臺灣博碩士論文加值系統

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。

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.

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

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