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研究生：	邢中熹 Hsing, Chung-Hsi
論文名稱：	介白素十九在全身性發炎性疾病的研究 Study of Interleukin-19 in Systemic Inflammatory Diseases
指導教授：	張明熙 Chang, Ming-Shi
學位類別：	博士 Doctor
系所名稱：	醫學院 - 藥物生物科技研究所 Institute of Biopharmaceutical Sciences
論文出版年：	2008
畢業學年度：	96
語文別：	英文
論文頁數：	122
中文關鍵詞：	介白素十九、細胞素、發炎反應、體外循環、敗血症、慢性腎衰竭
外文關鍵詞：	cytokines, interleukin-19, systemic inflammation, uremia, sepsis, cardiopulmonary bypass
相關次數：	點閱：118 下載：1
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細胞素在發炎性疾病佔有重要的角色，研究細胞素在發炎性疾病的作用對疾病的控制有很大的幫助，新型細胞素的發現也可增加對發炎性疾病機制的了解，甚至成為治療標的，是目前醫藥界積極進行的研究。介白素(IL)-19是最近新發現的細胞素，屬於IL-10家族之一，其生物功能所知仍有限。目前已知IL-19能引發免疫細胞產生IL-6、IL-8、TNF-α、ROS及單核球凋亡。IL-19的另一特徵是會影響Th1/Th2的分布，因此IL-19被認為與免疫調節相關。IL-19在臨床疾病上的探討很少，僅知與慢性局部發炎性疾病如氣喘與乾癬有關，而IL-19在全身性發炎性疾病的影響尚無所知。我們初步觀察發現IL-19在心臟手術體外循環後所引起的急性全身性發炎反應中，會明顯上升，但作用不明，於是我們首先假設：在體外循環後IL-19的上升與其他發炎性細胞素的變化相關；而在敗血症等急性全身性發炎反應中，IL-19亦可能上升且與組織傷害的機制有關。另在長期血液透析病患常合併慢性全身性發炎反應，且會發生Th1/Th2調節異常與免疫抑制作用，於是我們再假設：接受長期血液透析的腎衰竭病患其產生之慢性全身發炎會引起IL-19的變化且與Th1/Th2調節異常相關。研究結果發現，體外循環後血清中IL-19的上升與IL-6、IL-10、及TNF-α的變化相似，單核球活化是IL-19的重要來源之一，體外細胞實驗也發現IL-6及TNF-α可促使單核球製造IL-19。我們也證實敗血症病患血液中IL-19濃度較正常人明顯增加。以免疫組織化學染色法分析IL-19在正常人身體內的組織及細胞存在情形，發現IL-19主要出現在皮膚、肺臟、肝臟、腎臟等器官的上皮細胞，巨噬細胞，及內皮細胞。因我們也發現這些細胞具有IL-19接受器，進一步推測IL-19對組織細胞有重要作用。在體外細胞實驗中，IL-19可引起肺上皮細胞凋亡及肝上皮細胞產生ROS等發炎物質；IL-19也促使肺與肝上皮細胞產生趨化因子IL-1β、IL-6、IL-8、CCL5、及CXCL9；IL-19並增加嗜中性球的移動，且減少其凋亡，此現象在敗血症病患更為明顯。在動物實驗中，內毒素休克小鼠的主要器官包括肺臟、肝臟、腎臟、及心臟組織中IL-19及其接受器 mRNA明顯增加；以electroporation方法將可溶性IL-19接受器DNA質體轉移入小鼠體內做為拮抗IL-19之用，可發現小鼠在拮抗IL-19處理後可減少內毒素休克造成的肺臟及肝臟嗜中性球浸潤與血清中ALT及AST的上升，表示IL-19在急性全身性發炎反應中是傷害性的角色，IL-19會加重內毒素休克所引起組織的傷害。在洗腎患者，血清中CRP上升，IL-19含量也有偏高的現象且與發炎性細胞素(IL-6與TNF-α)及Th2細胞素(IL-4、IL-5、IL-6、IL-10與IL-13)間有很高的統計相關性；正常人的單核球在體外給予洗腎病患的血清刺激，可增加IL-19產生；IL-19也可刺激T細胞產生更多的Th2細胞素。我們的研究顯示，洗腎病患之全身性慢性發炎反應可引起IL-19上升，其可能參予腎衰竭病患的Th1/Th2調節異常作用。我們的研究提出了IL-19在全身性發炎性疾病中可能的作用，相信本研究對於進一步釐清IL-19的功能及其與臨床病症的關連性有很重要的貢獻。

Cytokines are important mediators in systemic inflammatory diseases. It is valuable while to discovery novel cytokines and to identify their functions and effects on the inflammatory diseases. IL-19 is a newly discovered proinflammatory cytokine belonging to IL-10 family. At the present time, knowledge about IL-19 on inflammatory diseases is still limited. Previous reports showed that IL-19 induced immune cells to produce IL-6, IL-8, TNF-α and ROS and undergo apoptosis. IL-19 was also involved in Th1/Th2 polarization which is related to immune regulation. Clinically, IL-19 was reported to be involved in the mechanism of chronic local inflammatory diseases such as psoriasis and asthma. In our preliminary exploration, we found that IL-19 was obviously increased in systemic inflammatory response syndrome (SIRS) after cardiac surgery with cardiopulmonary bypass (CPB). We, therefore, were interesting about the novel effects of IL-19 on acute and chronic systemic inflammatory diseases. We hypothesize that, first, the levels of IL-19 after CPB is associated with the changes of other proinflammatory cytokines which were associated with organ dysfunction after cardiac surgery. Second, IL-19 is induced in sepsis/SIRS and related to the pathogenesis of tissue injury. Third, according to the status of chronic systemic inflammation in uremic patients with hemodialysis, we hypothesize that IL-19 is altered and associated with Th1/Th2 dysregulation in uremia which may affect immunosupression in these patients. Our results showed that IL-19 was induced and associated with the production of IL-6, IL-10, and TNF-α after CPB. IL-19 transcripts in monocytes from patients were increased after CPB, which indicated that monocyte is one of the important sources of IL-19. In vitro experiments showed that IL-6 and TNF-α upregulated IL-19 protein expression in monocytes. We then survey the distribution of IL-19 in tissues and cells using immunohistochemistry study and found that skin, lung, liver and kidney were major organs expressing IL-19. Specific epithelial cells, macrophages, and endothelial cells were the major cell types stained positive for IL-19. In addition, these cells also expressed IL-19 receptors indicated that