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系統識別號 U0026-0708201416215900
論文名稱(中文) 研究化學性誘導丙型干擾素媒介皮膚炎症病理機制
論文名稱(英文) Investigating the Pathogenesis in Chemically Induced IFN-γ-mediated Skin Inflammation
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 102
學期 2
出版年 103
研究生(中文) 謝嘉原
研究生(英文) Chia-Yuan Hsieh
學號 S98981042
學位類別 博士
語文別 英文
論文頁數 93頁
口試委員 指導教授-林秋烽 副教授
召集委員-林以行 教授
口試委員-謝奇璋 教授
口試委員-王德華 副教授
口試委員-王莉芳 副教授
口試委員-李志宏 副教授
中文關鍵字 皮膚炎症  豆蔻酰佛波醇乙酯  丙型干擾素  肝醣合成酶激酶-3  巨噬細胞移動抑制因子  細胞死亡  化學趨化作用  自然殺手T細胞  化學趨化受體 
英文關鍵字 Skin inflammation  Chemical  Interferon-γ  Glycogen synthase kinase-3  Macrophage migration inhibitor factor  Cell death  Chemotaxis  Natural killer T  CD74  CXC chemokine receptor 2 
學科別分類
中文摘要 皮膚提供最大的免疫屏障。異常的皮膚免疫反應導致多種發炎性皮膚疾病,包含乾癬、接觸性皮膚炎、濕疹,等其他皮膚炎。為了研究皮膚炎的治療策略,我們使用豆蔻酰佛波醇乙酯 (TPA) 誘導實驗性的類乾癬皮膚發炎徵狀。皮膚組織丙型干擾素 (IFN-γ) 的過度表現被推測是乾癬疾病的進程主因。由於肝醣合成酶激酶-3 (GSK-3) 能促進丙型干擾素訊息傳遞,然而肝醣合成酶激酶-3在皮膚發炎的角色仍然不清楚。本論文中,實驗證明小鼠丙型干擾素受體1 (IFNGR1) 的缺乏可削弱TPA誘導急性和慢性皮膚發炎反應,包含小鼠耳朵增厚、真皮層白血球與顆粒性白血球的發炎浸潤、細胞間黏附因子1 (CD54) 的表現、表皮層過度增生以及真皮層血管新生作用,卻不影響CD3 T細胞的浸潤作用。為了釐清肝醣合成酶激酶-3於丙型干擾素媒介皮膚炎症的致病角色,透過藥物靛玉紅衍生物 (BIO) 處理或慢病毒攜帶shRNA干擾子轉殖方法進而抑制肝醣合成酶激酶-3皆能夠降低皮膚發炎反應,但仍不影響CD3 T細胞的浸潤作用。抑制肝醣合成酶激酶-3能有效地減少CD3 T細胞表現丙型干擾素係透過減少T細胞轉錄因子 (T-bet) 入核調控丙型干擾素訊息RNA轉錄表現。過去研究證實巨噬細胞移動抑制因子 (MIF) 可直接趨化CD3 T細胞的移行作用,但是巨噬細胞移動抑制因子是否媒介丙型干擾素產生細胞之趨化作用仍是未知的。巨噬細胞移動抑制因子的釋放經常是伴隨著細胞傷害致使細胞通透增加之後,所以我們偵測被豆蔻酰佛波醇乙酯刺激的小鼠耳朵和人類角質細胞株HaCaT的巨噬細胞移動抑制因子釋放程度。結果指出豆蔻酰佛波醇乙酯直接地造成的細胞毒殺作用會伴隨著巨噬細胞移動抑制因子釋放。以巨噬細胞移動抑制因子拮抗藥物 (ISO-1) 治療能有效地降低豆蔻酰佛波醇乙酯誘發的小鼠耳朵增厚、白血球浸潤、表皮層細胞增生和真皮層血管新生作用。重要的是阻斷巨噬細胞移動因子能有效地減少表現丙型干擾素之自然殺手T細胞於皮膚真皮層的浸潤;豆蔻酰佛波醇乙酯和巨噬細胞移動抑制因子分別地刺激自然殺手T細胞表現丙型干擾素產生和促進移轉作用。研究顯示巨噬細胞移動抑制因子係透過胞膜CD74和化學趨化受體CXCR2共同調控CD44/CD74/CXCR2/CXCR4/CD56bright/CD3自然殺手T細胞的趨化作用;而且,自然殺手細胞的剔除結果抑制了豆蔻酰佛波醇乙酯誘發的皮膚炎症。在豆蔻酰佛波醇乙酯誘導皮膚發炎模式下,巨噬細胞抑制因子是從受傷害的角質細胞釋放的,接著誘導具有CD74和CXCR2表現且能產生丙型干擾素的自然殺手T細胞趨化移轉。除此之外,肝醣合成酶激酶-3活化也可能調節自然殺手T細胞的丙型干擾素產生抑或是調控丙型干擾素訊息傳遞進而促使丙型干擾素所媒介的皮膚炎症病程發展。本研究證實標靶於巨噬細胞抑制因子和肝醣合成酶激酶-3可將運用於皮膚炎症的潛在性治療策略。
英文摘要 Skin provides the largest immunity barrier. Abnormal immune responses in skin result in a large variety of inflammatory skin diseases, including psoriasis, contact dermatitis, eczema, and others. To investigate the therapeutic strategies of dermatitis, we used the 12-O-tetradecanoylphorbol-13-acetate (TPA) to induce an experimental model of psoriasis-like skin inflammation. Overexpression of interferon (IFN)-γ in skin is considered a major contributor of psoriatic progression. The role of glycogen sythase kinase (GSK)-3, which facilitates IFN-γ signaling pathway, is still unclear in skin inflammation. We