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研究生:李宗霖
研究生(外文):Tsung-Lin Lee
論文名稱:探討IL-15對於表皮層之先天性免疫反應調控
論文名稱(外文):Regulation of innate immune response in the epidermis by IL-15
指導教授:顧家綺
指導教授(外文):chia-chi ku
口試委員:李建國賴亮全王莉芳
口試委員(外文):Chien-Kuo LeeLiang-chuan LaiLi-Fang Wang
口試日期:2013-07-22
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:免疫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:英文
論文頁數:102
中文關鍵詞:第十五號細胞激素表皮細胞皮膚發炎先天性免疫反應
外文關鍵詞:IL-15EpidermisSkin inflammationinnate immune response
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IL-15是一個多功能的細胞激素,除了是維持自然殺手細胞發育與記憶型CD8+ T細胞數恆定的生長因子,在人類的發炎性疾病與自體免疫相關疾病中,也被證實是一種具有促發炎反應功能的細胞激素。中研院基因突變鼠動物模式核心實驗室(MMPCF)利用ENU的致突變機制所產生的191品系突變鼠(簡稱P191)在IL-15基因上的第七外顯子具有的點突變容易導致生成IL-15選擇性剪接異構體(本論文中稱為IL-15_ASE7)。過去在HSV-1疱疹病毒的小鼠動物實驗模式中,我們發現P191小鼠的皮膚比B6小鼠容易產生較大的疱疹傷口,且皮膚的修復時間延遲,真皮層中表現Gr-1與F4/80表面抗原的白血球浸潤細胞數量也較B6小鼠少,此實驗結果顯示出皮膚中表現IL-15_ASE7可能會影響皮膚控制HSV-1病毒感染的抗病毒免疫反應與受損皮膚的修復。
本研究論文發現,P191小鼠皮膚中的IL-15與IL-15_ASE7 mRNA表現量相當,但是在不改變總表現量的狀態下,骨骼肌與脾臟中的IL-15_ASE7大約比IL-15多出兩倍。本研究藉由機械性刺激的方式比較刮擦刺激後P191小鼠皮膚與野生型B6和IL-15基因缺失鼠(Il-15-/-)皮膚在先天性免疫反應方面的差異,以探討高量IL-15_ASE7表現在皮膚組織的可能影響。組織切片的病理分析結果顯示P191小鼠的表皮細胞增生程度(p=0.03)以及真皮層增厚現象(p=0.02)均較B6小鼠低,特別是在刮擦處真皮層的嗜中性白血球浸潤顯著地比B6小鼠減少(p<0.01**)。藉由DNA微陣列分析B6與P191刮擦皮膚的全基因組轉錄圖譜,顯示氧化磷酸化與穀胱甘肽代謝有關的基因群在B6與P191小鼠中有差異表現。定量PCR的實驗結果證實Uqcrb基因與抗氧化Sod-1基因表現量在刮擦刺激48小時之後的P191小鼠皮膚分別明顯地下降2倍(p<0.01**)與3倍(p<0.01**)。此外,表皮細胞分化基因如Krt,Ivl以及Lor在P191小鼠中表現量皆較高實驗結果顯示P191小鼠皮膚在受損刺激下表皮細胞的活化程度不若B6小鼠皮膚顯著。雖然B6 的表皮細胞所產生的發炎細胞激素包括G-CSF,KC與MCP-1經過刮擦後顯著上升,甚至在Il-15-/-鼠中更明顯,然而在P191小鼠表皮細胞所產生的這些發炎細胞激素不論在轉錄與轉譯層次都比B6 與Il-15-/-下降。將P191小鼠的皮膚移植到B6宿主上,經由刮擦所刺激的嗜中性白血球浸潤也同樣明顯較B6 皮膚減少。顯示出在IL-15_ASE7的表現下,可能會影響表皮細胞受到刺激活化後的狀態,進而影響隨後的發炎反應進行。IL-15_ASE7如何調控皮膚發炎,其詳細的分子機制需要更多實驗進行佐證。

Interleukin-IL-15 (IL-15) is a pleiotropic cytokine. Not only IL-15 is known as a growth factor for the development of natural killer cells and the homeostasis of memory CD8+ T cells, it is also demonstrated as a pro-inflammatory cytokine in several human inflammatory disorder and autoimmune diseases. An ENU-mutagenized pedigree 191 (P191) generated at the Mouse Mutagenesis Program Core Facility (MMPCF) was found bearing a mutation in the exon 7 of IL-15 mRNA and thus enhanced the generation of alternatively spliced IL-15 mRNA isoform, IL-15_ASE7. Using HSV-1 zosteriform mouse model, our laboratory has previously found that HSV-1 created more severe skin lesions and delayed skin healing in P191 compared with B6 mice. Reduced dermal infiltrating cells such as Gr-1+ and F4/80+ granulocytes were also observed in P191 lesional skin, suggesting expression of IL-15_ASE7 in P191 might modulate innate immunity in skin after viral infection.
