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研究生:齊珮伶
研究生(外文):Pei Ling Chi
論文名稱:探討細胞間白素-1β刺激人類風濕性關節炎其纖維母細胞調控磷酯酶A2之表現機轉
論文名稱(外文):Mechanisms underlying Interleukin-1β-induced Expression of Cytosolic Phospholipase A2 in Human Rheumatoid Arthritis Synovial Fibroblasts
指導教授:楊春茂楊春茂引用關係
指導教授(外文):C. M. Yang
學位類別:博士
校院名稱:長庚大學
系所名稱:生物醫學研究所
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:2012
畢業學年度:100
論文頁數:165
中文關鍵詞:類風濕性關節炎磷酯酶A2細胞間白素
外文關鍵詞:rheumatoid arthritisphospholipase A2interleukin
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類風濕性關節炎的主要特徵是細胞激素作用在關節腔內滑液膜的組織上,產生大量的慢性發炎細胞介質。細胞質型磷脂水解酶A2是一種速率決定步驟酵素,可以分解細胞膜上磷脂質釋出花生四烯酸,因此,在生合成20個碳之脂肪酸過程中扮演起始與調控的角色。在關節發炎過程中,細胞內有一些訊號傳導路徑對於氧化還原反應是敏感的,以及活性氧物質的增加皆參與調控生化因子的生產。第一型血紅素氧化酶是一種具細胞保護作用的蛋白質,在發炎過程中,經由降低細胞氧化壓力和調節多種細胞作用來保護受損的組織。在本論文中,我們探討在人類類風濕性關節炎滑液膜內的纖維母細胞藉由細胞間白素-1β的誘發,促進細胞質型磷脂水解酶A2蛋白表現的調控機制。同時,我們也探討滑液膜內的纖維母細胞若是大量表現第一型血紅素氧化酶,在細胞間白素-1β的誘導下,是否可以有效的控制細胞質型磷脂水解酶A2蛋白的表現。我們所使用的滑液膜內的纖維母細胞是從病人置換關節時所取出滑液膜上的組織。在活體動物的實驗中,利用細胞間白素-1β誘發關節腔發炎反應,使用免疫組織化學染色法觀察免疫細胞浸潤情形及細胞質型磷脂水解酶A2蛋白的表現。研究中,將細胞處理藥理性抑制劑或轉染siRNA或shRNA入細胞內,藉此抑制目標基因的表現,再利用西方墨點轉漬法、即時聚合連鎖反應、啟動子區域基因表現分析法觀察細胞間白素-1β誘發細胞質型磷脂水解酶A2蛋白的表現機制。利用流式細胞儀偵測螢光強度觀察細胞內產生的活性氧化物質。細胞間白素-1β可促進輔助活化因子,p300的活化,增加啟動子與轉錄因子(NF-κB及AP-1)之間的結合能力,利用染色質免疫沈澱法,進一步了解細胞質型磷脂水解酶A2的轉錄機制。細胞間白素-1β導致胞質型磷脂水解酶A2蛋白增加的情況下,利用酵素連結免疫吸附法偵測前列腺素產生的程度。將細胞感染帶有第一型血紅素氧化酶基因重組的病毒,藉此誘發此蛋白在滑液膜內的纖維母細胞大量表現,觀察細胞間白素-1β所誘發胞質型磷脂水解酶A2蛋白表現是否會受影響。研究結果顯示,胞間白素-1β透過MyD88/c-Src-dependent MMP/HB-EGF路徑轉活化至EGFR/PI3K/Akt,促進p300與NF-κB p65轉錄因子活化,增加細胞質型磷脂水解酶A2的蛋白表現。進一步的研究發現,細胞間白素-1β會促進Akt磷酸化並使其轉移至到細胞核內,幫助組蛋白(H3及H4)乙醯化,增加輔助活化因子p300及轉錄因子NF-κB p65與啟動子的結合能力,啟動細胞質型磷脂水解酶A2的轉錄。由此可知,細胞間白素-1β促進轉錄因子NF-κB p65轉錄機制是透過PI3K/Akt這條路徑所調控。
另一方面,細胞間白素-1β會透過NADPH oxidase的活化產生活性氧化物質。同時,細胞內加入清除活性氧化物 (NAC)或者抑制NADPH oxidase活性的藥物,以及轉染siRNA或shRNA入細胞內,抑制目標基因的表現皆可以降低細胞間白素-1β所誘發的胞質型磷脂水解酶A2蛋白表現。當細胞內表現過量的第一型血紅素氧化酶蛋白的時候,也可以抑制細胞間白素-1β所誘發的胞質型磷脂水解酶A2蛋白表現。我們進一步的發現,在細胞間白素-1β的刺激之下,p47phox會磷酸化並轉移到細胞膜上活化NADPH oxidase進而促使活性氧化物的釋放,若是使用MEK1/2(U0126)或JNK1/2(SP600125)藥理性抑制劑則會減少活性氧化物的產生。此外,細胞間白素-1β會增加轉錄因子AP-1與啟動子的結合能力,促進細胞質型磷脂水解酶A2的轉錄,然而,當細胞內有清除活性氧化物質(NAC)或第一型血紅素氧化酶大量存在的時候此結合能力會受到抑制。由此可知,細胞間白素-1β促進轉錄因子AP-1轉錄機制是透過NADPH oxidase/ROS這條路徑所調控。此外,當細胞間白素-1β增加細胞質型磷脂水解酶A2蛋白質表現的同時也會促使前列腺素產生的釋放量增加。綜合以上的實驗結果,人類類風濕性關節炎滑液膜內的纖維母細胞在細胞間白素-1β作用之下,可經由MyD88/c-Src-dependent MMP/HB-EGF,EGFR/PI3K/Akt,以及p42/p44 MAPK- 與JNK1/2-dependent NADPH oxidase/ROS等不同訊號傳遞路徑來分別活化NF-κB p65和 AP-1等重要轉錄因子,最後引發細胞質型磷脂水解酶A2的蛋白大量表現及前列腺素的生成。此外,我們也發現細胞大量存在第一型血紅素氧化酶時,會藉由本身具有抗氧化的能力進而降低細胞質型磷脂水解酶A2蛋白的合成。綜合以上的研究結果,在關節腔內利用細胞間白素-1β的作用,所引發的發炎反應實驗模式,藉此增加對於滑液膜內纖維母細胞訊號傳遞機制的了解,期望可以帶來更多降低發炎反應治療的新策略。

