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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 顧家綺(Chia-Chi Ku) | |
| dc.contributor.author | Chih-Hsiu Wang | en |
| dc.contributor.author | 王之秀 | zh_TW |
| dc.date.accessioned | 2021-06-15T05:52:15Z | - |
| dc.date.available | 2015-09-09 | |
| dc.date.copyright | 2010-09-09 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-08-18 | |
| dc.identifier.citation | Alves, N.L., Arosa, F.A., and van Lier, R.A. (2007). Common gamma chain cytokines: dissidence in the details. Immunol Lett 108, 113-120.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/47248 | - |
| dc.description.abstract | 介白質-15 (interleukin-15, IL-15) 為多效性的細胞激素，在免疫細胞的功能及恆定性扮演重要的角色。IL-15蛋白的表現已知在轉錄與轉譯的過程都必須受到嚴格的調控，究竟已報導的IL-15選擇性剪接異構體是否也參與此一調控的過程仍不清楚。
本論文首先分析IL-15異構體的生化特性，我們將原型IL-15與IL-15ΔE7的cDNA選殖到表達質體，藉由N端的IL-2 leader peptide增加分泌性與C端的FLAG為蛋白標記，經由轉染到COS-7細胞株中探討兩者在蛋白質表現、分泌性、細胞表現位置與生物活性等方面的差異。利用西方墨點法結合內糖苷酶 (endoglycosidase H, Endo H) 分析，雖然IL-15異構體和原型IL-15都具有Endo H的敏感性，但是醣類修飾的程度可能不同；進一步以酵素結合免疫吸附分析 (ELISA) 測得IL-15異構體在細胞中或分泌至細胞外的量都相對較低；而且利用免疫螢光染色觀察到大部分的IL-15異構體都累積在內質網。分泌出細胞外的IL-15異構蛋白不僅不具有生物活性，還能抑制原型IL-15的生物活性。接著我們針對IL-15 受體的 alpha 次單元 (IL-15Rα) 探討IL-15異構體的作用機制，利用流式細胞分析技術發現雖然原型IL-15能增加IL-15Rα在細胞表面的表現，但是IL-15異構體卻能抑制IL-15增強IL-15Rα表現的作用；另外，將IL-15異構體與IL-15Rα共同轉染至細胞中，發現IL-15Rα會累積在細胞中而無法運輸至細胞膜上。這些結果暗示IL-15異構體可能藉由降低IL-15Rα在細胞膜的表現量而抑制trans-presentation的訊息傳遞。 總之，本實驗發現，累積在內質網的IL-15異構體無法有效分泌至細胞外，一旦分泌出細胞外，極低量的IL-15異構體可能藉由降低IL-15Rα在細胞膜上的表現而影響原型IL-15的訊息傳遞。這些現象將有助於未來進一步了解IL-15在體內的調控機制。 | zh_TW |
| dc.description.abstract | Interleukin 15 (IL-15) is a pleiotropic cytokine which plays an essential role in innate and adaptive immune cell function and homeostasis. Expression of IL-15 protein is known to be tightly controlled at transcriptional and translational levels. Whether alternative pre-mRNA splicing is also involved in regulating IL-15 function is not clear.
In this study, the biochemical properties and biological functions of IL-15ΔE7 which is encoded from an alternatively spliced mRNA having partial deletion in the exon 7 of IL-15 gene were assessed in vitro. The full length of IL-15 and IL-15ΔE7 cDNAs encoding the mature protein was cloned individually in an expression plasmid flanked with IL-2 leader peptide at the N-terminus and a FLAG tag at the C-terminus and were expressed in COS-7 cells by transient transfection method. Both IL-15 and IL-15ΔE7 were sensitive to Endo H treatment. However, their banding patterns on SDS-PAGE were different by Western blotting, suggesting the post-translational modifications on these proteins were different. Most of the IL-15ΔE7 protein retained intracellularly and accumulated in the ER as identified by colocalization with ER chaperone calnexin. Very few IL-15ΔE7 protein was secreted and failed to support HT-2 cell proliferation as well as inhibited the biological activity of IL-2 and IL-15 in a dose dependent manner. In addition, flow cytometric analysis showed that the exogenous addition of IL-15ΔE7 reduced the upregulation of surface IL-15 receptor α (IL-15Rα) induced by IL-15. Co-transfection of IL-15ΔE7 and IL-15Rα led to the intracellular accumulation of IL-15Rα which might inhibit the trans-presentation by limiting expression of IL-15Rα on the cell surface. In summary, IL-15ΔE7 was accumulated in the ER without efficient secretion. Once secreted, the extremely low amount of IL-15ΔE7 may have a regulatory role for IL-15 signaling by limiting IL-15Rα surface expression. The functional mechanism as well as the biological significance of this alternative splice variant remain to be clarified. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T05:52:15Z (GMT). No. of bitstreams: 1 ntu-99-R97449002-1.pdf: 4588999 bytes, checksum: c7e10787d65c6dcda91d53b6c06355dc (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | Abstract i
