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研究生:李慧君
研究生(外文):Hui Chun Lee
論文名稱:探討TNF-alpha與IL-1beta刺激人類氣管平滑肌細胞調控cPLA2蛋白的表現機轉
論文名稱(外文):Mechanisms underlying Tumor Necrosis Factor-alpha-and Interleukin-1beta-induced Cytosolic Phospholipase A2 Expression in Human Tracheal Smooth Muscle Cells
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:146
中文關鍵詞:細胞激素磷脂酶A2
外文關鍵詞:cytokinephospholipase A2
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呼吸道發炎過程中,引起發炎的前驅物細胞激素例如:腫瘤壞死因子(TNF-) 以及介白素(IL-1β)都已被證實會調控許多發炎基因的表現。前列腺素prostaglandins (PG)的產生是必須透過細胞磷脂酶A2 [cytosolic phospholipase A2 (cPLA2)]水解細胞膜磷脂質sn-2位置造成花生四烯酸arachidonic acid (AA)的釋出再經由cyclooxygenase作用產生前列腺素,因此細胞磷脂酶A2在這過程中扮演一個非常重要的角色。在人類氣管平滑肌細胞(tracheal smooth muscle cells)的研究中,對於細胞磷脂酶A2的表現以及前列腺素(PG)的產生受到TNF- 和IL-1β的刺激下都會明顯的表現,因此,接下來我們將利用Western blotting, RT-PCR, promoter activity and ELISA assay來進一步探討在TNF- 和IL-1β的作用下引起細胞磷脂酶A2的表現及前列腺素(PG)的產生有哪些機制參與在這當中,從我們的結果可以證明不管是在TNF- 或IL-1β都能明顯的造成細胞磷脂酶A2蛋白以及mRNA的表現;promoter activity以及前列腺素(PG)的產生,同時對於這樣的影響在我們的實驗當中也可以看到主要是受到一些訊號分子的影響包括:MAPKs (ERK1/2, p38, JNK1/2), Src/EGFR, PDGFR/P13K/Akt, PLC/Ca2+, 及PKC isoforms,當以專一性的抑制劑(U0126, SB202190, SP600125, PP1, AG1296, AG1478, LY294002, SH-5, U73122, BAPTA/AM, GÖ6976, Ro-318220 and rottlerin) 前處理或是使用siRNAs (MEK1, p42, p38, JNK2, Src, Akt)轉殖也都能同樣明顯的抑制細胞磷脂酶A2的表現以及前列腺素(PG)的產生。另外,TNF- 或IL-1β引起細胞磷脂酶A2的表現也會受到轉錄因子NF-B所使用的抑制劑(helenalin)或dominant negative mutants NIK and IKK-所抑制,同時TNF- 或IL-1β也都能夠明顯引起NF-B(p65/p50) translocation,當使用dominant negative mutants of NIK, IKK- and IKK-也能明顯抑制其translocation情形,但MAPKs的活化並不會影響NF-B的translocation。因此在這我們認為細胞磷脂酶A2的表現是必須分別透過MAPKs以及NF-B的調控而來。除此之外,細胞激素所引起細胞磷脂酶A2的表現對於細胞核內一些co-activator,如p300/CBP等HAT(Histone acetyltransferas)的活性影響,在使用p300 siRNA轉殖或是p300 inhibitor curcumin也都能明顯看到細胞磷脂酶A2受到抑制,同時進一步的利用ChIP (Chromatin immunoprecipitation) assay也能明顯的看到在TNF- 或IL-1β的刺激下p300,acetyl-histone H4都能明顯結合至cPLA2 promoter上。而在先前的研究報告已指出對於CBP/p300的活化主要是受到MAPK 或是 Akt phosphorylation(磷酸化)的調控,因此在這裡我們也個別使用了MAPK 及Akt 路徑的抑制劑來證實,從結果可以發現JNK,p38 以及 Akt 路徑的抑制劑都明顯抑制p300 and histone H4結合到cPLA2 promoter上。相反的,TNF- 或IL-1β的刺激引起CaMKII-的磷酸化是會造成核內HDACs(Histone de-acetyltransferase)的export (輸出)而引起genes repression,但從研究結果卻顯示當處理KT5926 (CaMKII 抑制劑)或是siRNA (CaMKII)轉殖都不會影響細胞磷脂酶A2的蛋白表現,因此對此複雜機制仍有待進一步探討。
由以上結果證明,人類氣管平滑肌細胞在TNF- 或IL-1β的刺激下的刺激下,可同時經由NIK/IKK, MAPKs (ERK1/2, p38, JNK1/2) Src/EGFR/P13K/Akt, PLC/Ca2+ and PKC isoforms等多條訊號傳遞路徑來分別活化p300等重要的轉錄因子,最後引發細胞磷脂酶A2的蛋白大量表現.
Pro-inflammatory cytokines including tumor necrosis factor- (TNF-) and interleukin-1(IL-1) have been reported to up-regulate multiple inflammatory genes in airway inflammation. The cytosolic phospholipase A2 (cPLA2) plays a critical role in catalyzing the hydrolysis of glycerophospholipids to liberate arachidonic acid (AA) which is further converted into prostaglandins (PG) catalyzed by cyclooxygenase (COX). In human tracheal smooth muscle cells (HTSMCs), the amount of de novo synthesis of cPLA2 protein and PGE2 production was induced by cytokines (TNF- and IL-1. Therefore, in present study, we investigated whether different mechanisms