The chronic production of inflammatory mediators by cytokines in synovial tissues is an important feature of rheumatoid arthritis. Cytosolic phospholipase A2 (cPLA2) is a rate-limiting enzyme to catalyze arachidonic acid release, and plays a critical role in initiating and regulating the multistage biosynthetic process of eicosanoids. Some intracellular signaling pathways are redox-sensitive and reactive oxygen species (ROS) are involved in the regulation of the production of biochemical factors involved in joint inflammation. Heme oxygenase-1 (HO-1) can exert protective effects against oxidative stress and tissue injury during inflammatory responses. In this study, we investigated the mechanisms underlying IL-1β-induced cPLA2 expression in human rheumatoid arthritis synovial fibroblasts (RASFs). Furthermore, we examined whether HO-1 induction would be an effective strategy to control cPLA2 expression in RASFs. Synovial tissue was obtained from patients with RA who were undergoing joint replacement surgery. In an IL-1β-mediated inflammatory arthritis animal model, neutrophils infiltration, bone erosion, and cPLA2 expression in mouse ankle synovium were observed by immunohistochemistry. IL-1β-induced cPLA2 expression was determined by western blot, real-time PCR, and gene promoter assay using pharmacological inhibitors and transfection with short hairpin RNAs (shRNAs) or small interfering siRNAs (siRNAs). IL-1β-induced ROS generation was determined by a flow cytometer. The recruitment of p300, NF-κB and AP-1 to the cPLA2 promoter was determined by chromatin immunoprecipitation (ChIP) assay. PGE2 biosynthesis was evaluated by enzyme-linked immunosorbent assay. Overexpression of HO-1 was performed by infection of RASFs with a recombinant adenovirus containing the HO-1 gene. Here, we reported that IL-1β-induced cPLA2 expression and PGE2 release was mediated through a myeloid differentiation factor 88 (MyD88)/c-Src-dependent matrix metalloproteinase (MMP)/heparin-binding epidermal growth factor (HB-EGF) cascade linking to transactivation of the EGF receptor (EGFR)/ phosphatidylinositol 3-kinase (PI3-kinase)/Akt, p300, and NF-κB p65 pathways. IL-1β also stimulated Akt phosphorylation and nuclear translocation. Activation of Akt eventually led to the acetylation of histone residues by phosphorylation and recruitment of p300 and enhanced its histone acetyltransferase activity on the NF-κB elements of the cPLA2 promoter. IL-1β-induced NF-κB transcriptional activity was mediated through a PI3K/Akt-dependent cascade.
