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研究生:林筠
研究生(外文):Yun Lin
論文名稱:多元不飽和脂肪酸對肝癌細胞中細胞激素誘導之C反應蛋白表現的機制探討
論文名稱(外文):The mechanisms of polyunsaturated fatty acids on cytokine-induced C-reactive protein expression in HepG2 cells
指導教授:姜安娜姜安娜引用關係
指導教授(外文):An-Na Chiang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:83
中文關鍵詞:C-反應蛋白多元不飽和脂肪酸
外文關鍵詞:CRPPUFAs
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C-反應蛋白(C-reactive protein,CRP)是肝臟因應發炎反應而合成的急性期蛋白質。發炎前驅細胞激素如介白素-1�狺峇階朘�-6已被證實能夠分別經由活化nuclear factor-kappaB(NF-�羠)及signal transducer and activator of transcription-3 (STAT3)兩種訊息傳遞路徑以誘導CRP的基因表現。已有許多例證顯示血液中CRP濃度提升將與發炎反應及心血管疾病的發展有關。實驗與臨床分析指出n-3 多元不飽和脂肪酸(polyunsaturated fatty acids,PUFAs)具有預防發炎反應及動脈粥狀硬化發生的潛力;然而,對於n-3 PUFAs在肝臟細胞中是否能夠調控CRP的表現與其可能參與的機制卻仍有待釐清。本研究的目的即是探討PUFAs是否能夠透過NF-�羠及STAT3訊息傳遞路徑影響CRP的表現,實驗首先利用PUFAs如docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), linoleic acid (LA)及arachidonic acid (AA)觀察在HepG2細胞中以細胞激素誘導之CRP表現的調控作用。HepG2細胞先以PUFAs預處理24小時,再以細胞激素IL-1�狺呰L-6誘導細胞產生發炎反應,結果顯示DHA與EPA能夠降低細胞激素所誘導之CRP基因與蛋白分泌表現,且處理n-3 PUFAs之實驗組別其CRP啟動子活性亦有下降之現象。此外,n-3 PUFAs還能夠有效抑制轉錄因子NF-�羠及磷酸態之STAT3轉移入細胞核。雖然DHA與EPA在全細胞萃取之蛋白當中對STAT3之磷酸化作用無任何調控差異,但處理tyrosine phosphatase之專一抑制劑sodium orthovanadate (Na3VO4)則可抑制DHA及EPA對磷酸態STAT3在細胞核中表現量的調控,由此合理推測n-3 PUFAs可能藉由活化tyrosine phosphatase進而增加STAT3被送出細胞核之情形。本研究顯示n-3 PUFAs或許可藉由抑制NF-�羠的活化以及促進STAT3之去磷酸化作用而降低細胞激素誘導之CRP表現,也為n-3 PUFAs在抗發炎反應之調控機制及作用角色提供了一個展新的研究領域。
C-reactive protein (CRP) is an acute-phase protein produced by the liver in response to inflammation. Pro-inflammatory cytokines such as interleukin (IL)-1�� and IL-6 have known to induce CRP expression through the activation of nuclear factor-kappaB (NF-�羠) and signal transducer and activator of transcription-3 (STAT3), respectively. Several observations indicate that elevated plasma CRP levels are associated with the progression of inflammation and cardiovascular disease. Experimental and clinical studies provide evidence that n-3 polyunsaturated fatty acids (PUFAs) are potential therapeutic agents for the prevention of inflammation and atherosclerosis. However, the role and mechanisms of n-3 PUFAs in the regulation of hepatic CRP expression are still unknown. The aim of this study was to investigate whether PUFAs regulate the CRP levels through NF-�羠 and STAT3 signaling pathway. The effects of PUFAs such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), linoleic acid (LA) and arachidonic acid (AA) on the regulation of cytokine-induced CRP expression in HepG2 cells were investigated in the present study. HepG2 cells were pretreated with PUFAs for 24 hours before stimulation with cytokines IL-1�� and IL-6. It shows that DHA and EPA reduced cytokine-induced CRP expression at both protein and mRNA levels. Promoter activities of CRP gene were also down-regulated in the n-3 PUFA-treated HepG2 cells. n-3 PUFAs significantly decreased the translocation of transcription factors NF-�羠 and phosphorylated STAT3 to nucleus. Nevertheless, DHA or EPA had no effect on the phosphorylation of STAT3 in total cell lysates. Sodium orthovanadate (Na3VO4), an inhibitor of tyrosine phosphatase, reversed the inhibitory effects of DHA and EPA on nuclear phosphorylated STAT3 expression. Thus, we suggest that n-3 PUFAs enhanced the export of phosphorylated STAT3 from nucleus through the activation of phosphatase. In conclusion, these results indicate that n-3 PUFAs may inhibit cytokine-induced CRP expression via NF-�羠 activation and STAT3 de-phosphorylation. This study provides an insight to the benefits and mechanisms of n-3 PUFAs on inflammation.
目 錄
內容                              頁數
英文摘要..........................................................I
中文摘要..........................................................III
緒論..............................................................1
實驗材料..........................................................12
實驗方法..........................................................18
細胞培養............. .........................................18
細胞處理藥品之製備.............................................19
收集細胞處理後之細胞培養液.....................................20
萃取細胞全蛋白質及細胞核蛋白質.................................21
蛋白質濃度之定量...............................................22
十二烷基硫酸鈉-聚丙烯醯胺凝膠電泳分析..........................23
西方墨點法.....................................................25
萃取全RNA....................................................27
反轉錄反應.....................................................28
聚合酶連鎖反應.................................................28
細胞存活率分析.................................................28
質體建構.......................................................29
質體萃取.......................................................32
細胞轉染.......................................................33
Luciferase assay..................................................34
��-galactosidase活性分析..........................................35
統計分析.......................................................36
實驗結果..........................................................37

多元不飽和脂肪酸對肝癌細胞受細胞激素刺激誘導之CRP蛋白分泌量的影響.............................................................37
多元不飽和脂肪酸對肝癌細胞受細胞激素刺激誘導之CRP mRNA表現量的影響...........................................................37
多元不飽和脂肪酸、IL-1�狺呰L-6對肝癌細胞存活率之影響............38
多元不飽和脂肪酸對肝癌細胞受細胞激素刺激活化CRP基因上游-300 bp序列之活性調控影響...............................................38
多元不飽和脂肪酸對肝癌細胞受細胞激素刺激所誘導p50及p65轉移入核之表現量的影響...................................................40
多元不飽和脂肪酸對肝癌細胞受細胞激素刺激誘導磷酸化之STAT3轉移入核之表現量的影響.................................................41
多元不飽和脂肪酸對肝癌細胞受細胞激素刺激誘導之STAT3磷酸化之調控影響.............................................................42
多元不飽和脂肪酸對肝癌細胞受細胞激素誘導核內累積磷酸化STAT3之調控影響...........................................................42
討論..............................................................44
圖表..............................................................52
參考文獻..........................................................68
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