IL-19 plays an important role in these cells. In patients of severe sepsis, serum levels of IL-19 were higher in patients than in healthy volunteers. IL-19 induced apoptosis in lung epithelial cells and ROS production in liver cells in vitro. IL-19 also promoted neutrophil chemotaxis, reduced neutrophil apoptosis, and induced the production of proinflammatory cytokines and chemokines (IL-1β, IL-6, IL-8, CCL5, and CXCL9) in lung epithelial cells. In lipopolysaccharide (LPS)-challenged mice, transcripts of IL-19 and its receptors were upregulated in heart, lung, liver, and kidney tissue. Neutrophil infiltration in lung and liver tissue, and serum levels of ALT and AST, were lower in mice electroporated with IL-19 soluble receptor plasmid DNA before LPS treatment compared to control mice. These findings suggested that IL-19 plays as a detrimental role in SIRS. In uremic patients, a status of chronic systemic inflammatory disease, serum levels of IL-19 showed wide distributed amount individuals. However, IL-19 levels in the uremic patients but not in healthy controls correlated positively with both the proinflammatory cytokines (IL-6 and TNF-α) and the Th2 cytokines (IL-4, IL-5, IL-6, IL-10, and IL-13). Cultured monocytes from uremic patients with high IL-19 serum levels produced more IL-19 in vitro. In addition, uremic serum upregulated the production of IL-19 in resting monocytes. Compared with T cells from healthy controls, uremic T cells expressed more endogenous Th2 cytokine transcripts and further responded to IL-19 stimulation in Th2 cytokine production in vitro.
In conclusion, serum IL-19 was induced and correlated with IL-6 and TNF-α in acute and chronic systemic inflammation. The upregulated IL-19 in endotoxic shock/sepsis was involved in lung and liver tissue injury. IL-19 also correlated with Th2 immune responses and induced Th1/Th2 cytokine dysregulation in uremia. Our findings provide a new concept that IL-19, the recent discovered cytokine, is an important molecule and might to be a potential therapeutic target in systemic inflammatory diseases.

摘要	3 
Abstract	5
誌謝	7
Abbreviation list	13 
Introduction	15
Background	15
IL-19 belonging to IL-10 family cytokines	15
Cloning of IL-19	16
Genomic structure of IL-19	16
Expression of IL-19	17
IL-19 receptors	18
Biological functions of IL-19	19
IL-19 is a proinflammatory cytokine	19
IL-19 induces ROS production and apoptosis of monocytes	19
IL-19 in Th1/Th2 regulation	20
Clinical implication of IL-19 in inflammatory diseases	20
Role of IL-19 in psoriasis	20
Role of IL-19 in asthma	21
IL-10 and systemic inflammatory diseases	22
Systemic inflammatory response syndrome (SIRS) and sepsis	22
Role of IL-10 in SIRS and sepsis	24
Cardiopulmonary bypass (CPB) induced acute systemic inflammation	24
Role of IL-10 in CPB	25
Uremia with hemodialysis induced chronic systemic inflammation	25
Immunodeficiency and Th1/Th2 imbalance in uremia	26
Role of IL-10 in uremia	26
Potential roles of IL-19 in systemic inflammatory diseases	27
Rationale and specific aims	28
Materials and methods	29
Results	44
Induction of IL-19 after cardiac surgery with cardiopulmonary bypass	44
Induction of IL-10, IL-6, and TNF-α after CPB	44
IL-19 was induced after CPB	44
IL-19 correlated with IL-6 and TNF-α after CPB	44
IL-19 mRNA was induced in the peripheral monocytes after CPB	44
IL-6, TNF-α, IFN-γ, GM-CSF, and LPS upregulated the production of IL-19 by monocytes in vitro	45
Tissue microarray analysis of interleukin-19 expression	45
IL-19 was expressed in tissues with specific cell types	45
Epithelial and myoepithelial cells stained positive for IL-19	46
Endothelial cells stained positive for IL-19	46
Macrophages stained positive for IL-19	47
IL-19 induced signal transduction in lung epithelial cells and hepatocytes	47
IL-19 is involved in the pathogenesis of endotoxic shock	47
IL-19 increased in patients with severe sepsis and septic shock	47
LPS induced lung and liver injury in mice	48
LPS upregulated IL-19 and its receptors in the tissue of septic mice	48
IL-19 induced apoptosis, ROS production, and TNF- and COX-2 expression	49
