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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 許秉寧(Ping-Ning Hsu) | |
dc.contributor.author | Shih-Chia Huang | en |
dc.contributor.author | 黃世嘉 | zh_TW |
dc.date.accessioned | 2021-06-15T06:57:48Z | - |
dc.date.available | 2014-03-03 | |
dc.date.copyright | 2011-03-03 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-01-28 | |
dc.identifier.citation | Abrahamsen, H., Baillie, G., Ngai, J., Vang, T., Nika, K., Ruppelt, A., Mustelin, T., Zaccolo, M., Houslay, M., and Tasken, K. (2004). TCR- and CD28-mediated recruitment of phosphodiesterase 4 to lipid rafts potentiates TCR signaling. J Immunol 173, 4847-4858.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48462 | - |
dc.description.abstract | Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)是TNF分子族群中的成員之一,已經被證實可在T細胞活化時引起共活化作用。然而,對於TRAIL的細胞內訊息傳遞,以及其引發的共活化刺激訊息如何輔助T細胞受器的刺激作用,進而造成T細胞活化目前仍然未知。本論文的目的在於研究TRAIL的訊息傳遞路徑,並且瞭解TRAIL共活化刺激作用如何幫助T細胞受器刺激作用造成T細胞活化的分子機制。我們發現在TRAIL共活化刺激中,能夠藉由引起PKCθ-IKK-IκB 訊息傳遞路徑的活化來引發NF-κB的活化。此外,TRAIL共活化刺激也能引起PLCγl-calcium-NFAT訊息傳遞路徑與PI3K-Akt訊息傳遞路徑的活化。我們也發現TRAIL共活化刺激能放大T細胞受器近端激酶的訊息傳遞。更進一步地,在TRAIL共活化刺激中,TRAIL能夠和Lck交互作用,並且這樣的交互作用能夠影響TRAIL共活化刺激所引起的訊息傳遞。然而,在沒有刺激T細胞受器而只有單獨刺激TRAIL時,也能夠引起T細胞受器近端激酶以及下游PI3K-Akt訊息傳遞路徑、NFAT與NF-κB的活化。雖然單獨刺激TRAIL能夠引起類似於TRAIL共活化刺激時的訊息傳遞反應,但是不足以造成T細胞活化。最後,我們發現在TRAIL共活化刺激下,能夠引起Lck與PKCθ進入脂質筏(lipid rafts)內,造成脂質筏的重組,而這樣的現象在單獨刺激T細胞受器或是TRAIL都不會發生。擾亂脂質筏的結構能夠阻止TRAIL共活化刺激所引起的T細胞活化,這表示TRAIL共活化刺激訊息是在脂質筏內將訊息匯聚到T細胞受器的訊息傳遞內。因此我們的結論是在TRAIL共活化刺激下,能夠引起訊息分子進入脂質筏內,而Lck進入脂質筏內能匯聚TRAIL的訊息與T細胞受器的訊息,最後造成T細胞活化。 | zh_TW |
dc.description.abstract | Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, has been demonstrated to mediate costimulation effect in T cell activation. However, the intra-cellular signaling transduced by TRAIL and the TRAIL costimulatory signaling complementing to TCR stimulation-induced T cell activation remain largely unknown. Aims of this study were to investigate the signaling pathway transduced by TRAIL and the mechanism of TRAIL costimulation to TCR stimulation-induced T cell activation. Our results demonstrated that TRAIL costimulation-induced NF-kappaB activation depended on the PKCtheta-IKK-IkappaB signaling pathway. The PLCgamma1-calcium-NFAT signaling pathway and PI3K-Akt pathway were also activated in TRAIL costimulation. We also demonstrated that TRAIL costimulation amplified TCR proximal kinases signaling. Furthermore, we demonstrated that TRAIL associated with Lck during TRAIL costimulation and the association was required for downstream signaling. DR4-Fc alone stimulation without anti-CD3 mAb also induced the phosphorylation of TCR proximal tyrosine kinases and activated the downstream PI3K-Akt, NFAT and NF-kappaB signaling pathways, but these effects were insufficient for T cell proliferation. Finally, we demonstrated that the TRAIL costimulation induced Lck and PKCtheta recruitment and resulted in lipid rafts reorganization, while these events did not occur in TCR or DR4-Fc alone stimulation. Blocked TRAIL costimulation-induced T cell activation by disruption of lipid rafts indicated the kinases-enriched lipid rafts provided the platform for TRAIL costimulatory signaling integrating into TCR signaling. These results demonstrate that TRAIL costimulation regulates the reorganization of signaling molecules of lipid rafts and then Lck recruitment into lipid rafts integrates the multiple signals from TRAIL and TCR resulting in T cell activation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T06:57:48Z (GMT). No. of bitstreams: 1 ntu-100-D92449004-1.pdf: 2492949 bytes, checksum: dff2090eab0f4129abf229b34e65d77b (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | 誌謝....................................................................................................................................i
中文摘要..........................................................................................................................iii Abstract...........................................................................................................................iv Chapter I. Introduction...................................................................................................1 Part A. T lymphocyte activation........................................................................................1 Part B. Costimulatory molecules other than CD28...........................................................1 Part C. TRAIL and biological function.............................................................................3 Part D. TRAIL and T cell costimualtion............................................................................4 Part E. The costimulatory signaling in T cell activation..................................................5 Part F. Lipid rafts and T cell activation.............................................................................7 Part G. Rational and significance.......................................................................................9 Chapter II. Materials and methods..............................................................................10 Materials..........................................................................................................................10 Methods...........................................................................................................................16 Chapter III. Results.......................................................................................................23 Part A. TRAIL costimulation activates NF-κB pathway.................................................23 Part B. TRAIL costimulation activates NFAT pathway...................................................25 Part C. TRAIL costimulation activates PI3K-Akt pathway.............................................26 Part D. TRAIL costimulation