In this study, I demonstrated that comparable levels of canonical IL-15 and IL-15_ASE7 mRNA were expressed in skin but about two-fold increase in the transcription of IL-15_ASE7 mRNA in the skeletal muscles and the spleen of P191 mice by TaqMan q-PCR analysis. The effects of elevated IL-15_ASE7 in skin on innate immune responses were further investigated by mechanically stimulating flank skin of P191 compared with wild type B6 and Il-15-/- mice. Histological and immunohistochemical analysis of skin sections demonstrated that proliferation of epidermal keratinocytes (p=0.03) and the dermal thickness (p=0.02) were reduced in P191 compared with B6 mice. Dermal cellular infiltration especially in the recruitment of neutrophils in P191 lesional skin was also reduced (p<0.01**) compared with in B6 abraded skin. Genome-wide transcriptional profiling of B6 and P191 abraded skin by DNA microarray showed that genes involved in oxidative phosphorylation and glutathione metabolism were distinguishably expressed between B6 and P191 abraded skin. Particularly, transcriptional levels of Uqcrb and anti-oxidant Sod-1 gene were significantly reduced by 2-fold (p<0.01**) and 3-fold (p<0.01**) in P191 skin at 48 hours after abrasion. Additionally, expression of genes for keratinocyte differentiation, such as Krt10, Ivl, and Lor were higher in P191 compared with B6 skin. Results from these experiments suggested that proliferation and activation of the epidermal keratinocytes were alleviated in P191 mice in response to abrasion stimulation. While inflammatory cytokines produced by the epidermal keratinocytes including G-CSF, KC, MCP-1 were significantly induced by abrasion in B6 and even higher in Il-15-/- mice, they were all decreased in P191 abraded skin both at transcriptional and translational levels. Reduction of neutrophils recruitment to P191 abraded skin was also observed when the skin was grafted on the wild type host. These experiments have suggested that expression of IL-15_ASE7 in skin might have function on the homeostasis of epidermal keratinocytes and subsequently in modulate cutaneous inflammation. More experiments will be performed to clarify the detailed mechanisms by which IL-15_ASE7 regulates the process.

