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研究生:陳月英
研究生(外文):Yueh-Ying Chen
論文名稱:探討在人類類風濕性關節炎之滑液膜纖維母細胞內LPS誘發cPLA2表現之機轉
論文名稱(外文):Mechanisms of lipopolysaccharide-unduced expression of cytosolic phospholipase A2 in synovial fibroblasts of human 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:138
中文關鍵詞:類風濕性關節炎
外文關鍵詞:rheumatoid arthritislipopolysaccharide
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類風濕性關節炎是一種慢性發炎疾病, LPS 為革蘭氏陰性菌的內毒素, 其與此疾病的關節受損進展息息相關, PGE2是一種發炎介質, 造成關節內纖維母細胞的破壞及組織的疼痛, 其可由COX-2代謝花生四烯酸(AA)所形成。cPLA2可催化核膜上的磷脂質, 讓AA從中釋放而出, 此時再由COX-2代謝AA形成PGE2等發炎介質。LPS刺激人類類風濕性關節炎纖維母細胞是否可造成cPLA2的生成, 進而增加PGE2的量, 這其中的訊號傳遞路徑還未有研究報告顯示。在本篇論文中, 我們發現隨著LPS刺激細胞的時間與濃度增加後, cPLA2蛋白質與mRNA的表現也有相對增加的趨勢。而此作用會被p38, JNK MAPKs, PLC, PKC, Ca+2, Src, EGFR, PDGFR, PI3K 以及 NF-B等各自專一性的抑制劑有所抑制。而我們也利用了dominative plasmid 來確定 MEK1/2, ERK2, p38, JNK, p85, Akt, NIK, IKKα and IKKβ參與在LPS誘發cPLA2表現過程當中。在LPS造成NF-B translocation 和 IκBα degradation 是不經由p42/p44, p38 以及 JNK來調控的,它們是各自獨立調控cPLA2。此外PDGFR是受PKC的調控, 而PKC, Src, PDGFR, EGFR, PI3K也包含在LPS 刺激 p38, JNK MAPK 磷酸化當中。這些實驗結果針對在人類類風濕性關節炎纖維母細胞內,LPS調控發炎反應的產生以及機轉有了一個新的概念。可增加我們對LPS誘發人類類風濕性關節炎纖維母細胞cPLA2的表現之機轉和發炎上的調控關係有進一步的瞭解,為未來類風濕性關節炎的治療提供一個新的參考方向。
Lipopolysaccharide (LPS) stimulation is associated with development of rheumatoid arthritis (RA) and with greater progression of joint damage. PGE2 is an inflammatory mediator produced by the COX-2-mediated AA metabolism, which is originated from cPLA2 activation. LPS in inflammation has been shown to activate cytosolic phospholipase A2 (cPLA2), and associated with release of arachidonic acid. We have found that LPS induces cPLA2 expression which leads to prostaglandin E2 biosynthesis. However, the mechanisms underlying LPS-induced cPLA2 expression are not completely understood in synovial fibroblasts of human rheumatoid arthritis. In this study, we demonstrated that LPS induced cPLA2 protein expression in a time- and concentration-dependent manner, which was attenuated by pharmacological inhibitors of MAPKs (SB202190 and SP600125), PLC (U73122 and D609), PKC (Ro318220, Rotterlin and Gö6976), Ca2+ (BAPTA/EDTA), Src (PP1), EGFR (AG1478), PI3K (LY294002) and NF-B (Helenalin). In addition, we transfected with dominant negative plasmids of p38, JNK, p85, Akt, Src, NIK, IKKα and IKKβ also abolished LPS-induced cPLA2 expression. Furthermore, we confirm that p38, JNK2, p85, Akt, Src and NIK involved in LPS-induced cPLA2 expression, shRNA transfection technique were performed. In this study suggested that LPS stimulated p38 and JNK MAPKs activation. Moreover, tyrosine kinase (Src), RTK signaling pathway (EGFR, PDGFR, PI3K/AKT), and PKC were involved in LPS-stimulated p38 and JNK MAPKs phosphorylation. In addition, LPS could induce NF-B translocation and IκBα degradation, which were not regulated by MAP Kinases. These results provide a new insight into the regulation of cPLA2 by LPS in RASFs. An increased understanding of signal transduction pathways involved in LPS-induced cPLA2 expression in the synovial fibroblasts may be of potential therapeutic value in the treatment of inflammatory disease included rheumatoid arthritis.
英文摘要 (Abstract in English)………………………………………………II中文摘要 (Abstract in Chinese) …………………………………………….IV

縮寫表 (Abbreviations) ……………………………………………………...V

抑制劑表(Inhibitors) ………………………………………………………..VIII

緒論 (Introduction) …………………………………………………………..1

研究方向 (Specific aims) …………………………………………………...31
材料與方法 (Materials and Methods) ………………………………………32
結果 (Results) ……………………………………………………………….38
Part I : The mechanism underlying LPS-induced cPLA2 expression:
involvement of p38 and JNK MAPK and NF-B in RASFs…………38
Part II: Mechanisms underlying LPS-induced p38 and JNK activation:
involvement of PKC and transactivation of Src/PDGFR,EGFR
/PI3K/Akt in RASFs………………………………………………….48
討論 (Discussion) …………………………………………………………...54
結論 (Summary) ……………………………………………………….........58
圖表 (Figure legends) ………………………………………………….........59
參考文獻 (References) ……………………………………………………..118
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