firstly confirmed IFN-γ receptor 1 deficiency attenuated the acute and chronic skin inflammatory responses in mice, including ear swelling, the dermal inflammatory infiltration of leucocytes and granuocytes, the expression of intercellular adhesion molecule 1 (CD54), epidermal hypoperliferation, and dermal angiogenesis, but not affected the infiltration of CD3+ cells. To verify the pathogenic role of GSK-3 in IFN-γ-mediated skin inflammation, inhibiting GSK-3 pharmacologically by administering to 6-bromoindirubin-3’-oxime and genetically with lentiviral-based short-hairpin RNA decreased skin inflammatory responses but still not affected the infiltration of CD3+ cells. Notably, inhibiting GSK-3 reduced the IFN-γ production and the nuclear translocation of T-box transcription factor Tbx21, a transcription factor of IFN-γ expression, in CD3+ cells. Regarding Macrophage migration inhibitory factor (MIF) may directly trigger the migration of CD3+ T cells, it is still unknown whether MIF triggers an initial step for the chemotaxis of IFN-γ-producing cells in TPA-induced skin inflammation. The release of MIF can be observed usually accompanied by the cell damage; therefore, we measured the release level of MIF in TPA-challenged mice ear and human keratinocytic HaCaT cells. The results indicated TPA directly caused cytotoxicity which leading to MIF release concurrently. Treatment with the MIF antagonist (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, ISO-1, considerably attenuated TPA-induced ear swelling, leukocyte infiltration, epidermal cell proliferation, and dermal angiogenesis. Blocking MIF greatly diminished the dermal infiltration of murine IFN-γ+ natural killer (mNK) T cells as well as mNKT cells. Administering exogenous TPA and MIF promoted IFN-γ production and migration respectively particularly in NKT cells. MIF specifically triggered the chemotaxis of human CD44+CD74+CXCR2+CXCR4+CD56brightCD3+ (hNKT) cells via CD74 and CXCR2; furthermore, the depletion of NK1.1 positive cells abolished the TPA-induced skin inflammation. For TPA-induced skin inflammation, MIF is released from damaged keratinocytes and then triggers the chemotaxis of CD74+CXCR2+ mNKT cells for IFN-γ production. In these cells, GSK-3 activation possibly mediates not only the IFN-γ production in NKT cells but IFN-γ signaling pathway in targeting cells to facilitate IFN-γ-mediated skin disease progression. These findings suggest that targeting MIF and GSK-3 may be the potential therapeutic strategies against skin inflammation.
