola, S., NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 107 (3), 247-254 (2001).
54 Wilson, E.H., Weninger, W., & Hunter, C.A., Trafficking of immune cells in the central nervous system. J Clin Invest 120 (5), 1368-1379.
55 Henderson, R.B., Hobbs, J.A., Mathies, M., & Hogg, N., Rapid recruitment of inflammatory monocytes is independent of neutrophil migration. Blood 102 (1), 328-335 (2003).
56 Nahrendorf, M., Swirski, F.K., Aikawa, E., Stangenberg, L., Wurdinger, T., Figueiredo, J.L., Libby, P., Weissleder, R., & Pittet, M.J., The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 204 (12), 3037-3047 (2007).
57 Kielian, T., Barry, B., & Hickey, W.F., CXC chemokine receptor-2 ligands are required for neutrophil-mediated host defense in experimental brain abscesses. J Immunol 166 (7), 4634-4643 (2001).
58 Liu, B. & Hong, J.S., Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304 (1), 1-7 (2003).
59 Glass, G.A., DeLisle, D.M., DeTogni, P., Gabig, T.G., Magee, B.H., Markert, M., & Babior, B.M., The respiratory burst oxidase of human neutrophils. Further studies of the purified enzyme. J Biol Chem 261 (28), 13247-13251 (1986).
60 Qin, L., Liu, Y., Wang, T., Wei, S.J., Block, M.L., Wilson, B., Liu, B., & Hong, J.S., NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 279 (2), 1415-1421 (2004).
61 Johnson, F. & Giulivi, C., Superoxide dismutases and their impact upon human health. Mol Aspects Med 26 (4-5), 340-352 (2005).
62 Nystrom, T., Role of oxidative carbonylation in protein quality control and senescence. EMBO J 24 (7), 1311-1317 (2005).
63 Suzuki, Y.J., Carini, M., & Butterfield, D.A., Protein carbonylation. Antioxid Redox Signal 12 (3), 323-325.
64 Minghetti, L., Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol 63 (9), 901-910 (2004).
65 Leonardo, C.C. & Pennypacker, K.R., Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury. J Neuroinflammation 6, 13 (2009).
66 Cuadrado, E., Rosell, A., Penalba, A., Slevin, M., Alvarez-Sabin, J., Ortega-Aznar, A., & Montaner, J., Vascular MMP-9/TIMP-2 and neuronal MMP-10 up-regulation in human brain after stroke: a combined laser microdissection and protein array study. J Proteome Res 8 (6), 3191-3197 (2009).
67 Fauci, A.S., Infectious diseases: considerations for the 21st century. Clin Infect Dis 32 (5), 675-685 (2001).
68 Kim, K.S., Pathogenesis of bacterial meningitis: from bacteraemia to neuronal injury. Nat Rev Neurosci 4 (5), 376-385 (2003).
69 Arnoni, M.V., Berezin, E.N., Safadi, M.A., Almeida, F.J., & Lopes, C.R., Streptococcus pyogenes meningitis in children: report of two cases and literature review. Braz J Infect Dis 11 (3), 375-377 (2007).
70 Nadeau, S. & Rivest, S., Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood-brain barrier. Neuroscience 93 (4), 1449-1464 (1999).
71 Laflamme, N. & Rivest, S., Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor kappaB alpha within specific cellular populations of the rat brain. J Neurochem 73 (1), 309-321 (1999).
72 Olleros, M.L., Vesin, D., Lambou, A.F., Janssens, J.P., Ryffel, B., Rose, S., Fremond, C., Quesniaux, V.F., Szymkowski, D.E., & Garcia, I., Dominant-negative tumor necrosis factor protects from Mycobacterium bovis Bacillus Calmette Guerin (BCG) and endotoxin-induced liver injury without compromising host immunity to BCG and Mycobacterium tuberculosis. J Infect Dis 199 (7), 1053-1063 (2009).
73 McCoy, M.K., Ruhn, K.A., Martinez, T.N., McAlpine, F.E., Blesch, A., & Tansey, M.G., Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats. Mol Ther 16 (9), 1572-1579 (2008).
74 O'Neill, L.A. & Kaltschmidt, C., NF-kappa B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci 20 (6), 252-258 (1997).
75 Bakalkin, G., Yakovleva, T., & Terenius, L., NF-kappa B-like factors in the murine brain. Developmentally-regulated and tissue-specific expression. Brain Res Mol Brain Res 20 (1-2), 137-146 (1993).
76 Bhakar, A.L., Tannis, L.L., Zeindler, C., Russo, M.P., Jobin, C., Park, D.S., MacPherson, S., & Barker, P.A., Constitutive nuclear factor-kappa B activity is required for central neuron survival. J Neurosci 22 (19), 8466-8475 (2002).