Abstract (Chinese) iii Abbreviations iv Table of Contents v List of Figures viii Chapter I. Introduction 1 Part I. Interleukin 15 (IL-15) 1 1. Biology 1 2. IL-15 mRNA isoforms and transcriptional control 2 3. Structure of IL-15 mature protein, translational control, and post-translational modification 4 Part II. IL-15 receptor (R) complex and IL-15 signal transduction pathway 5 Part III. IL-15/IL-15Rα trans-presentation 9 Part IV. IL-15 and human disease 11 Chapter II. Aims of The Study 14 Chapter III. Materials and Methods 16 Part I. Methods 16 1. Cell lines and cell culture 16 2. Construction of IL-15 and IL-15ΔE7 isoform expression vectors 16 3. COS-7 cell transfection and supernatant and lysate collection 17 3.1 COS-7 cell transfection 17 3.2 Supernatant and lysate collection 17 4. Immunoprecipitation, endoglycosidase H analyses, and Western blotting 17 4.1 Immunoprecipitation 18 4.2 Endoglycosidase H analyses 18 4.3 Western blotting 18 5. Immunofluorescence staining of intracellular IL-15 protein 19 6. IL-15 enzyme-linked immunosorbent assays 19 7. IL-15 biological assay using HT-2 cells 20 7.1 The biological activity of IL-15ΔE7 isoform 20 7.2 The inhibitory effect of IL-15ΔE7 isoform on wild type IL-15 or IL-2 20 8. Flow cytometry analysis 21 8.1 IL-2 or IL-15 receptor expression on HT-2 cells 21 8.2 The effect of IL-15ΔE7 isoform on IL-15-mediated IL-15R expression 22 Part II. Materials 23 1. Antibodies 23 1.1 Unconjugated antibodies 23 1.2 Fluorochrome-conjugated antibodies 23 1.3 Horseradish peroxidase- (HRP) or alkaline phosphatase (AP)-conjugated antibodies 24 2. PCR primers 24 3. Solutions 25 Chapter IV. Results 28 1. Molecular cloning of murine IL-15, IL-15ΔE7 isoform, and IL-15Rα 28 2. The comparisons of IL-15 protein expression, glycosylation, bioactivity, and cellular localization with IL-15L or IL-2L 28 3. Different protein expression pattern of IL-15 and IL-15ΔE7 isoform 31 4. ER-retained species of IL-15 and IL-15ΔE7 isoform exist in COS-7 cells 32 5. The poor efficiency in the generation of cellular and secreted IL-15ΔE7 isoform 33 6. Functional analysis of IL-15ΔE7 isoform 34 7. IL-15ΔE7 isoform accumulates close to the trans-Golgi network (TGN) 35 8. IL-15ΔE7 isoform colocalizes with the ER chaperone calnexin 35 9. Possible regulatory functions of IL-15ΔE7 isoform 37 10. IL-15ΔE7 isoform inhibits the upregulation of surface IL-15Rα expression induced by rIL-15 39 11. Co-transfection of IL-15ΔE7 and IL-15Rα leads to the accumulation of IL-15Rα 40 12. Interaction of IL-15ΔE7 with IL-15Rα 41 Chapter V. Discussion 43 1. The regulatory functions of IL-15ΔE7 isoform 43 2. The biological relevance of IL-15ΔE7 isoform 47 3. The differences in the biochemical properties and biological functions of IL-15 and IL-15ΔE7 isoform protein 49 4. Conclusions 52 References 55 Figures 66 Appendix 84 | |
| dc.language.iso | en | |
| dc.subject | 介白質-15受體 | zh_TW |
| dc.subject | 內質網 | zh_TW |
| dc.subject | 介白質-15 | zh_TW |
| dc.subject | 異構蛋白 | zh_TW |
| dc.subject | isoform | en |
| dc.subject | endoplasmic reticulum | en |
| dc.subject | IL-15 receptor | en |
| dc.subject | interleukin-15 | en |
| dc.title | 探討介白質-15異構蛋白的特性與功能 | zh_TW |
| dc.title | Biochemical and functional analysis of
an IL-15 alternative splice variant | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 繆希椿,鄭貽生,黃佩欣 | |
| dc.subject.keyword | 介白質-15,異構蛋白,介白質-15受體,內質網, | zh_TW |
| dc.subject.keyword | interleukin-15,isoform,IL-15 receptor,endoplasmic reticulum, | en |
| dc.relation.page | 85 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-08-18 | |
| 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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