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研究生:蔡宇曾
研究生(外文):Yu-Tseng Tsai
論文名稱:1.探討巨噬細胞中cAMPphosphodiesterase抑制劑Rolipram誘導下游基因KSRP表現抑制發炎反應的機制2.探討ROS誘導p66shc與PIN1的交互作用調控NFκB訊息途徑、細胞凋亡及細胞老化
論文名稱(外文):1. Study on the mechanism of KSRP induced by cAMP phosphodiesterase inhibitor Rolipram for down-regulation of pro-inflammatory responses in macrophages 2. Reactive oxygen species induce p66shc interacting with PIN1 to regulate NFκB signaling activation,
指導教授:唐世杰
指導教授(外文):Shye-Jye Tang
學位類別:碩士
校院名稱:國立臺灣海洋大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
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:120
中文關鍵詞:phosphodiesterase 抑制劑KSRP發炎反應活性氧自由基p66shcPIN 1凋亡老化
外文關鍵詞:phosphodiesterase inhibitorKSRPinflammationROSp66shcPIN 1apoptosissenescence
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PART I
嚴重細菌感染引起發炎反應,並可能造成敗血症,導致死亡,在臨床上Phosphodiesterase (PDE) 抑制劑用於治療發炎性疾病,如氣喘、慢性肺部疾病及敗血症,了解其作用機制有助於未來在治療方面的應用。於本研究中,以LPS誘導RAW 264.7細胞產生發炎反應,處理PDE抑制劑,或合併處理Protein kinase A (PKA) 抑制劑H89,以Nitric oxide (NO) 測定其抑制發炎反應的情形,以及是否透過PKA相關的訊息路徑。結果証實非專一性PDE抑制劑IBMX和PDE 4抑制劑Rolipram皆透過cyclic AMP / PKA訊息路徑來抑制NO產生。並進一步透過觀察K - homology splicing regulator protein (KSRP) 在細胞質的蛋白質表現量,証實抑制PDE導致KSRP蛋白質表現量增加,推斷抑制PDE使cAMP增加,透過PKA / cAMP response element binding protein (CREB) 訊息路徑促進KSRP的蛋白質表現,而KSRP是促進mRNA降解的調控蛋白,在細胞質中KSRP表現量增加,使iNOS mRNA穩定性下降,NO產量減少,發炎反應受抑制。這些結果顯示,PDE抑制劑在抑制LPS所誘導的發炎反應以抑制PDE 4最為有效,並且顯現KSRP對iNOS mRNA的調控,與PKA/CREB這些細胞外調控的新連結。
PART II
在細胞進行氧化反應時,伴隨著Reactive oxygen species (ROS)產生,ROS累積增加,會造成DNA或蛋白質氧化傷害增加,使得細胞老化、發炎或凋亡。文獻指出,peptidyl-prolyl isomerase PIN1會促進NFκB轉錄活性。同時,在氧化壓力的刺激下,p66shc於Serine 36位置會被PKC磷酸化,並受到prolyl isomerase PIN1活化,p66shc使ROS增加,最後造成細胞凋亡。
在細胞進行發炎反應時,NFκB會被活化,同時,ROS的濃度也會提高,高濃度的ROS反而會抑制NFκB活性,但機制尚不清楚。本實驗探討在RAW 264.7細胞內高濃度ROS的情況下,除了PIN1會調控p65之外,p66shc是否也參與其中,影響調控NFκB,並影響下游pro-inflammatory cytokines的表現和發炎反應。由結果推論中活化p66shc對於NFκB沒有調控作用,且p66shc S36 突變株同樣沒有抑制效果。
另一方面,探討對於ROS刺激下,p66shc與PIN 1之間的作用,對於細胞凋亡以及細胞老化有何影響,透過大量表現p66shc和其S36突變株,以及PIN 1於HEK 293細胞中,並觀測其細胞染色體凝集現象,本研究結果發現,在H2O2的刺激下,p66shc會促進細胞凋亡,並且與S36磷酸化與否無關,以及PIN 1也會促進細胞凋亡,並且是透過相同的途徑,PIN 1藉由p66shc活化來造成細胞凋亡。但在細胞老化方面,則有相反地結果。結果發現,以SA-β-galactosidase staining測定其細胞老化的情況,p66shc有促進細胞老化的作用,並且與S36磷酸化無關,而PIN1則會抑制老化的發生,可能存在其他的調控機制。這些結果顯示,ROS的確會透過影響p66shc和PIN 1的作用來促進細胞凋亡及細胞老化,但兩者的機制並不相同,在H2O2的刺激下,PIN 1會透過p66shc來促進細胞凋亡,但PIN 1會抑制p66shc活化所造成的細胞老化,顯示其中存在複雜的機制調控細胞走向老化或凋亡。
PART I
Sepsis is the systemic immune response to severe bacterial infection, and might cause death. Phosphodiesterase (PDE) inhibitors are used in cure chronic inflammatory disease like asthma, chronic pulmonary disease and sepsis. Therefore, investigation of the inhibition mechanism of phosphodiesterase inhibitor is beneficial for application in therapy. We treated with LPS in RAW 264.7 macrophage cell line to induce inflammatory response, pretreated phosphodiesterase inhibitor, and measured nitric oxide (NO) production to analyze inhibition effect of inflammatory response. Moreover, we co-pretreated PKA inhibitor H89 to investigate whether PKA is involved or not. We provided the evidence that non-specific phosphodiesterase inhibitor IBMX and PDE 4 inhibitor Rolipram were inhibited NO production through cyclic AMP / PKA pathway. Moreover, we provided the evidence by analysis of K - homology splicing regulator protein (KSRP) protein expression in cytosol, that inhibition of PDE increased KSRP protein expression. These results suggested inhibition of PDE cause increased of cAMP level, and promoted KSRP expression through PKA / cAMP response element binding protein (CREB) pathway. KSRP is a regulatory protein which promotes mRNA decay. For this reason, increased expression level of KSRP in cytosol will decay its target mRNA, iNOS mRNA. And then, NO production might be decreased, inflammatory response might be inhibited. These findings demonstrated the highly inhibition effect of PDE 4 inhibitor among PDE inhibitor to decreased LPS-induced inflammatory response. Moreover, it link KSRP-mediated mRNA degradation to extra cellular regulatory network have been identified.
