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系統識別號 U0026-0812200914151561
論文名稱(中文) mIL-20R1a在狼瘡性腎炎與腎臟鈣鹽沉積的研究
論文名稱(英文) Study of a novel transcript of mouse interleukin-20 receptor, mIL-20R1a in lupus nephritis and renal crystal deposition
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 魏琪珍
研究生(英文) Chi-Chen Wei
學號 s5888112
學位類別 博士
語文別 英文
論文頁數 116頁
口試委員 指導教授-張明熙
召集委員-賴明德
口試委員-黎煥耀
口試委員-楊倍昌
口試委員-沈家瑞
口試委員-孫光蕙
中文關鍵字 草酸鈣  腎上皮細胞  細胞凋亡  狼瘡性腎炎  細胞激素  腎結石  腎絲球間質細胞 
英文關鍵字 lupus nephritis  renal epithelial cells  calcium oxalate  cytokines  kidney stone formation  glomerular mesangial cells  apoptosis 
學科別分類
中文摘要 已知經由各種不同機制所產生出來的可溶性受體 (soluble cytokine recep-tor),可拮抗、促進細胞激素的作用,或直接作用於細胞。近來被鑑定出的介白素-10 (interleukin-10, IL-10) 家族成員包括IL-19, IL-20, IL-22, IL-24及IL-26。這些細胞激素的作用必須透過細胞膜上的第二類受器複合體 (class II cytokine receptor family, CRF2),傳遞訊息以產生不同的反應。本研究鑑定出一屬於CRF2的新穎蛋白,為IL-19、IL-20及IL-24共用的細胞膜受體 (mouse (m)IL-20R1) 基因,產生alternative splicing而形成,稱為mIL-20R1a。mIL-20R1a缺乏穿透細胞膜的區域 (transmembrane domain),屬於分泌性蛋白。初步結果顯示,mIL-20R1a與mIL-19或mIL-20之間並無明顯作用; 因而推論mIL-20R1a可能並不參與調控這些細胞激素的作用。為進一步探討其作用,首先尋找可能對mIL-20R1a產生反應的細胞; 發現mIL-20R1a可單獨作用於正常老鼠 (DBA/W MCs) 及紅斑性狼瘡老鼠的腎絲球間質細胞 (Glomerular mesangial cells) (NZB/W MCs),進而引起AKT與JNK的磷酸化。而且較多的mIL-20R1a可結合至NZB/W MCs細胞表面; 加上NZB/W MCs比DBA/W MCs表現更多的mIL-20R1a,因此推測mIL-20R1a可能與狼瘡性腎炎有關。NZB/W MCs與NZB/W MCs在經過mIL-20R1a作用後,均可表現較多趨化因子 (CCL2、CCL5及CXCL10); 但是mIL-20R1a只能刺激NZB/W MCs產生較多SLE病程相關的重要因子 (MMP-2、MMP-9及TGF-beta1); 在DBA/W MCs則無此種現象。mIL-20R1a的刺激也可使DBA/W MCs與NZB/W MCs產生SLE致病過程中相當重要的過氧化物 (ROS)。而幾種對狼瘡性腎炎具有促進作用的因子: angiotensin II、PDGF及LPS均可促使mIL-20R1a在DBA/W MCs的表現量上升。藉由分析mIL-20R1a在正常與SLE小鼠各器官的表現,得知SLE小鼠的脾臟可大量表現mIL-20R1a,包括單核細胞 (monocytes)、B細胞及T細胞,且mIL-20R1a可進一步刺激SLE小鼠的B細胞產生較高量的mIL-10; 反之,mIL-20R1a則僅表現於正常小鼠的脾臟單核細胞且對正常B細胞產生mIL-10並無明顯影響。此外,利用基因轉殖鼠進一步研究mIL-20R1a在體內的功能。分析mIL-20R1a基因轉殖鼠可觀察到大量鈣鹽沉積於腎小管,藉由分析mIL-20R1a對草酸鈣在腎上皮細胞的作用所造成的影響,進而探討過量mIL-20R1a與鈣鹽形成的關聯。結果顯示: mIL-20R1a可增強數種草酸鈣引起的腎上皮細胞變化,包括細胞凋亡 (apoptosis)、鈣質進入細胞、趨化因子的產生及ROS的生成。綜合以上結果可知,mIL-20R1a應可藉由對腎絲球間質細胞產生的作用,參與狼瘡性腎炎致病的過程; 而導致疾病惡化的幾種因子 (angiotensin II、PDGF與LPS) 又能正向促進mIL-20R1a的表現,因而進一步放大mIL-20R1a的作用。此外,mIL-20R1a藉由加強草酸鈣作用,造成更多腎上皮細胞受損,產生多種作用及相關因子,致使鈣鹽容易沉積,有助於加速腎結石的形成。
