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系統識別號 U0026-3007201401462900
論文名稱(中文) 介白素二十在肝臟疾病中的研究
論文名稱(英文) The Study of Interleukin-20 in Liver Disease
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 102
學期 2
出版年 103
研究生(中文) 邱乙書
研究生(英文) Yi-Shu Chiu
學號 tb8981065
學位類別 博士
語文別 英文
論文頁數 102頁
口試委員 指導教授-張明熙
口試委員-林以行
口試委員-楊孔嘉
口試委員-張定宗
口試委員-陳昌熙
口試委員-張基隆
口試委員-邱紫文
口試委員-徐士蘭
中文關鍵字 介白素-20  肝纖維化  肝癌 
英文關鍵字 IL-20  Liver fibrosis  Hepatocellular carcinoma 
學科別分類
中文摘要 介白素-20 (IL-20) 是歸類於介白素-10 (IL-10) 家族的細胞激素,目前已知和類風 濕性關節炎、動脈粥狀硬化、骨質疏鬆症和乳腺癌等疾病有關。然而,IL-20 與肝臟 疾病的相關性尚未被發現,因此本研究將探討 IL-20 在肝臟疾病中所扮演的角色。 在本研究的第一部分研究中,發現 IL-20 在肝纖維化、肝硬化和肝癌病患的肝臟細 胞和肝星狀細胞中有大量表現,表示 IL-20 在肝臟疾病中扮演重要角色。接著以四 氯化碳 (CCl4) 處理大鼠肝臟細胞株 (Clone-9) 後,會促使 Clone-9 細胞中 IL-20 表 現量增加,IL-20 更進一步誘導 TGF-β1 和 p21WAF1 表現量增加,並且使得 Clone-9 細胞生長受到抑制。此外,IL-20 會激活大鼠肝星狀細胞 (HSCs),並促使 HSCs 的 TGF-β1、TNF-α 和 Col-I 的表現量增加,更使得HSCs 的移動能力亦增加。利用 CCl4 誘導小鼠肝損傷模式後,不論短期肝損傷或是長期肝損傷,小鼠血清中的 IL-20 都 有顯著上升。在短期小鼠肝臟損傷模式裡,拮抗 IL-20 的單株抗体 (7E) 和拮抗 IL-20 受体 (IL-20R1) 的單株抗体 (51D) 都可以有效的降低 CCl4 所誘導的肝細胞損傷、 TGF-β1 表現和趨化因子的產生。在長期小鼠肝臟損傷模式裡,7E 和 51D 可以有效 抑制 CCl4 所誘導的 HSCs 的的活化、 TGF-β1 和胞外基質的產生及堆積,進而減 緩肝纖維化。IL-20R1 基因剔除小鼠同樣具有抵抗 CCl4 所誘導肝損傷的能力。我們 可以確定 IL-20 在肝纖維化的重要性,並且證實 7E 和 51D 可用於治療肝纖維化。 然而,長期的肝臟損傷所誘導的持續性發炎反應為造成肝纖維化發展為肝硬化或肝癌 的主因,因此本研究第二部分更進一步探討 IL-20 在肝癌中的機轉。肝癌病患的癌 細胞中具有高量表達的 IL-20,然而 IL-20 的表現量和肝癌病患的預後和存活率呈反比 (相關度> 3)。在肝癌病患癌細胞及三株人類肝癌細胞中,IL-20 和 cyclin D1 的表 現量呈現高度正相關, IL-20 會藉由調控 cyclin D1、MMP-13、TNF-α 和 p21WAF1 等基因的表現而促使肝癌細胞 (ML-1) 的增殖和轉移。7E 可以有效抑制接種於小鼠 下的 ML-1 細胞的生長,並且降低 cyclin D1、TNF-α、MMP-9,和 VEGF 等基因的 表現。IL -20 在肝癌中亦扮演重要角色,7E 則可有效抑制肝癌生長。
英文摘要 Interleukin (IL)-20 is a proinflammatory cytokine of the IL-10 family and involved in rheumatoid arthritis, atherosclerosis, osteoporosis and breast cancer. However, the pathophysiological roles of IL-20 in liver disease have not been extensively studied. We explored the involvement of IL-20 in liver disease and the therapeutic potential of IL-20 antagonists for treating liver fibrosis and hepatocellular carcinoma (HCC). In first part, compared with the normal liver tissue from healthy individuals, the amount of IL-20 was much higher in hepatocytes and hepatic stellate cells in liver biopsies from patients with fibrosis, cirrhosis, and hepatocellular carcinoma. Carbon tetrachloride (CCl4) treatment induced IL-20 that further upregulated the expression of transforming growth factor (TGF)-β1 and p21WAF1 and resulted in cell cycle arrest in the Clone-9 rat hepatocyte cell line. IL-20 activated quiescent rat hepatic stellate cells (HSCs) and upregulated TGF-β1 expression. IL-20 also increased TGF-β1, tumor necrosis factor (TNF)-α, and type I collagen expression, and promoted the proliferation and migration of activated HSCs. Serum IL-20 was significantly elevated in mice with short-term and long-term CCl4-induced liver injury. In mice with short-term liver injury, anti-IL-20 monoclonal antibody (7E) and anti-IL-20 receptor (IL-20R1) monoclonal antibody (51D) attenuated hepatocyte damage caused by CCl4, TGF-β1, and chemokine production. In mice with long-term liver injury, 7E and 51D inhibited CCl4-induced cell damage, TGF-β1 production, liver fibrosis, HSC activation, and extracellular matrix accumulation, which was caused by the reduced expression of tissue inhibitors of metalloproteinases as well as increased metalloproteinase (MMP) expression and Col-I production. IL-20R1-deficient mice were protected from short-term and long-term liver injury. We identified a pivotal role of IL-20 in liver injury and showed that 7E and 51D may be therapeutics for liver fibrosis. When the injury is prolonged, an inflammatory response is induced, which leads either to tissue regeneration and repair in fibrosis, cirrhosis, and finally, hepatocellular carcinoma. Furthermore, in the second part, we explored the function of IL-20 in HCC. HCC tumor tissue expressed higher levels of IL-20 than did non-tumor tissue. High IL-20 expression in HCC was correlated with poor overall survival (relative risk: > 3). IL-20 and cyclin D1 expression were also highly correlated in HCC patient specimens and 3 human HCC cell lines. IL-20 also increased cell proliferation and migration, and it regulated MMP-13, TNF-α, cyclin D1, and p21WAF1 expression in the murine HCC cell line ML-1. 7E attenuated tumor growth in mice inoculated with ML-1 cells. The expression of cyclin D1, TNF-α, MMP-9, and vascular endothelial growth factor was significantly inhibited after 7E treatment. We demonstrate that IL-20 is important in the pathogenesis of HCC and that 7E inhibits HCC tumor progression.
論文目次 中 文 摘 要 ................................................................................................I Abstract...............................................................................................III
誌 謝 ......................................................................................................V
Contents..............................................................................................VII Contents of Tables...................................................................................X Contents of Figures.................................................................................XI Abbreviations.......................................................................XIII Introduction.........................................................................1