論文目次 Content
Abstract in English I
Abstract in Chinese III
Acknowledgement V
Content VI
Table List IX
Figure List IX
Appendix List X
Abbreviations XII

Chapter 1 Introduction 1
1-1 Skin immune surveillance 1
1-2 Psoriasis 2
1-3 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like skin inflammation 3
1-4 IFN-γ signaling pathway 4
1-5 Glycogen synthase kinase-3 5
1-6 Macrophage migration inhibitory factor 6
1-7 Natural killer T cells in skin disorders 7
Chapter 2 Objectives and Specific Aims 10
Chapter 3 Materials and Methods 12
3-1 Drugs and reagents 12
3-2 Acute and chronic models of TPA-induced skin inflammation 13
3-3 Cell culture 14
3-4 TPA stimulation of human keratinocytes in vitro 15
3-5 Analysis of cytotoxicity and apoptosis 15
3-6 H&E staining 16
3-7 Immunostaining 16
3-8 Enzyme-linked immunosorbent assay 18
3-9 Short hairpin RNA transfection in vitro and in vivo 18
3-10 Western blot analysis 19
3-11 Luciferase reporter assay 20
3-12 Separation of human and mouse peripheral blood mononuclear cells 20
3-13 Isolation of human CD56+CD3+ (hNKT), CD56+CD3- (hNK), and murine CD3+NK1.1+ (mNKT) cells 21
3-14 The cellular marker magnetic isolation 22
3-15 Surface marker analysis 23
3-16 Stimulation of primary human blood cells 24
3-17 Transmigration assay 25
3-18 Depletion of granulocyte and NK1.1+ cells 26
3-19 Treatment of MIF antagonist ISO-1 26
3-20 Image quantification 26
3-21 Statistical analyses 28
Chapter 4 Results 29
4-1 IFNGR1 is required for TPA-induced acute skin inflammation 29
4-2 TPA activates GSK-3 and induces GSK-3-regulated IFN-γ signaling 29
4-3 GSK-3 facilitates TPA-induced acute skin inflammatory responses 30
4-4 GSK-3 facilitates TPA-induced ear swelling and granulocyte infiltration 31
4-5 GSK-3 facilitates TPA-induced IFN-γ production in CD3-positive cells by regulating T-bet nuclear translocation 31
4-6 GSK-3 facilitates IFN-γ-mediated chronic TPA-induced psoriasis-like cutaneous inflammation 32
4-7 TPA stimulation directly causes MIF release and cytotoxicity in keratinocytes in vivo and in vitro 32
4-8 The MIF antagonist ISO-1 attenuates TPA-induced acute and chronic skin inflammation in mouse ears 33
4-9 The pharmacological inhibition of MIF reduces the TPA-induced infiltration of dermal IFN-γ+ mNKT cells 35
4-10 TPA, but not MIF, induces IFN-γ production in CD56+CD3+ hNKT cells in vitro 36
4-11 MIF promotes the transmigration of CD56+CD3+ NKT cells in a CD74- and CXCR2-mediated manners 36
4-12 CD74+CXCR2+ mNKT cells are present in TPA-treated skin tissues 38
4-13 NK1.1 depletion attenuates TPA-induced ear swelling, CD54 expression, and granulocyte infiltration 38
4-14 MIF triggers the recruitment of mNKT cells in vivo 39
Chapter 5 Conclusion 40
Chapter 6 Discussion 41
6-1 The pathogenic roles of MIF and GSK-3 compared with this study and others in psoriasis 41
6-2 The effect of TPA and MIF challenges in isolated NKT, NK, and T cells in vitro for IFN-γ production 42
6-3 The unique findings of a subtype NKT cells 43
6-4 The potential effects of chemokine receptors for NKT cells 44
6-5 The effect of GSK-3 for IFN-γ production and IFN-γ signaling 45