英文摘要 We identified a novel soluble protein, mouse (m)IL-20R1a, generated by alternative splicing of the mIL-20R1 gene, which encodes one subunit of the receptor complex for mIL-19, mIL-20, and mIL-24. mIL-20R1a has 77.14% amino acid identity with the extracellular domain of mIL-20R1. However, no significant interaction between mIL-20R1a and mIL-19 or mIL-20 was detected. Therefore, we aimed to clarify whether mIL-20R1a might function as a novel effector on certain cells. Competitive binding assays demonstrated that mIL-20R1a bound to cell surfaces and resulted in AKT and JNK phosphorylation in primary mesangial cells (MCs) isolated from either the wild-type mice, DBA/W mice, or the SLE-prone mice, NZB/W mice. mIL-20R1a-treated NZB/W MCs produced higher level of chemokines and renal fibrogenic factors than mIL-20R1a-treated DBA/W MCs did. mIL-20R1a also induced generation of reactive oxygen species (ROS) in two MCs. Angiotensin II, PDGF, and LPS, all of which were involved in the pathogenesis of lupus nephritis, further enhanced mIL-20R1a expression in DBA/W MCs. Endogenous mIL-20R1a was upregulated in the bladder, colon, and spleen tissue of NZB/W mice. While the expression of mIL-20R1a in kidney, ovary, and small intestine tissue of NZB/W mice was lower than that of DBA/W mice. Elevated mIL-20R1a in the spleen tissue of NZB/W mice was expressed mainly in monocytes, B cells, and T cells. mIL-20R1a further enhanced mIL-10 production by the anti-IgM antibody-stimulated B cells in NZB/W mice. Furthermore, overexpression of mIL-20R1a in transgenic FVB/N mice resulted in the pathological change of excess calcium deposited in the kidneys. The interplay between renal epithelial cells and calcium oxalate (CaOx) was important in the crystallization involved in the formation of renal stones (nephrolithiasis). Thus, we investigated the responses of mouse renal proximal (TKPTS) and collecting (M-1) tubule cell lines to CaOx with or without mIL-20R1a. The renal epithelial cell lines exposed to CaOx in the presence of mIL-20R1a showed significantly increased LDH release; loss of cell viability through apoptosis; increased CaOx internalization; higher IL-6, TNF-alpha and MCP-1 expression; and higher ROS production. IL-6, TNF-alpha, and MCP-1 were also upregulated in the kidneys of mIL-20R1a transgenic mice. Taken together, mIL-20R1a-mediated effects on mesangial cells may involved in the disease progression of lupus nephritis. In addition, the effects of mIL-20R1a on CaOx-exposed renal epithelial cells demonstrated that mIL-20R1a functioned as an aggravating factor in promoting calcium deposition involved in the development of renal stones in mice.