IL-19 induced neutrophil chemotaxis and chemokine production	50
The effect of IL-19 on neutrophil apoptosis	50
Electroporation of soluble mouse IL-20R1 and IL-20R2 plasmid DNA reduced tissue damage in endotoxic shock in mice	51
Expression of IL-19 correlates with Th2 cytokines in uremic patients	52
IL-19 was upregulated in uremic patients on hemodialysis	52
Serum levels of IL-19 correlated with expression levels of IL-6 and TNF-α	52
Th2 cytokines IL-4, -5, -10, and -13 were increased in uremic patients	53
IL-19 levels correlated with IL-4, -5, -10, and -13 levels	53
IL-19 mRNA in monocytes correlated with serum IL-19 levels in uremic patients	54
Uremic serum upregulated IL-19 transcripts of healthy monocytes in vitro	54
Oxidized low density lipoprotein (OxLDL) induced monocytes to express IL-19	55
T cells expressed Th2 cytokines in response to IL-19 in vitro	55
Discussion	56
IL-19 was induced and associated with post-CPB induced SIRS	56
Bidirectional stimulatory effect between IL-19 and either IL-6 or TNF-α.	57
Tissue expression and distribution of IL-19	58
IL-19 is involved in the pathogenesis of endotoxic shock	61
Expression of IL-19 correlates with Th2 cytokines in uremic patients	64
Conclusion	68
References	70
Table 1. Demographics and clinical characteristics in patients with cardiac surgery	83
Table 2. Levels of cytokines, C-reactive protein and white blood cell count of patients with cardiac surgery.	84
Table 3. Immunostaining of IL-19 in normal tissue	85
Table 4. Primer pairs used for the study of IL-19 in endotoxic shock	87
Table 5. Clinical characteristics of uremic patients and healthy controls	88
Table 6. Serum levels of CRP, TNF-α and IL-6 in uremic patients and healthy individuals	89
Table 7. Serum levels of Th2 cytokines in uremic patients and healthy individuals	90
Figures and figure legends	91
Figure 1. Serum levels of IL-19 but not IL-20 increased in patients undergoing cardiac surgery with CPB.	91
Figure 2. IL-19 was induced and correlated with IL-6 and TNF-α after CPB.	92
Figure 3. IL-19 transcripts in monocytes were upregulated 8 hours after CPB use.	93
Figure 4. Cytokines regulate the production of IL-19 by human monocytes in vitro	94
Figure 5. Immunohistochemical staining of IL-19 in selected normal human tissues represented on the TMA.	96
Figure 6. IL-19 transcripts were expressed in non-pathological tissues.	97
Figure 7. IL-19 induced signal transduction in A549 (A) and Huh-7 (B) cells.	98
Figure 8. Increased IL-19 serum levels in sepsis patients.	99
Figure 9. LPS induced cytokine production and caused lung and liver injury in mice.	101
Figure 10. Tissue IL-19 and its receptors transcripts were up-regulated in mice after LPS challenge.	103
Figure 11. IL-19 induced apoptosis as well as the production of ROS and inflammatory factors.	105
Figure 12. IL-19 promoted neutrophil migration and induced chemotactic factors in lung epithelial cells.	108
Figure 13. Effects of IL-19 on neutrophil apoptosis in vitro.	109
Figure 14. Effects of electroporation of sIL-20R1 or sIL-20R2 on tissue protection in endotoxin shock.	111
Figure 15. Effect of electroporation of sIL-20R1 or sIL-20R2 on CXC chemokines production in lung tissue in mice endotoxin shock.	112
Figure 16. The IL-19 levels in the serum of 73 uremic patients and 33 healthy controls were analyzed using ELISA.	113
Figure 17. The serum level of IL-19 was positively correlated with IL-6 (A) and TNF-α (B) in uremic patients (n = 73).	114
Figure 18. Th2 cytokines IL-4 (A), -5 (B), -10 (C), and -13 (D) were correlated with IL-19 expression in uremic patients.	115
Figure 19. IL-19 transcript in monocytes was correlated with serum protein expression.	116
Figure 20. Uremic but not healthy serum induced IL-19 transcripts in human peripheral monocytes.	117
Figure 21. OxLDL induced IL-19 transcripts in human peripheral monocytes.	118
Figure 22. IL-19 upregulated the production of IL-4 and IL-13 by T cells in vitro.	120
Figure 23. Summary of the roles of IL-19 in systemic inflammatory diseases.	121
Publications	122
                                    

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