77 Levenson, J.M., Choi, S., Lee, S.Y., Cao, Y.A., Ahn, H.J., Worley, K.C., Pizzi, M., Liou, H.C., & Sweatt, J.D., A bioinformatics analysis of memory consolidation reveals involvement of the transcription factor c-rel. J Neurosci 24 (16), 3933-3943 (2004).
78 Meffert, M.K. & Baltimore, D., Physiological functions for brain NF-kappaB. Trends Neurosci 28 (1), 37-43 (2005).
79 Meffert, M.K., Chang, J.M., Wiltgen, B.J., Fanselow, M.S., & Baltimore, D., NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 6 (10), 1072-1078 (2003).
80 Furukawa, K., Estus, S., Fu, W., Mark, R.J., & Mattson, M.P., Neuroprotective action of cycloheximide involves induction of bcl-2 and antioxidant pathways. J Cell Biol 136 (5), 1137-1149 (1997).
81 Gutierrez, H., Hale, V.A., Dolcet, X., & Davies, A., NF-kappaB signalling regulates the growth of neural processes in the developing PNS and CNS. Development 132 (7), 1713-1726 (2005).
82 Chiarugi, A., Characterization of the molecular events following impairment of NF-kappaB-driven transcription in neurons. Brain Res Mol Brain Res 109 (1-2), 179-188 (2002).
83 Koulich, E., Nguyen, T., Johnson, K., Giardina, C., & D'Mello, S., NF-kappaB is involved in the survival of cerebellar granule neurons: association of IkappaBbeta [correction of Ikappabeta] phosphorylation with cell survival. J Neurochem 76 (4), 1188-1198 (2001).
84 Grilli, M. & Memo, M., Nuclear factor-kappaB/Rel proteins: a point of convergence of signalling pathways relevant in neuronal function and dysfunction. Biochem Pharmacol 57 (1), 1-7 (1999).
85 Qin, Z.H., Chen, R.W., Wang, Y., Nakai, M., Chuang, D.M., & Chase, T.N., Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum. J Neurosci 19 (10), 4023-4033 (1999).
86 Schneider, A., Martin-Villalba, A., Weih, F., Vogel, J., Wirth, T., & Schwaninger, M., NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med 5 (5), 554-559 (1999).
87 Ridder, D.A. & Schwaninger, M., NF-kappaB signaling in cerebral ischemia. Neuroscience 158 (3), 995-1006 (2009).
88 Pizzi, M. & Spano, P., Distinct roles of diverse nuclear factor-kappaB complexes in neuropathological mechanisms. Eur J Pharmacol 545 (1), 22-28 (2006).
89 Kaltschmidt, C., Kaltschmidt, B., & Baeuerle, P.A., Stimulation of ionotropic glutamate receptors activates transcription factor NF-kappa B in primary neurons. Proc Natl Acad Sci U S A 92 (21), 9618-9622 (1995).
90 Guerrini, L., Blasi, F., & Denis-Donini, S., Synaptic activation of NF-kappa B by glutamate in cerebellar granule neurons in vitro. Proc Natl Acad Sci U S A 92 (20), 9077-9081 (1995).
91 Schreck, R., Rieber, P., & Baeuerle, P.A., Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 10 (8), 2247-2258 (1991).
92 Terai, K., Matsuo, A., McGeer, E.G., & McGeer, P.L., Enhancement of immunoreactivity for NF-kappa B in human cerebral infarctions. Brain Res 739 (1-2), 343-349 (1996).
93 Howard, E.F., Chen, Q., Cheng, C., Carroll, J.E., & Hess, D., NF-kappa B is activated and ICAM-1 gene expression is upregulated during reoxygenation of human brain endothelial cells. Neurosci Lett 248 (3), 199-203 (1998).
94 Gabriel, C., Justicia, C., Camins, A., & Planas, A.M., Activation of nuclear factor-kappaB in the rat brain after transient focal ischemia. Brain Res Mol Brain Res 65 (1), 61-69 (1999).
95 Zhang, X., Polavarapu, R., She, H., Mao, Z., & Yepes, M., Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein mediate cerebral ischemia-induced nuclear factor-kappaB pathway activation. Am J Pathol 171 (4), 1281-1290 (2007).
96 Kaushal, V. & Schlichter, L.C., Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci 28 (9), 2221-2230 (2008).
97 Garden, G.A. & Moller, T., Microglia biology in health and disease. J Neuroimmune Pharmacol 1 (2), 127-137 (2006).
98 Pineau, I., Sun, L., Bastien, D., & Lacroix, S., Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL-1 receptor/MyD88-dependent fashion. Brain Behav Immun 24 (4), 540-553.
99 Bruun, C., Heding, P.E., Ronn, S.G., Frobose, H., Rhodes, C.J., Mandrup-Poulsen, T., & Billestrup, N., Suppressor of cytokine signalling-3 inhibits Tumor necrosis factor-alpha induced apoptosis and signalling in beta cells. Mol Cell Endocrinol 311 (1-2), 32-38 (2009).
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