論文目次 Chinese Abstract I
English Abstract III
Acknowledgement V
Abbreviations VII
Contents IX
Contents of Figure XIII


I. Literature review 1
1. Soluble cytokine receptors 1
1.1 Mechanisms of soluble cytokine receptor generation 1
1.1.1 Proteolytic cleavage and shedding of cell surface cytokine receptors 1
1.1.2 Generation of soluble cytokine receptors by alternative splicing 2
1.1.3 Soluble cytokine-binding proteins 2
1.1.4 Exosome-associated cytokine receptors 2
1.2 Mechanisms of soluble receptor action 3
1.2.1 Receptor downmodulation. 3
1.2.2 Soluble receptors as binding inhibitors 3
1.2.3 Soluble receptors as serum binding proteins. 4
1.2.4 Soluble receptors as donors of ligand sensitivity. 4
1.2.5 Soluble receptors associating with non-binding subunits only when expressed endogenously. 4
1.3 Soluble cytokine receptors as therapeutic agents 5
1.3.1 TNF- inhibitors 5
1.3.2 IL-1 receptor antagonist 5
2. The IL-10 family 6
2.1 Receptor complex for IL-10 family cytokines 6
2.2 The biologic and clinical effects of IL-10-related cytokines 7
2.2.1 IL-19 7
2.2.2 IL-20 8
2.2.3 IL-22 8
2.2.4 IL-24 9
2.2.5 IL-26 9
2.2.6 IL-28 and IL-29 10
2.3 IL-22 binding protein (IL-22BP): A decoy receptor that regulates IL-22- mediated cellular responses 10
3. Lupus nephritis 11
3.1 Pathogenesis of lupus nephritis 11
3.2 Murine models of SLE 13
4. Kidney stone formation 13
II. Rationale 17
III. Specific aims 18
IV. Materials and methods 20
V. Results 34
1. Isolation of mIL-20R1 splice variant 34
2. No significant interaction between mIL-20R1a and mIL-19 and mIL-20 34
3. Study of mIL-20R1a in lupus nephritis 35
3.1 Binding of mIL-20R1a to cell surfaces of mesangial cells 35
3.2 NZB/W MCs expressed more mIL-20R1a than DBA/W MCs did 36
3.3 Signal transduction pathway of mIL-20R1a in mesangial cells 36
3.4 mIL-20R1a induced the expression of chemokines and SLE-related mediators in NZB/W MCs but not in DBA/W MCs 37
3.5 mIL-20R1a induced mesangial cells to produce ROS 38
3.6 Regulation of IL-10 family cytokines and their receptors by mIL-20R1a 38
3.7 Expression of mIL-20R1a induced by angiotensin II, platelet-derived growth factor (PDGF), and lipopolysaccharide (LPS) 39
3.8 Expression of mIL-20R1a in tissue from DBA/W and NZB/W mice 39
3.9 mIL-20R1a was detected in the monocytes, B cells, and T cells from spleen tissue of NZB/W mice 40
3.10 mIL-20R1a increased the production of mIL-10 by anti-mIgM antibody-stimulated B cells of NZB/W mice 41
4. Study of mIL-20R1a on renal calcium deposition 41
4.1 Overaccumulated calcium crystal in the renal tubules of mIL-20R1a transgenic mice
41
4.2 mIL-20R1a increased CaOx-induced signals in renal epithelial cells 42
4.3 mIL-20R1a increased CaOx-induced cell injury of renal epithelial cells 43
4.4 mIL-20R1a induced cell apoptosis in renal epithelial cells 43
4.5 mIL-20R1a increased CaOx adhesion and endocytosis in renal epithelial cells 44
4.6 mIL-20R1a treatment of renal epithelial cells increased CaOx-induced ROS production 44
4.7 mIL-20R1a upregulated nephrolithiasis-associated cytokines and chemokines in renal epithelial cells 45
4.8 IL-6, TNF-, and MCP-1 were upregulated in the kidneys of mIL-20R1a transgenic mice 45
VI. Discussion 47
VII. Conclusion 54
VIII. References 55
IX. Figures and figure legends 71
X. Publications 99
XI. Biographical note 100
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