participating in cytokines-induced expression of cPLA2 and enhanced synthesis of PGE2 analyzed by Western blotting, RT-PCR, promoter activity and ELISA assay. Our results demonstrated that cytokines significantly increased cPLA2 protein, mRNA, luciferase activity and PGE2 productions, and these effects were regulated by several of signaling transduction molecules including, MAPKs (ERK1/2, p38, JNK1/2), Src/EGFR,PDGFR/P13K/Akt, PLC/Ca2+, and PKC isoforms. Pretreatment with their respective inhibitors (U0126, SB202190, SP600125, PP1, AG1296, AG1478, LY294002, SH-5, U73122, BAPTA/AM, GÖ6976, Ro-318220 and rottlerin) or transfection with siRNAs (MEK1, p42, p38, JNK2, Src, Akt) significantly attenuated phosphorylation protein kinases, cPLA2 expression and PGE2 synthesis induced by cytokines. In addition, expression of cPLA2 by cytokines was also inhibited by a NF-B inhibitor (helenalin) or by over-expression of dominant negative mutants of NIK and IKK-. Cytokines-induced NF-B translocation was blocked by transfection with dominant negative mutants of NIK, IKK- and IKK-, but not by these MAPKs inhibitors, suggesting that MAPKs and NF-B independently regulated cPLA2 expression and PGE2 synthesis. Furthermore, down-regulation of p300 by p300 siRNA transfection or pretreatment of cells with p300 inhibitor curcumin almost completely blocked cytokines-dependent cPLA2 expression. Most surprisingly, p300 was associated with the cPLA2 promoter (-595 to +75), which was dynamically linked to histone H4 acetylation stimulated by cytokines, as determined by chromatin immunoprecipitation assay (ChIP). Furthermore, an enrichment of p300 and histone H4-associated cPLA2 DNA complexes appeared in cytokines-treated HTSMCs. Furthermore, activation of CBP/p300 mediated through MAPK or Akt phosphorylation has been reported. Herein, we found that inhibition of JNK, p38 and Akt pathway by their specific inhibitors causes a decrease recruitment of p300 and histone H4 interacted with cPLA2 promoter. On the contrary, phosphorylation of CaMKII by cytokines may lead to nucleus export of HDACs and induce genes repression. However, KT5926 (a CaMKII inhibitor) and siRNA for CaMKII had no effect on cPLA2 expression, this complicated mechanism remains to be investigated. Thus, these results provide a new insight into the molecular mechanisms that activation of NIK/IKK, MAPKs (ERK1/2, p38, JNK1/2) Src/EGFR/P13K/Akt, PLC/Ca2+ and PKC isoforms signaling pathways may eventually stimulate p300 activity, assemble transcription factors, and lead to cPLA2 expression induced by cytokines in HTSMCs. Increased understanding of mechanisms underlying cPLA2 gene expression induced by cytokines will create opportunities for the development of anti-airway inflammation therapeutic strategies.
Table of Contents (目錄)……………………………….……..1
Acknowledgements (誌謝)……...………………….………..4
Abbreviations (縮寫表)…………………………………….……....5
Abstract in Chinese (中文摘要)..……...…………………………..8
Abstract in English (英文摘要)...……...…………………………10
INTRODUCTION…………………….…….….…...………….….......12