Chinese Abstract i
English Abstract iii
Contents v
Figures ix
Tables x
Chapter I Introduction 1
1. Interleukin-15 1
1.1. Types of IL-15 mRNA isoforms 2
1.2. Distribution of IL-15 mRNA isoforms 4
1.2.1. SSP-IL-15 mRNA and LSP-IL-15 mRNA 4
1.2.2. IL-15_ΔE6 mRNA and IL-15_ASE7 mRNA 4
1.3. Properties of IL-15 isoforms 5
1.3.1. Cellular localization of IL-15 isoforms 5
1.3.2. Regulatory function of IL-15 isoforms 6
2. Immunological function of epidermal keratinocytes 7
2.1. Composition of keratinocytes in the epidermis 7
2.2. Cytokine production by epidermal keratinocytes 9
2.3. Potential function of IL-15 in the keratinocytes 10
3. Aims of this study 11
Chapter II Materials and Methods 14
1. Mice 14
2. Abrasion of mouse flank skin 14
3. Skin graft 15
4. Hydrodynamic injection (in vivo gene transfer) 15
5. Histological analysis of skin section 16
5.1. Skin sections 16
5.2. Hematoxylin and eosin (H & E) staining 16
5.3. Immunohistochemical (IHC) staining 17
6. DNA microarray experiment 19
7. Quantification of gene expression 20
7.1. Preparation of tissue homogenates 20
7.1.1. Full skin, muscle, and spleen 20
7.1.2. Epidermis 21
7.2. RNA extraction 21
7.2.1. Full skin, epidermis, and muscle 21
7.2.2. Splenocytes 22
7.3. RNA quantitative and qualitative assessment 23
7.4. DNase treatment 23
7.5. cDNA synthesis 24
7.6. Reversed transcription PCR (RT-PCR) 25
7.7. Real-time quantitative PCR (q-PCR) by SYBR Green dye 26
7.8. TaqMan q-PCR 27
8. Cytokines and chemokines assay 28
8.1. Full-skin protein lysate 28
8.2. Multiplex cytokine analysis 28
9. IL-15 ELISA analysis 29
10. Statistical analysis 30
11. Buffers and solutions 30
11.1. 1X Glycine buffer 30
11.2. 1X Tris-NaCl NaN3 (TNN) 30
11.3. 4% Paraformaldehyde (PFA) 31
11.4. 10X Gey’s solution 31
11.5. 10X Phosphate buffer saline (PBS) 31
11.6. 10X Tris-borate-EDTA (TBE) 32
11.7. 10X Tris-buffer saline (TBS) 32
11.8. 10X Tyrode’s solution 32
11.9. Avertin (2,2,2 tribromoethanol) solution 33
12. List of antibodies 33
13. Chemicals, reagents, and kits 34
14. Reverse transcription PCR (RT-PCR) primer sequences 37
15. Real-time quantitative PCR (q-PCR) primer sequences 38
16. TaqMan probe sequences 40
Chapter III Results 41
1. Analysis of IL-15 and IL-15 isoforms mRNA in the tissues of wild type B6 and ENU-mutagenized pedigree 191 (P191) mice 41
1.1. Prominent expression of IL-15_ASE7 mRNA was found in P191 mice 42
1.2. P191 mice expressed similar amount of IL-15 mRNA but additional amount of IL-15_ASE7 mRNA in the epidermis 42
1.3. Both IL-15 and IL-15_ASE7 mRNA preserved the same signal peptide coding sequences 44
2. Histopathological analysis of abraded skin in wild type B6, P191, and Il-15-/- mice 45
2.1. Needle abrasion induced skin inflammation was impaired in P191 mice 45
2.2. Neutrophil infiltration was decreased in the abraded skin of P191 mice 46
2.3. Less thickness of epidermal layer in P191 abraded skin was resulting from decreased keratinocyte proliferation 47
3. Analysis of the gene expression profiles in the abraded skin of wild type B6 and P191 mice 48
3.1. Differential signaling pathways were found in the abraded skin of wild type B6 and P191 mice 49
3.2. Keratinocyte differentiating genes were enriched expression in the abraded skin of P191 mice. 50
4. Analysis of inflammatory cytokines and chemokines in the abraded skin of wild type B6, P191, and Il-15-/- mice 52
4.1. IL-15 protein expression could be induced in the skin after needle abrasion 52
4.2. G-CSF, KC, and MCP-1 protein expression were enhanced in Il-15-/- mice but impaired in P191 mice 53
5. The reduced production of cytokines in P191 abraded skin was affected at transcriptional level in the epidermis 55
6. The genotype of P191 skin determined the decreased infiltration of neutrophils 56
7. Overexpression of IL-15 and IL-15_ASE7 in wild type B6 mice 57
Chapter IV Discussion 59
1. IL-15 expression and signal peptide distribution 60
2. Epidermal proliferation was attenuated in P191 mice 62
3. Reduced production of cytokines and chemokines expressed involved in neutrophils recruitment in P191 inflammatory skin 64
4. Conclusion 66
Chapter V Figures 68
Chapter VI Tables 90
References 91
Appendix 101
1. Schematic illustration of LSP-IL-15 mRNA and SSP-IL15 mRNA. 101
2. Schematic illustration of IL-15 mRNA (canonical), IL-15_

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