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研究生:劉純如
研究生(外文):Chun-Ju Liu
論文名稱:探討TNF-alpha在人類風濕性關節炎之滑液膜纖維母細胞上誘發磷脂酶A2表現機轉
論文名稱(外文):Mechanisms of Tumor Necrosis Factor-alpha-induced Expression of Cytosolic Phospholipase A2 in Human Synovial Fibroblast of Rheumatoid Arthritis
指導教授:楊春茂楊春茂引用關係
指導教授(外文):Chuen-Mao Yang
學位類別:碩士
校院名稱:長庚大學
系所名稱:天然藥物研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:139
中文關鍵詞:磷脂酶A2 前列腺素 類風濕性關節炎滑液膜纖維母細胞
外文關鍵詞:Rheumatoid arthritisMAPKscytosolic phospholipase A2
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中文摘要
類風濕性關節炎(RA)是一種複雜的全身性自體免疫疾病,當嚴重且持續發展病程時最終會導致關節的損傷與破壞。在類風濕性關節炎滑液中發現腫瘤壞死因子-alpha (Tumor necrosis factor-alpha;TNF-alpha)有大量的表現。目前研究指出有些調控因子的機制,例如:磷脂酶A2 (cPLA2)發現能調控類風濕性關節炎的病理生理現象。磷脂酶A2在類風濕性關節炎中扮演著相當重要的角色,當細胞激素包括TNF-a會誘發磷脂酶A2的表現,進而促使花生四烯酸的釋放而導致前列腺素prostaglandin E2(PGE2)合成增加。過去研究TNF-a已經被發現能活化mitogen-activated protein kinases (MAPKs) 包括extracellular signal-regulated kinase (ERK1/2, p42/p44), p38, 和c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK), 然而在人類風濕性關節炎之滑液膜纖維母細胞Rheumatoid Arthritis Synovial Fibroblast cells(RASFs)中TNF-a所誘發調控磷脂酶A2信號路徑的調控機制至今尚未了解。在本論文中,我們發現TNF-a誘發cPLA2的蛋白質及mRNA表現與PGE2合成會受到藥理性抑制劑 p38 (SB202190), JNK (SP600125), PDGFR (AG1296), EGFR (AG1478), PI3K (LY294002), Src (PP1), PLC (D609, U73122), PKC (Ro318220, GÖ6976, Rottlerin), 和Ca2+ (BAPTA/EDTA)的抑制,以及轉殖dominant negative mutants of p38, JNK, Src, Akt 和 p85, 也都能一致性地抑制其表現,而TNF-alpha所誘發MAPKs (ERK1/2, p38, JNK), Src, PDGFR, EGFR, 和Akt磷酸化現象同樣地受到這些專一性藥理抑制劑與轉殖dominant negative mutants所抑制。此外,TNF-a誘發cPLA2的蛋白質及mRNA表現也會受到選擇性NF-kB抑制劑(helenalin) 與轉殖dominant negative mutants 包括NF-kB inducing kinase(NIK), IkB kinase-a (IKK-alpha), 和IkB kinase-beta (IKK-beta),進一步地藉由細胞分核質分析與免疫螢光染色法也同樣證實在TNF-a誘發造成 IkB-alpha degradation 和 NF-kB translocation,而這樣的機制受到helenalin所抑制,但卻不會被前處理SB202190, SP600125和U0126所抑制。此外TNF-alpha誘發PGE2合成能被分前處理SB202190, SP600125, Helenalin, PP1 and AG1478所抑制。TNF-a在短時間下能誘發cPLA2的磷酸化,而且磷酸化會受到MAPKs (U0126, SP600125), PLC (D609, U73122), PKC (Ro-318220, GÖ6976, Rottlerin, GF109203X), 和Ca2+ (BAPTA/EDTA) 所抑制,這些實驗結果顯示出TNF-a所誘發RASFs所造成的cPLA2的磷酸化與蛋白質表現和PGE2釋放之間相互調控關係,最後總歸上述結果說明了在RASFs中TNF-a誘導cPLA2表現是透過MAPKs (p38, JNK) , NF-kB, PKC and transactivation of growth factor receptors pathways所調控的。這些結果提供了更新且完整的機轉能進一步了解在類風濕性關節炎TNF-a所引起的免疫反應,作為未來治療新的參考方向。
ABSTRACT
Rheumatoid arthritis (RA) is a complex systemic autoimmune disease that ultimately leads to the progressive destruction of articular. Elevated levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha(TNF-alpha) have been found in the synovial fluid. Several factors have been implicated to trigger the mechanisms for the pathologenesis of RA, such as cytosolic phospholipase A2 (cPLA2). cPLA2 plays a pivotal role in RA which mediates agonist-induced arachidonic acid release for prostaglandin (PG) synthesis during stimulation with cytokines including TNF-a. Although TNF-alpha has been reported to activate all of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK1/2, p42/p44 MAPK), p38 MAPK and c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK). The relationship between the activation of these pathways and expression of cPLA2 remains largely unknown. Therefore, whether activation of these signaling pathways by TNF-alphalinked to cPLA2 expression is needed determining in RA. Here, we reported that TNF-alpha induced cPLA2 protein