activates TCR proximal tyrosine kinases.........................27 Part E. TRAIL costimulation is independent of CD28 costimulation.............................28 Part F. TRAIL associates with Lck in TRAIL costimulation and mediates NF-κB activation.........................................................................................................................29 Part G. TRAIL engagement alone activates proximal tyrosine kinases, Akt, NF-κB, and NFAT, but is insufficient for T cell proliferation.............................................................29 Part H. Recruitment of Lck and PKCθ into lipid rafts in TRAIL costimulation...........31 Chapter IV. Discussions.................................................................................................33 Part A. The molecular mechanism of TRAIL-mediated T cell costimulation.................33 Part B. Lipid rafts link TRAIL molecule and TRAIL-transduced signal........................34 Part C. The recruitment of Lck and PKCθ into lipid rafts is required for their kinase activity.............................................................................................................................36 Part D. The physiological function of TRAIL-mediated T cell costimulation................38 Part E. Conclusion...........................................................................................................39 Chapter V. References...................................................................................................41 Chapter VI. Figures.......................................................................................................52 Figure 1 TRAIL costimulation induced human primary T cell proliferation is suppressed by NF-κB inhibitor treatment............................................................................52 Figure 2 TRAIL costimulation induces nucleus translocation of NF-κB in Jurkat T cells....................................................................................................................53 Figure 3 The DNA binding activity of NF-κB is increased upon TRAIL costimulation.....................................................................................................54 Figure 4 TRAIL costimulation induces PKCθ-IKK-IκB pathway activation.................55 Figure 5 TRAIL costimulation induces NF-κB pathway activation in human primary T cells....................................................................................................................56 Figure 6 TRAIL costimulation induces nucleus translocation and DNA binding activity of NFAT in Jurkat cells......................................................................................57 Figure 7 TRAIL costimulation does not induce ERK and JNK phosphorylation...........58 Figure 8 TRAIL costimulation enlarges PLCγ1 phosphorylation and Calcium flux......59 Figure 9 TRAIL costimulation induced human primary T cell proliferation is suppressed by PI3K and Akt inhibitor treatment.................................................................61 Figure 10 TRAIL costimulation induces Akt and GSK-3β phosphorylation..................63 Figure 11 Akt regulates TRAIL costimulation-induced NFAT activation.......................64 Figure 12 TRAIL costimulation induces proximal tyrosine kinases phosphroylation....66 Figure 13 TRAIL costimulatory pathway is independent to CD28 costimulatory pathway............................................................................................................68 Figure 14 Lck associates with TRAIL upon TRAIL costimulation in Jurkat cells.........69 Figure 15 Lck is required for TRAIL costimulation-mediated NF-κB activation...........70 Figure 16 TRAIL engagement alone induces NF-κB pathway activation.......................71 Figure 17 TRAIL engagement alone induces PLCγ1 phosphorylation and activation of NFAT................................................................................................................73 Figure 18 TRAIL engagement alone induces Akt and GSK-3β phosphorylation...........74 Figure 19 TRAIL engagement alone induces proximal tyrosine kinases phosphorylation...............................................................................................75 Figure 20 TRAIL engagement alone is insufficient to induce T cell proliferation..........76 Figure 21 Lipid rafts is required for IL-2 production upon TRAIL costimulation..........77 Figure 22 Disruption of lipid rafts integrity suppresses TRAIL costimulation-induced phosphorylation of ZAP70, Akt and PLCγ1 and the nucleus translocation of NFAT................................................................................................................78 Figure 23 TRAIL costimulation recruits Lck and PKCθ into lipid rafts.........................80 Figure 24 TRAIL costimulation induces the translocation of Lck and PKCθ into lipid rafts..................................................................................................................82 Figure 25 The model of TRAIL-tranduced reverse signal pathway................................83 Figure 26 The model of TRAIL costimulatory signal integrating to TCR signal resulting in maximal activaiton of T cells......................................................................84 | |
dc.language.iso | en | |
dc.title | TRAIL引發T細胞共活化刺激作用的訊息傳遞機制 | zh_TW |
dc.title | Signal transduction pathways in TRAIL-mediated T cell costimulation | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 謝世良,司徒惠康,賴明宗,繆希椿 | |
dc.subject.keyword | TRAIL共活化作用, | zh_TW |
dc.subject.keyword | TRAIL costimulation, | en |
dc.relation.page | 85 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-01-28 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 免疫學研究所 | zh_TW |
顯示於系所單位: | 免疫學研究所 |
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