1. Background and Significance……………………..……………...12

◎ Role of cytokines in airway inflammatory diseases
◎ Role of cyclooxygenase and PGE2 in airway inflammatory diseases
◎ Role of cPLA2 in airway inflammatory diseases
◎ Role of MAPKs in airway inflammatory diseases
◎ Role of PI3K/Akt in airway inflammatory diseases
◎ Transactivation of RTK in airway inflammatory diseases
◎ Roles of calcium, calmodulin and PKC in airway inflammatorydiseases
◎ Role of transcription factor NF-B in airways inflammatory diseases
2. Figures and Tables…………………..………………………….....23
3. Specific Aims…………………….………………………………..31
4. Metrial and methods………….…………………………………..32
5. Results………….…………………....………………………….....38


PART I Mechanisms underlying tumor necrosis factor--induced cytosolic phospholipase A2 expression in human tracheal smooth muscle cells…………………………………………38
SECTION I
 TNF--induced de novo cPLA2 protein and mRNA expression
 Inhibition of MAPKs and NF-B blocks TNF--induced PGE2 production
 TNF-- induced cPLA2 expression via p42/p44 MAPK phosphorylation
 TNF--induced cPLA2 expression via p38 MAPK phosphorylation
 TNF--induced cPLA2 expression via JNK phosphorylation
 Involvement of NF-B activation in TNF--induced cPLA2 expression
 TNF--induced cPLA2 expression requires ongoing transcription and translation
 TNF--induced cPLA2 promoter activity
 Phosphorylation by p38 and JNK stimulates p300 and histone acetyl transferase activity in TNF--induced cPLA2 expression
 Effects of MAPK kinase inhibitors on TNF--stimulated transient phosphorylation of cPLA2

SECTION II
 TNF--stimulated cPLA2 gene expression and PGE2 production are inhibited by pretreatment with PP1, AG1478, LY294002 and SH-5.
 Inhibition of Src/EGFR-PDGFR/PI3K/Akt blocks TNF--induced cPLA2 protein expression.
 Recruitment of p300 to cPLA2 promoter by Akt phosphorylation is required for TNF--induced cPLA2 expression.
 Phospholipase C and calcium, but not CaMK selectively regulate TNF--induced cPLA2 expression and PGE2 production in HTSMCs
 Involvment of PKC isoforms in regulating PGE2 production and cPLA2 expression by TNF- in HTSMCs

PART II Mechanisms underlying interleukin-1β-induced cytosolic phospholipase A2 expression in human tracheal smooth muscle cells…………………………………………………82
SECTION I
 IL-1-induced de novo cPLA2 protein and mRNA expression
 Inhibition of MAPKs and NF-B blocks IL-1-induced PGE2 production
 IL-1- induced cPLA2 expression via p42/p44 MAPK phosphorylation
 IL-1-induced cPLA2 expression via p38 MAPK phosphorylation
 IL-1-induced cPLA2 expression via JNK phosphorylation
 Involvement of NF-B activation in IL-1-induced cPLA2 expression
 IL-1-induced cPLA2 expression requires ongoing transcription and translation
 IL-1-induced cPLA2 promoter activity
 Phosphorylation by p38 and JNK stimulates p300 and histone acetyl transferase activity in IL-1-induced cPLA2 expression
 Effects of MAPK kinase inhibitors on IL-1-stimulated transient phosphorylation of cPLA2

SECTION II
 IL-1-stimulated cPLA2 gene expression and PGE2 production are inhibited by pretreatment with PP1, AG1478, LY294002 and SH-5.
 Inhibition of Src/EGFR-PDGFR/PI3K/Akt blocks IL-1-induced cPLA2 protein expression.
 Recruitment of p300 to cPLA2 promoter by Akt phosphorylation is required for IL-1-induced cPLA2 expression.
 Phospholipase C and calcium, but not CaMK selectively regulate IL-1-induced cPLA2 expression and PGE2 production in HTSMCs
 Involvment of PKC isoforms in regulating PGE2 production and cPLA2 expression by IL-1 in HTSMCs

PART III Discussion and Conclusion..........…….............….............125

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