跳到主要內容

臺灣博碩士論文加值系統

(3.237.38.244) 您好!臺灣時間:2021/07/24 17:30
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:張菀純
研究生(外文):Wan-Chun Chang
論文名稱:在尿酸結晶引起的發炎反應中正向調節PPAR-gamma和其共同活化子PGC-1beta的表現量
論文名稱(外文):Up-regulation of PPAR-gamma and its co-activator PGC-1beta during the uric acid crystals induced inflammation
指導教授:洪舜郁
指導教授(外文):Shuen-Iu Hung
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
畢業學年度:97
語文別:中文
論文頁數:38
中文關鍵詞:尿酸結晶
外文關鍵詞:MSUPPAR-gamma
相關次數:
  • 被引用被引用:0
  • 點閱點閱:288
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
「痛風」,一個全世界發生率年年上升且發病平均年齡逐漸下降的常見疾病,一般認為是人體內尿酸新陳代謝異常與免疫失調所引發之急性關節發炎。當血液中尿酸濃度過高(高尿酸血症)而尿酸結晶(MSU)開始形成並沉積到關節或其他軟組織時,會刺激巨噬細胞聚集吞噬進而釋放發炎性細胞激素,引發一連串免疫反應;然而,「高尿酸血症」只是一常見病因而非絕對必要條件。在2003年Akahoshi, T.等人1提出尿酸結晶(MSU)能立即且專一性引發健康受試者周邊血液單核球細胞(PBMCs)的PPARγ基因表現;而PPARγ的共同活化子PGC-1β也在幾年前被發現能調控巨噬細胞的極化反應與替代性活化反應途徑而抑制免疫反應2。但是,PPARγ和PGC-1β在急性痛風關節炎所扮演的角色仍未清楚。本研究利用不同濃度尿酸結晶(MSU)刺激人類單核球細胞株(THP-1),發現發炎性細胞激素IL-1β和TNF-α的釋放量會隨著時間趨勢與刺激濃度的增加而增多。Real-timer PCR數據也指出,細胞內PPARγ和PGC-1β基因表現也會隨之向上調控而增強。此外,取健康受試者/痛風病患的臨床檢體,周邊血液單核球細胞或關節滑液細胞,比較PPARγ和PGC-1β的基因表現量,發現痛風病患組的基準值比健康受試者組高;而當加入不同濃度尿酸結晶(MSU)刺激後,痛風病患組在較低濃度下(100 μg/mL)即可明顯增加PPARγ和PGC-1β的表現量,健康受試者組別卻需要到高濃度下(200 μg/mL)才能顯示差異。由此可知,PPARγ和PGC-1β對痛風發作的免疫反應有一定的正相關。藉由本研究能幫助我們更了解PPARγ和PGC-1β在急性痛風發炎中所扮演的角色。
Gout, also known as “acute gouty arthritis”, is a common disease with increasing incidence worldwide. It is recognized as not only a metabolic disorder but also an inflammatory disease that the deposition of monosodium urate monohydrate (MSU) crystals in the joint and soft tissue triggers cytokines cascades, leading to inflammatory responses. Molecule involved in the regulation of both metabolism and inflammation of gout is still unclear. A recent study reported that MSU crystals could rapidly and selectively induce peroxisome proliferator-activated receptor gamma (PPARγ) gene expression in the monocytes of healthy donors1. In addition, the co-activator of PPARγ (PGC-1β) was reported to be involved in the regulation of the macrophage polarization and alternative activation pathway2. Since both PPARγ and PGC-1β are involved in the metabolism and inflammation, I hypothesized that they may attenuate crystals-induced acute inflammation. Therefore, PPARγ and PGC-1β could be a therapeutic target of gout. In this study, MSU crystals were used to stimulate THP-1 cell (human monocytic cell line) to enhance inflammatory cytokines as an in vitro cell culture model of gout. I found that the levels of inflammatory cytokines (interleukin-1β and TNF-α) released by THP-1 cells increased in dose-dependent and time-dependent manners upon the treatment of MSU crystals. The results of real-time quantitative PCR further validated the increase of PPARγ and PGC-1β mRNA in the MSU-treated monocytes. In addition, the gene expression levels of PPARγ and PGC-1β in the peripheral blood mononuclear cells (PBMCs) and synovial fluid cells of patients with gout were higher than the healthy volunteers. Upon the stimulation of lower concentration of MSU, the gene expression of PPARγ and PGC-1β were greatly up-regulated in the PBMCs of gouty patients. In conclusion, my data suggest PPARγ and its co-activator PGC-1β are up-regulated in the uric acid crystals induced inflammation.
摘要 ii
Abstract ii
英文縮寫對照表 iii
目次 iv
壹、緒論 1
第一章 痛風 1
第一節 痛風疾病介紹(代謝異常) 1
第二節 痛風疾病介紹(免疫失調) 2
第三節 臨床診斷與治療 3
第二章 PPARs 5
第一節 PPARγ 5
第二節 PGC-1 7
貳、研究目的與假說 8
参、實驗設計 9
肆、材料與方法 10
伍、實驗結果 16
陸、討論 19
參考文獻 23
圖 26
1. Akahoshi, T., et al. Rapid induction of peroxisome proliferator-activated receptor gamma expression in human monocytes by monosodium urate monohydrate crystals. Arthritis Rheum 48, 231-239 (2003).
