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系統識別號 U0026-2106201117512700
論文名稱(中文) T細胞聚集在類風濕性關節炎的機制
論文名稱(英文) The mechanisms of T cells accumulation in rheumatoid arthritis
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 99
學期 2
出版年 100
研究生(中文) 林裕萍
研究生(英文) Yu-Ping Lin
學號 s5893142
學位類別 博士
語文別 中文
論文頁數 70頁
口試委員 口試委員-許秉寧
口試委員-張晃猷
口試委員-呂增宏
口試委員-葉才明
召集委員-劉明煇
指導教授-楊倍昌
中文關鍵字 類風濕性關節炎  T細胞 
英文關鍵字 rheumatoid arthritis  p38 MAPK  Zap70 
學科別分類
中文摘要 類風濕性關節炎是一種慢性的關節發炎疾病,全世界大約有百分之0.5-1的人患有此病。在罹病發炎的關節處有許多周邊的T細胞浸潤,而且這些自體活化的T細胞不容易死亡。這種不正常的T細胞活化可能為類風濕性關節炎發病的原因之一。本篇論文要探討的主題是,造成T細胞累積在關節處的機制。第一部分的研究項目是,為何關節處的T細胞不容易透過Fas的訊息傳遞而誘發細胞凋亡。除此之外,人類類風濕性關節炎關節處的組織含有高量的SDF-1 (吸引T細胞移動的細胞趨化因子)。而且,在動物研究模式中發現,T細胞表面SDF-1的受體--CXCR4的表現量高,則類風濕性關節炎的發病程度較嚴重。為了釐清T細胞受到SDF-1吸引而移動的機制,在第二部分的研究重點是,T細胞如何經由調控CXCR4下游的分子--Zap70蛋白進而增加其移動、浸潤的能力。
首先,我們發現,類風濕性關節炎關節處的T細胞表現較多的磷酸化p38 MAPK。類風濕性關節炎之關節液或是可溶性膠原蛋白 (為一種大量存在關節處的細胞外間質蛋白)都會誘發Jurkat細胞內p38 MAPK的磷酸化,並且減低Fas所誘發的細胞凋亡。1 integrin的阻斷抗體可抑制這種異常增加的p38 MAPK的磷酸化。過度表現持續活化的1 integrin (G429N)則會誘發Jurkat細胞內p38 MAPK磷酸化。此外,利用SB202190抑制p38 MAPK的活性,不只會增加Caspase-8和Caspase-3的酵素活性,並且增加Fas訊息所誘發細胞凋亡。利用confocal顯微鏡以及免疫沉澱法發現,Jurkat細胞生長在含有類風濕性關節炎之關節液的培養液中,其細胞內磷酸化的p38 MAPK與Caspase-8之間結合的量會增加。綜合這些結果推測,在發炎的環境中經由1 integrin的訊號會增加細胞內p38 MAPK磷酸化,抑制Caspase-8的活性,進而降低Fas訊息所誘發的細胞凋亡。這可能是T細胞累積在類風濕性關節炎關節處的原因之一。
本論文的第二部分,是研究CXCR4下游的分子Zap70是如何調控T細胞的移動,期待可以釐清T細胞聚積到發炎關節組織的訊號。從Jurkat細胞在3D膠原蛋白膠和-Slide細胞趨化實驗中發現,Zap70會調控Jurkat細胞移動時的方向性。抑制了細胞內Zap70的活性,並不會影響Jurkat細胞在膠原蛋白和fibronectin細胞外間質上隨機移動的能力,但卻會減少Jurkat細胞transmigration的數量,也打亂了Jurkat細胞在-Slide趨化實驗中對於SDF-1的方向性。觀察Zap70缺乏的Jurkat突變細胞株—p116細胞的爬行能力發現,其隨機移動的能力雖然活躍,但是無法朝著有化學趨化因子存在的方向移動。當黏附在fibronectin上時,p116細胞大部分是處於非極化的型態,其細胞前緣形成lamellipodia的數量比較少,而且pseudopod縮回的速度也比wild-type Jurkat細胞快。因為Zap70會與Talin形成複合體,當以SDF-1刺激細胞增加其細胞內Zap70的磷酸化後,Talin和integrin的結合增加並會促進integrin活化。此外在p116細胞中和Talin結合的integrin比較少,而且活化態的integrin也比較少。因此,Zap70可能是經由Talin來調控integrin的活化,進而控制T細胞移動的方向性。
綜合這些結果,我們認為未來在研發抗發炎藥物時,針對細胞內p38 MAPK來影響T細胞的存活或是控制細胞內Zap70的活性來干擾T細胞浸潤到發炎組織,可能是治療類風濕性關節炎藥物的新方向。
英文摘要 Rheumatoid arthritis (RA) is a chronic disease which affects 0.5 to 1 percent of people in the world. The failure of synovial T cell apoptosis and increase in the recruitment of peripheral T cells to the rheumatoid synovium maybe associate to the pathogenesis of RA. The aim of this study was to investigate the mechanisms that may contribute to the T cells present in inflammatory joints. First, we studied why the synovial T cells are resistant to Fas-mediated apoptosis. Previously study shown that SDF-1(stromal cell-derived factor 1) was highly expression in RA synovial tissue. Moreover, CXCR4, the receptor of SDF-1, expression in T cells was important for the development of RA animal model. Thus, we investigated how Zap70, the CXCR4 downstream signal molecule, controls T cells migration.
