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系統識別號 U0026-0812200914280253
論文名稱(中文) A群鏈球菌熱原性外毒素B所引發細胞凋亡及其促成介白素-8產生的途徑
論文名稱(英文) Pathways for SPE B-induced apoptosis and IL-8 production
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 張家雯
研究生(英文) Chia-Wen Chang
電子信箱 s5890130@mail.ncku.edu.tw
學號 s5890130
學位類別 博士
語文別 英文
論文頁數 168頁
口試委員 口試委員-莊偉哲
召集委員-林以行
指導教授-林銘德
口試委員-郭志峰
口試委員-吳俊忠
口試委員-賈景山
中文關鍵字 A群鏈球菌熱原性外毒素B  細胞凋亡  介白素-8 
英文關鍵字 IL-8  apoptosis  SPE B 
學科別分類
中文摘要 本研究在於了解熱原性外毒素B (SPE B)造成細胞凋亡的訊息途徑及其調節,以及SPE B引發介白素-8產生的路徑。我們先前的研究已確定integrin αvβ3和Fas為SPE B之接受器。然而G308S為SPE B帶有RSD片段的突變蛋白只能和Fas結合。C192S為不具蛋白酶活性之突變蛋白。因此此篇研究即利用SPE B、G308S及C192S重組蛋白來探討SPE B和A549細胞的關係。我們發現SPE B但非G308S可以刺激JAK2和STAT1的tyrosine磷酸化。在SPE B刺激下,被活化的JAK2/STAT1可以造成procaspase 8表現量增加。另一方面,SPE B和G308S都可以增加STAT1的Serine727磷酸化,而此活化會被anti-Fas抗體和p38 MAPK抑制劑SB203580所抑制。SPE B可以透過Fas接受器來活化p53,且受到p38抑制劑所抑制。這些結果推測Fas造成SPE B所引發Bax的表現是透過p38, STAT1, p53訊息傳遞。然而AG490 (JAK2抑制劑) 和SB203580皆可抑制SPE B所引發的細胞凋亡,但只有SB203580可抑制G308S所引發的細胞凋亡。這個和SPE B可造成procaspase 8和Bax表現量增加但G308S只會造成Bax表現量增加的發現有一致性。Procaspase 8及Bax互補的表現可以幫助A群鏈球菌更多能力去破壞細胞。SPE B引發細胞凋亡之後其命運仍是未知。利用共軛焦顯微鏡在37C下分析,我們偵測到SPE B和lysosome處在同一個位子。結果顯示SPE B的內吞作用是透過clathrin且在細胞內分解。Lysosome抑制劑chloroquine可抑制SPE B進到細胞和分解,且造成SPE B在培養液的分解有較多延遲。再者proteasome抑制劑MG132也會增加SPE B接受器的循環。抑制SPE B內吞作用和增加SPE B接受器的循環都會增強SPE B所引發的細胞凋亡。對於毒素的反應,細胞激素的釋出是一個重要的免疫反應。我們的結果顯示在SPE B處理下,利用ELISA assay測出A549細胞引起介白素-8的分泌。對於SPE B或G308S的處理都會增加介白素-8 mRNA的量。SPE B造成A549細胞表現介白素-8是透過Fas,接著會活化FADD、caspase 8、MEKK1、ERK及NF-κB。在SPE B刺激下,表皮細胞分泌出介白素-8會吸引免疫細胞,此可以抵抗外來的病原菌或毒素且除去死亡的細胞體。SPE B的內吞作用和介白素-8的分泌或許是宿主去除毒性物質的抵抗機制之一。本研究可詳細提供SPE B引發A549細胞凋亡和宿主防禦機制的了解,以及對於A群鏈球菌破壞黏膜內層表面和其所造成組織嚴重的傷害,提供了一種思維。
英文摘要 This study is to elucidate the signal pathway of the streptococcal pyrogenic exotoxin B (SPE B)-induced apoptosis and its regulation, as well as the pathway of SPE B-induced IL-8 production. We have previously identified integrin αvβ3 and Fas as receptors for SPE B. However, G308S, a mutant of SPE B with RSD motif, interacts with Fas only. C192S is a mutant protein with no protease activity. Thus, recombinant proteins SPE B, G308S and C192S were used in this research is to study the relationship between SPE B and A549 cells. We found that SPE B, but not G308S, stimulated the tyrosine phosphorylation of JAK2 and STAT1. Activated JAK2/STAT1 could upregulate procaspase 8 expression after SPE B stimulation. On the other hand, SPE B and G308S increased STAT1 phosphorylation on serine 727, which was inhibited by anti-Fas antibody and p38 MAPK inhibitor SB203580. p53 was also activated by SPE B through Fas receptor and inhibited by p38 inhibitor. These results suggested that Fas mediated the SPE B-induced upregulation of Bax expression through p38, STAT1 and p53 signal pathway. Furthermore, both AG490 (JAK2 inhibitor) and SB203580 inhibited SPE B-induced apoptosis, but only SB203580 inhibited G308S-induced apoptosis. This is consistent with the findings that SPE B upregulated both procaspase 8 and Bax expression, while G308S stimulated only Bax expression. The complementary upregulation of procaspase 8 and Bax may contribute GAS more ability to destroy cells. After SPE B induces apoptosis, its fate is unknown. Using confocal microscopy time-course analysis at 37C, we detected that the co-localization of SPE B with lysosome. The results indicated that the endocytosis of SPE B was through clathrin and degraded in cell. Lysosomal inhibitor, chloroquine, inhibited degradation and internalization of SPE B and resulted in a much more delayed degradation of SPE B in medium. And proteasome inhibitor, MG132 can enhance the recycle of SPE B receptor. The inhibited endocytosis of SPE B and enhanced recycle of SPE B receptor increased the level of SPE B-induced apoptosis. In response to toxin, cytokine release is an important immunoreaction. Our results showed that following exposure to SPE