2. Vats, D., et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4, 13-24 (2006).
3. Schumacher, H.R., Jr. The pathogenesis of gout. Cleve Clin J Med 75 Suppl 5, S2-4 (2008).
4. Weaver, A.L. Epidemiology of gout. Cleve Clin J Med 75 Suppl 5, S9-12 (2008).
5. Keith, M.P. & Gilliland, W.R. Updates in the management of gout. Am J Med 120, 221-224 (2007).
6. Fels, E. & Sundy, J.S. Refractory gout: what is it and what to do about it? Curr Opin Rheumatol 20, 198-202 (2008).
7. Pillinger, M.H. & Keenan, R.T. Update on the management of hyperuricemia and gout. Bull NYU Hosp Jt Dis 66, 231-239 (2008).
8. Saag, K.G. & Choi, H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther 8 Suppl 1, S2 (2006).
9. Wang, W.H., et al. Complex segregation and linkage analysis of familial gout in Taiwanese aborigines. Arthritis Rheum 50, 242-246 (2004).
10. Lee, M.S., et al. High prevalence of hyperuricemia in elderly Taiwanese. Asia Pac J Clin Nutr 14, 285-292 (2005).
11. Campion, E.W., Glynn, R.J. & DeLabry, L.O. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med 82, 421-426 (1987).
12. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237-241 (2006).
13. Reginato, A.M. & Olsen, B.R. Genetics and experimental models of crystal-induced arthritis. Lessons learned from mice and men: is it crystal clear? Curr Opin Rheumatol 19, 134-145 (2007).
14. Petrilli, V. & Martinon, F. The inflammasome, autoinflammatory diseases, and gout. Joint Bone Spine 74, 571-576 (2007).
15. Akahoshi, T., Murakami, Y. & Kitasato, H. Recent advances in crystal-induced acute inflammation. Curr Opin Rheumatol 19, 146-150 (2007).
16. Chapman, P.T., et al. Endothelial activation in monosodium urate monohydrate crystal-induced inflammation: in vitro and in vivo studies on the roles of tumor necrosis factor alpha and interleukin-1. Arthritis Rheum 40, 955-965 (1997).
17. So, A., De Smedt, T., Revaz, S. & Tschopp, J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 9, R28 (2007).
18. Hong, C. & Tontonoz, P. Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Curr Opin Genet Dev 18, 461-467 (2008).
19. Broeders, N. & Abramowicz, D. Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renal disease. Kidney Int 61, 354-355 (2002).
20. Lee, C.H., et al. PPARdelta regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci U S A 103, 3444-3449 (2006).
21. Vrins, C.L., et al. PPARd activation leads to increased trans intestinal cholesterol efflux. J Lipid Res (2009).
22. Savage, D.B. PPAR gamma as a metabolic regulator: insights from genomics and pharmacology. Expert Rev Mol Med 7, 1-16 (2005).
23. Zieleniak, A., Wojcik, M. & Wozniak, L.A. Structure and physiological functions of the human peroxisome proliferator-activated receptor gamma. Arch Immunol Ther Exp (Warsz) 56, 331-345 (2008).
24. Villacorta, L., Schopfer, F.J., Zhang, J., Freeman, B.A. & Chen, Y.E. PPARgamma and its ligands: therapeutic implications in cardiovascular disease. Clin Sci (Lond) 116, 205-218 (2009).
25. Takano, H. & Komuro, I. Peroxisome proliferator-activated receptor gamma and cardiovascular diseases. Circ J 73, 214-220 (2009).
26. Chawla, A., et al. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 7, 48-52 (2001).
27. Ricote, M., Li, A.C., Willson, T.M., Kelly, C.J. & Glass, C.K. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391, 79-82 (1998).
28. Jiang, C., Ting, A.T. & Seed, B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82-86 (1998).
29. Finck, B.N. & Kelly, D.P. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest 116, 615-622 (2006).
30. Lai, L., et al. Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart. Genes Dev 22, 1948-1961 (2008).
31. Lin, J., Handschin, C. & Spiegelman, B.M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1, 361-370 (2005).
32. Handschin, C. & Spiegelman, B.M. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 27, 728-735 (2006).
33. Liang, H. & Ward, W.F. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ 30, 145-151 (2006).
34. Benton, C.R., Wright, D.C. & Bonen, A. PGC-1alpha-mediated regulation of gene expression and metabolism: implications for nutrition and exercise prescriptions. Appl Physiol Nutr Metab 33, 843-862 (2008).
35. Leone, T.C., et al. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3, e101 (2005).
36. Meirhaeghe, A., et al. Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivo. Biochem J 373, 155-165 (2003).
37. Kamei, Y., et al. PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci U S A 100, 12378-12383 (2003).
38. Van Ginderachter, J.A., et al. Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. Immunobiology 211, 487-501 (2006).
39. Gordon, S. Alternative activation of macrophages. Nat Rev Immunol 3, 23-35 (2003).
40. Martinez, F.O., Helming, L. & Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27, 451-483 (2009).
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top