In the first part, we demonstrated that CD3+ T cells in RA synovia expressed high amounts of phospho-p38 MAPK. Exposure to RA synovial fluid or soluble collagen, a degradation product of extracellular matrix abundant in RA synovium, induced the phosphorylation of p38 MAPK in Jurkat cells accompanied by resistance against Fas-mediated apoptosis. Blocking 1 integrin by antibody diminished this effect. In addition, ectopic expression of auto-activated 1 integrin (G429N) in T cells profoundly induced the phosphorylation of p38 MAPK. Suppression of p38 MAPK sensitized T cells to Fas-mediated apoptosis and increased caspase-8 and caspase-3 cleavage. A physical interaction of p38 MAPK and caspase-8 was demonstrated by using confocal microscopic imaging and co-immunoprecipitation assay. RA synovial fluid markedly increased the formation of phospho-p38 MAPK/caspase-8 complex in Jurkat cells. In this part, our results suggested that abnormal activation of p38 MAPK to prevent Fas-mediated apoptosis may represent a common survival mechanism of RA synovial T cells.
In the second part of the study, we used a three-dimensional collagen matrix containing tumor spheroids and -Slide chemotaxis to investigate cell migration. We found that Zap70 regulated the directionality during cell chemotaxis. Jurkat cells actively migrated toward SDF-1, nutrition, and spheroids of MCF7 breast carcinoma cells embedded in collagen matrix. Inhibition of Zap70 activity impaired transmigration and -Slide chemotaxis but not the random movement of T cells in the collagen/fibronectin matrix. P116 cells, a Zap70 deficient variant of Jurkat, showed active random movement but failed to migrate against chemoattractants. P116 cells exhibited a reduced polarization of cell morphology, showing less lamellipodia formation accompanied with a fast pseudopod turnover rate. Instead of direct interacting with F-actin, Zap70 formed a complex with talin which is an integrin scaffold for F-actin. SDF-1 enhanced Zap70 phosphorylation and also stimulated binding of talin and 1 integrin activation. P116 cells showed reduced complex of talin and 1 integrin in parallel with impaired integrin activation. In this part, we demonstrated that Zap70 modulates integrin activation by interacting with talin, which contributes to directionality of T-cell migration.
Thus, targeting p38 MAPK to enhance T cells apoptosis or targeting Zap70 to disrupt the directional migration of T cells maybe severe as a potential anti-inflammation therapy.
論文目次 中文摘要 I
英文摘要 III
誌謝 V
總目錄 VII
圖目錄 X
縮寫索引 XII
緒論 1
研究目標 9
材料與方法 10
A. 材料
1. 細胞株. 10
2. 抗體 10
3. 抑制劑 11
4. 質體 12
5. 試劑、實驗材料 12
6. 儀器 14
7. 緩衝液、培養液 15
B. 方法
1. 分離人類周邊血液和類風濕關節炎之關節液中的單核球 17
2. 細胞培養 18
3. 細胞內免疫螢光染色 18
4. 流式細胞儀分析細胞凋亡 19
5. 西方墨點法 19
6. 基因轉染法 19
7. Caspase-3活性偵測法 20
8. 免疫沉澱反應法 20
9. 免疫螢光染色 20
10. 膠原蛋白誘發大鼠產生關節炎模式(collagen-induced arthritis, CIA) 21
11. 反轉錄聚合酶鏈式反應(RT-PCR) 21
12. -slide細胞趨化實驗 21
13. 在3D膠原蛋白膠中細胞遷移實驗 21
14. Trans-well細胞遷移實驗 22
15. 細胞形態和細胞突出觀察 22
實驗結果
類風濕性關節液中的T細胞其細胞內磷酸化p38 MAPK陽性的比例較高 23
類風濕性關節炎之關節液、可溶性膠原蛋白(soluble collagen )以及腫瘤壞死因子可以誘發Jurkat細胞內的p38 MAPK磷酸化 23
透過類風濕性關節炎之關節液所誘發細胞內p38 MAPK的磷酸化可以抑制由CH11所誘發的細胞凋亡 25
p38 MAPK可以調控T細胞的細胞凋亡 25
類風濕性關節炎之關節液可以增加Jurkat細胞中p38 MAPK與caspase-8的交互作用 26
P38 MAPK抑制劑可以降低類風濕性關節炎模式之大鼠關節腫脹的情況 26
Jurkat細胞需要表現Zap70蛋白,在3D的膠原蛋白環境中才能朝著腫瘤球體移動 27
缺乏Zap70 會使T 細胞在有趨化梯度的環境下失去方向性進而導致
transmigration的細胞數量下降 28
細胞內Zap70 影響了focal adhesion複合體形成和分解的周期 29
細胞內Zap70可以與Talin形成複合體進而活化細胞表面的integrin 30
培養液中含有可溶性膠原蛋白會抑制由類風濕性關節炎之關節液所誘發的CXCR4基因表現 31
討論
發炎環境誘發細胞內p38 MAPK磷酸化 32
P38 MAPK調控細胞凋亡 34
促發炎激素對細胞凋亡的關係 35
發炎環境影響T細胞的移動 36
Zap-70影響細胞移動時的方向性而非移動能力 36
Zap-70調控1 integrin活化 38
結論 41
參考文獻 42
圖 52
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