B, A549 cells initiated IL-8 release as measured by ELISA assay. The level of IL-8 mRNA increased in response to the treatment of SPE B or G308S. The production of IL-8 by SPE B in A549 cells is mediated by Fas, and followed by the activation of FADD, caspase 8, MEKK1, ERK, and NF-κB. IL-8 secreted from epithelial cells in response to SPE B stimulation can recruit immune cells in order to compete with extrinsic pathogens or toxin and the removal of the apoptotic cell body. The endocytosis of SPE B and IL-8 secretion may be a part of a host defense mechanism to remove toxic substances. This study can provide the understanding of the mechanism of SPE B-induced A549 cell apoptosis and host defense in detail as well as the intellect for GAS that destroys the surfaces of mucosal linings and causes serious damage of tissue.
論文目次 考試合格證明…………………………………………………………1
Contents………………………………………………………………2
中文摘要………………………………………………………………5
Abstract………………………………………………………………7
誌謝……………………………………………………………………9
List of figures……………………………………………………10
Abbreviation……………………………………………………… 12
Introduction……………………………………………………… 14
I. Pathogenesis of group A streptococcus………………… 14
II. Pathogenic factors of group A streptococcus…………15
III. Streptococcal pyrogenic exotoxin B (SPE B)…………17
IV. Apoptosis in pathogenesis and its signal pathway… 21
V. The role of JAK/STAT signal pathway in apoptotic protein expression……………26
VI. The role of p53 in cell apoptosis………………………28
VII. Endocytosis………………………………………………… 29
VIII. Cytokine secretion and regulated signal pathway…31
Specific Aims………………………………………………………34
Methods………………………………………………………………35
I. Cell culture……………………………………………………35
II. rSPE B, C192S and G308S……………………………………36
A. Purification of recombinant SPE B and its mutant C192S and G308S……………… 36
B. Preparation of 28 kDa-C192S……………………………… 38
III. Protein analysis……………………………………………39
A. Total cell lysates extraction…………………………… 39
B. Nuclear protein extraction…………………………………39
C. Mitochondrial protein extraction…………………………40
D. SDS-PAGE formula………………………………………………41
E. SDS-PAGE analysis…………………………………………… 42
F. Coomassie blue analysis…………………………………… 42
G. Western blotting and immunoprecipitation assay………43
H. Protease activity assay…………………………………… 45
IV. Reverse transcriptase polymerase chain reaction……45
V. Cytokine production by ELISA………………………………48
A. Collection of conditioned medium…………………………48
B. ELISA assay…………………………………………………… 48
VI. Short interfering RNA (siRNA) preparation……………49
VII. Reporter assay………………………………………………51
VIII. Chromatin immunoprecipitation (CHIP) ………………52
IX. Analysis of apoptosis………………………………………53
X. Interaction between protein and cell……………………54
A. Conjugation of protein with FITC…………………………54
B. Confocal microscopy………………………………………… 54
C. Cellular degradation of protein………………………… 55
D. Cell surface binding assay…………………………………55
XI. Statistical analysis……………………………………… 56
Results………………………………………………………………57
I. JAK2/STAT1 signal pathways regulate SPE B-induced procaspase 8 expression in A549 cells……………………57
II. p38/p53 signal pathways regulate SPE B-induced Bax expression in A549 cells………………………………… 60
III. The fate of SPE B after internalization and its implication in SPE B-induced apoptosis………………… 64
IV. The IL-8 production by SPE B in A549 cells………… 69
Discussion………………………………………………………… 73
I. JAK2/STAT1 regulates SPE B-induced apoptosis…………73
II. p38/p53 regulates SPE B-induced apoptosis……………75
III. The fate of SPE B after internalization…………… 76
IV. SPE B-induced IL-8 production in A549 cells…………79
V. The physiological role of SPE B-induced signal pathways in GAS infection……………………………………… 82
Conclusion………………………………………………………… 85
References………………………………………………………… 87
Figures…………………………………………………………… 112
Appendix……………………………………………………………152
Autobiography…………………………………………………… 165
Publications………………………………………………………166
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