6-6 The importance of GSK-3 activation in TPA-induced skin inflammation 46
6-7 The role of GSK-3 for human psoriatic therapy 47
6-8 The role of Gr-1+ cells in human psoriasis 48
Chapter 7 References 49
Tables 57
Table 1. The experimental animal models of psoriatic-like skin inflammation. 57
Figures 58
Figure 1. IFNGR1 deficiency attenuates TPA-induced acute skin inflammation, including ear swelling, granulocyte infiltration, and CD54 expression, but not CD3+ cell infiltration. 58
Figure 2. TPA induces GSK-3 activation followed by GSK-3-regulation of IFN-γ signaling. 59
Figure 3. Inhibiting GSK-3 decreases TPA-induced acute skin inflammation but not CD3+ cell infiltration. 62
Figure 4. The depletion of granulocytes attenuates TPA-induced ear swelling. 63
Figure 5. Local knockdown of GSK-3 attenuates TPA-induced edema and granulocyte infiltration. 64
Figure 6. Inhibiting GSK-3 decreases TPA-induced IFN-γ production and T-bet nuclear translocation. 65
Figure 7. Inhibiting GSK-3 attenuates chronic TPA-induced psoriasis-like skin inflammation including ear swelling, epidermal proliferation, and angiogenesis. 66
Figure 8. TPA directly induces the release of MIF from damaged keratinoyctes in vivo and in vitro by non-apoptotic cell death, not by IL-1β, IL-6, and TNF-α. 68
Figure 9. MIF antagnoinst, ISO-1, decreases TPA-induced acute skin inflammation in mice. 70
Figure 10. MIF antagonist, ISO-1, decreases TPA-induced chronic skin inflammation in mice. 71
Figure 11. Targeting MIF reduces the TPA-induced infiltration of IFN-γ+ mNKT cells by the pharmacological inhibition. 74
Figure 12. Only CD56+CD3+ hNKT cells of human PBMCs secrete IFN-γ after being sensitive to TPA, not CD4+, CD8+, or hNK. 75
Figure 13. MIF may trigger the transmigration activity of CD44+CD74+CXCR2+CXCR4+CD56brightCD3+ hNKT cells. 78
Figure 14. The recruitment of dermal CD74+CXCR2+NK1.1+CD3+ mNKT cells display a critical pathogenic role in TPA-induced skin inflammatory mice ears. 79
Figure 15. The murine NK1.1+ cells display a critical pathogenic role in TPA-induced skin inflammatory mice ears. 80
Figure 16. MIF antagonist, ISO-1, treatment reduced MIF-triggered recruitment of CD74+ or CXCR2+ mNKT cells. 81
Figure 17. MIF triggered the chemotaxis of CD74+CXCR2+NKT cells and GSK-3 facilitated IFN-γ production in NKT as well as IFNGR/STAT1 signaling in epidermal keratinocytes, determine the TPA-induced IFN-γ-mediated skin inflammation. 83
Appendix 84
Appendix I. The morphology and characteristics of human psoriatic lesion. 84
Appendix II. A hypothetic immunopathogenesis of psoriasis. 85
Appendix III. GSK-3 facilitates IFN-γ signaling by sustaining STAT1 activation. 86
Appendix IV. IFN-γ promotes Th17-mediated immune responses in psoriatic lesions. 87
Appendix V. GSK-3 positively mediates T-bet nuclear translocation and Th1 development. 88
Appendix VI. The pathogenic role of MIF in skin dermatitis. 89
Appendix VII. MIF signaling via the functional receptors complex of CD74, CD44, CD182 (CXCR2), and CD184 (CXCR4). 90
Appendix VIII. MIF antagonist, ISO-1, blocks the interaction between MIF and its receptors. 91
Curriculum Vitae 92
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