and mRNA expression and PGE2 synthesis, which was attenuated by pharmacological inhibitors of MAPKs (SB202190, SP600125), Src (PP1), PDGFR (AG1296), EGFR (AG1478), PI3K (LY294002), PLC (D609, U73122), PKC (Ro-318220, GÖ6976, Rottlerin), and Ca2+ (BAPTA/EDTA) and transfection with dominant negative mutants of p38, JNK, Src, Akt and p85, respectively. Consistently, TNF-a-stimulated phosphorylation of MAPKs (ERK1/2, p38, JNK), Src, PDGFR, EGFR, and Akt was attenuated by pretreatment with these selective inhibitors and transfection with dominant negative mutants of MEK1/2, ERK1/2, p38, and JNK, respectively. Furthermore, TNF-a-induced cPLA2 expression was inhibited by a selective NF-kB inhibitor (helenalin) and transfection with dominant negative mutants of NF-kB inducing kinase (NIK), IkB kinase-alpha (IKK-alpha), and IkB kinase-beta (IKK-beta), consistent with that TNF-alpha stimulated IkB-alpha degradation in cytosol and NF-kB translocation into nucleus in these cells determined by Western blotting and immunofluorescence staining. This NF-kB translocation was blocked by helenalin, but not by SB202190, SP600125 and U0126. Moreover, pretreatment with SB202190, SP600125, Helenalin, PP1 and AG1478 attenuated TNF-alpha-induced PGE2 synthesis. Moreover, TNF-alpha-stmulated cPLA2 phosphorylation was inhibited by MAPKs (U0126, SP600125), PLC (D609, U73122), PKC (Ro-318220, GÖ6976, rottlerin, GF109203X), and Ca2+ (BAPTA/EDTA), indicating the regulation by MAPKs (p42/p44, JNK), PLC, PKC and Ca2+, implying the involvement of cPLA2 in these responses. These findings suggest that phosphorylation and expression of cPLA2 correlates with the release of PGE2 from TNF-alpha-challenged RASFs were mediated through phosphorylation of MAPKs (p38, JNK), NF-kB, PKC and transactivation of growth factor receptors pathways. These results provide new insight into the mechanisms of TNF-alpha action that cytokines may promote inflammatory responses in the RA.
目錄(Contents)
指導教授推薦書
口試委員會審定書
碩士論文授權書
誌謝 (Acknowledgements)
目錄 (Contents)……………………………………v
縮寫表 (Abbreviations)…………………………… vii
抑制劑表 (Inhibitors)…………………………………x
中文摘要 (Abstract in Chinese)……………………xi
英文摘要 (Abstract in Enalish)…………………xiii
緒論 (Introduction)…………………………………1
附圖與圖表 (Appended Figures and Tables)……25
材料與方法 (Materials and Methods)............................. 35
實驗結果 (Results)…………………42
1.TNF-alpha-induced cPLA2 expression and PGE2 synthesis.
2.TNF-alpha-induced cPLA2 expression requires ongoing
transcription and translation.
3.TNF-alpha induced cPLA2 expression not via p42/p44 MAPK
phosphorylation.
4.TNF-alpha induced cPLA2 expression via p38 MAPK phosphorylation.
5. TNF-alpha induced cPLA2 expression via JNK phosphorylation.
6.TNF-alpha induced cPLA2 expression via RTK transactivation and
P13K/Akt signaling pathways.
7. TNF-alpha induced cPLA2 expression via PLC.
8. TNF-alpha induced cPLA2 expression via protein kinase C.
9.TNF-alpha induced cPLA2 expression via NF-B translocation.
10.TNF-alpha stimulated cPLA2 phosphorylation in RASFs
11.TNF-alpha stimulated PGE2 synthesis via MAPKs and NF-B pathway.
12. AA and PGE2 stimulated cPLA2 expression in RASFs.
圖表 (Figure legends)………………………………………57
討論 (Discussion)………………………………………………118
總結 (Summary)…………………………………………………125
參考文獻 (References)…………………………………126
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