I. Interleukin (IL)-20 ............................................................1
1. Identification of IL-20 .....................................................1
2. IL-20 belonge to the IL-10 family....................................1
3. Receptors of IL-20 ..........................................................1
4. Signaling of IL-20 ...........................................................2
5. Cellular sources of IL-20 and target cells of IL-20............2
6. Biological functions and clinical implications of IL-20.......3
IL-20 and psoriasis..............................................................3
IL-20 in atherosclerosis........................................................4
IL-20 and rheumatoid arthritis ............................................5
IL-20 in renal diseases ........................................................5
IL-20 and osteoporosis........................................................6
IL-20 and breast cancer ......................................................6
II. Liver disease ...................................................................7
1. Liver fibrosis ...................................................................8
Histology .............................................................................8
Damaged hepatocyte in liver fibrosis....................................9
Activated HSC in liver fibrosis ..............................................9
The ECM and activation of HSC.............................................9
TGF-β1 and fibrogenesis .....................................................9
Animal model of liver fibrosis ..............................................10
2. Hepatocellular carcinoma (HCC)........................................11
Inflammation and HCC ........................................................11
Pro-inflammatory cytokines and HCC...................................12
Cell cycle regulation in HCC ................................................12
Rationale..............................................................................14 Specific Aims........................................................................15
I. To study the role of IL-20 and liver fibrosis.......................15
II. To study the role of IL-20 and HCC..................................15
Materials and Methods.........................................................16
I. To study the role of IL-20 and liver fibrosis.......................16
II. To study the role of IL-20 and HCC...................................22 Results..................................................................................26
I. The role of IL-20 in liver fibrosis .......................................26
1. IL-20 was highly expressed in injured liver tissue..............26
2. TGF-β1 expression, cell cycle arrest, and p21WAF1 expression were upregulated in IL-20-treated Clone-9 cells...................26
3. Primary rat HSCs were activated, proliferated, and then migrated after IL-20 treatment..........................................................28
4. Short-term CCl4-induced liver injury was attenuated in 7E- and 51D-treated mice ................................................................29
5. Long-term CCl4-induced liver injury and metabolic liver injury was attenuated in 7E- and 51D-treated mice..............................29
6. Therapeutic potential of 7E and 51D for liver injury .........32
7. IL-20R1-/- mice were resistant to long-term CCl4-induced liver injury...................................................................................33
II. The role of IL-20 in HCC ..................................................33
1. IL-20 expression in tumor tissue was correlated with clinical outcome...............................................................................33
2. IL-20 expression was highly associated with cyclin D1 expression in HCC tumor tissue and human HCC cell lines ....................34
3. Cell migration and the expression of TNF-α and MMP-13 in IL-20-treated ML-1 cells................................................................34
4. Cell proliferation and cyclin D1 expression were inhibited in 7E-treated ML-1 cells...............................................................35
5. Tumor growth in vivo was lower in 7E-treated mice.........35
Discussion...........................................................................37
I. The role of IL-20 in liver fibrosis ......................................37
II. The role of IL-20 in HCC .................................................40
III. Therapeutic potential of IL-20 antagonist in liver disease ............................................................................................43 Conclusion..........................................................................45 References..........................................................................46
Tables................................................................................60
Figures and Figure legends.................................................69 Appendix...........................................................................101
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