Moreover, activation of RASFs by IL-1β led to ROS generation via NADPH oxidase. IL-1β-induced cPLA2 expression was mediated through NOX2 activation/ROS production, which was attenuated by N-acetylcysteine (a scavenger of ROS), the inhibitors of NOX (diphenyleneiodonium chloride and apocynin), MEK1/2 (U0126), JNK1/2 (SP600125), transfection with respective siRNAs or shRNAs, and overexpression of HO-1 in RASFs. We further found that IL-1β-induced phosphorylation of p47phox and translocation to the membrane as well as NADPH oxidase-dependent ROS production was attenuated by the inhibitor of MEK1/2(U0126) or JNK(SP600125) in RASFs. Furthermore, IL-1β-induced cPLA2 expression was mediated through recruitment of AP-1 to the cPLA2 promoter region which was attenuated by N-acetylcysteine and overexpression of HO-1. IL-1β-induced AP-1 transcriptional activity was mediated through a NADPH oxidase/ROS-dependent cascade. Up-regulation of cPLA2 by IL-1β increased PGE2 biosynthesis in RASFs. These results indicated that IL-1β-induced cPLA2 expression in RASFs at least two separate pathways: one is mediated through activation of MyD88/c-Src, MMP/HB-EGF, EGFR/PI3K/Akt, p300, and NF-κB and the other via activation of p42/p44 MAPK and JNK1/2 leading to phosphorylation of p47phox and ROS production, and AP-1 pathways. The induction of HO-1 could reverse IL-1β-induced cPLA2 expression through the antioxidant effect. These results provide insights into the mechanisms underlying IL-1β-enhanced joint inflammatory responses in RA and may inspire new targeted therapeutic approaches.

論文指導教授推薦書
論文口試委員審定書
國家圖書館博碩士論文電子檔案上網授權書-----------------------------iii
長庚大學博碩士論文著作授權書--------------------------------------------iv
致謝---------------------------------------------------------------------------------v
Abbreviations--------------------------------------------------------------------vi
Pharmacological Inhibitors-------------------------------------------------viii
摘要--------------------------------------------------------------------------------ix
Abstract--------------------------------------------------------------------------xii
Table of Contents---------------------------------------------------------------xv
CHAPTER I
Introduction
SECTION 1: Background and significance -----------------------------------1
SECTION 2: Specific aims ----------------------------------------------------30
SECTION 3: Appended figures and tables ----------------------------------32
CHAPTER II
SECTION 1: Materials ---------------------------------------------------------51
SECTION 2: Methods ----------------------------------------------------------53
CHAPTER III
Cytosolic Phospholipase A2 Induction and Prostaglandin E2 Release by Interleukin-1β via the Myeloid Differentiation Factor 88-Dependent Pathway and Cooperation of p300, Akt, and NF-κB Activity in Human Rheumatoid Arthritis Synovial Fibroblasts
SECTION 1: Introduction -----------------------------------------------------64
SECTION 2: Results ------------------------------------------------------------67
SECTION 3: Discussion -------------------------------------------------------75
SECTION 4: Figures and legends --------------------------------------------80
CHAPTER IV
HO-1 Attenuates IL-1β-induced cPLA2 Expression via a Decrease in NADPH Oxidase/ROS/AP-1 Activation in Human Rheumatoid Arthritis Synovial Fibroblasts
SECTION 1: Introduction -----------------------------------------------------96
SECTION 2: Results ------------------------------------------------------------99
SECTION 3: Discussion ------------------------------------------------------106
SECTION 4: Figures and legends -------------------------------------------115
CHAPTER V
Conclusion and perspectives
SECTION 1: Conclusion and perspectives --------------------------------129
SECTION 2: Summary -------------------------------------------------------133
PUBLICATIONS -------------------------------------------------------------134
REFERENCES----------------------------------------------------------------135

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