PART II
Accumulations of reactive oxygen species (ROS) which correlate with cellular respiration provoke oxidative damage in DNA and protein, and cause cell senescence, inflammation, and apoptosis. According to previous studies, PIN 1 increases transcriptional activity of NFκB. Likewise, in oxidative stress, p66shc is phosphorylated by PKC at Ser 36, and then activated by PIN 1. Translocations of p66shc to mitochondria, ROS are increased, and at last cell apoptosis.
In the process of inflammation, NFκB is activated and ROS are increased. Moreover, high levels of ROS inhibit NFκB activity. We investigated that the regulation of ROS to NFκB at high level ROS status in RAW 264.7 cells. Also, PIN 1 involve in NFκB regulation, but whether p66shc involves in the pathway to control NFκB signaling, downstream expression levels of proinflammatory cytokines and inflammatory response. Results suggested that p66shc didn’t regulate NFκB activity and the Ser-specific mutant of p66shc also.
In the otherwise, p66shc and PIN 1 interaction effect is investigated in ROS stimulation for cell apoptosis and senescence. We over-expressed p66shc, p66shc S36 mutant, and PIN 1 in HEK 293 cells, and investigated the status of chromatin condensation percentage. Results suggested, in stimulation of H2O2, p66shc increased apoptosis but not correlated with S36 phosphorylation. Also, PIN 1 promoted cell apoptosis in ROS stimulation through p66shc-dependent pathway. But the regulations were different in cell senescence. We measured cell senescence by SA-β-galactosidase staining. Results suggested that p66shc promoted senescence but not correlates with S36 phosphorylation in stimulation of H2O2. But PIN 1 inhibited senescence. There might have other regulatory mechanism. These results demonstrated that ROS stimulated cell apoptosis and senescence through regulating p66shc interacts with PIN 1. However, the mechanism of ROS-induced interaction between p66shc and PIN 1 is different. In stimulation of H2O2, PIN 1 promoted apoptosis through p66shc-dependent pathway, but PIN 1 inhibited p66shc-activated senescence. That means there have a complicated mechanism which correlated with p66shc and PIN 1 to regulate cell senescence or apoptosis.
PART I
目錄
目錄...............................................................................................................1
中文摘要.......................................................................................................4
英文摘要.......................................................................................................5
縮寫表...........................................................................................................6
壹、 前言
一、 敗血症與發炎反應
1、 敗血症 (Sepsis)..................................................................................7
2、 敗血症的治療.....................................................................................9
二、 敗血症相關訊息路徑
1、 Lipopolysaccharide (LPS) 誘導之發炎反應...................................11
2、 cAMP訊息傳導路徑.......................................................................14
三、 Phosphodiesterase (PDE)
1、 PDE家族..........................................................................................15
2、 PDE抑制劑及其應用......................................................................15
四、 RNA的穩定性
1、 poly A tail和mRNA穩定性...........................................................17
2、 poly A tail 和deadenylase...............................................................18
3、 ARE (Adenosine-uridine-rich element)........................................... 19
4、 AREBP (ARE binding protein) 和mRNA降解.............................20
5、 AREBP調控iNOS ARE-mRNA.....................................................22
五、 K-homology splicing regulator protein / fuse binding protein 2 (KSRP /FBP2)
1、 KSRP.................................................................................................23
2、 KSRP的調控....................................................................................24
?、實驗目的.............................................................................................25
參、實驗材料
一、細胞株.................................................................................................27
二、細胞培養.............................................................................................27
三、藥品來源.............................................................................................27
四、藥品及buffer的配製.........................................................................27
五、抗體.....................................................................................................30
六、Kit........................................................................................................31
肆、實驗方法
一、細胞培養
1、細胞繼代...............................................................................................32
2、細胞冷凍...............................................................................................32
3、細胞解凍...............................................................................................32
4、Seeding .................................................................................................33
二、NO assay
1、NO測定...............................................................................................33
2、細胞存活率測定 (MTS assay)...........................................................34
三、西方墨點法
1、細胞質與細胞核分離..........................................................................35
2、蛋白質定量..........................................................................................36
3、SDS-PAGE(Sodium dodecyl sulfate – polyacrylamide gel electrophoresis)..........................................................................................36
4、西方墨點法 (Western blotting).......................................................... 37
伍、結果
一、非專一性PDE抑制劑IBMX抑制發炎反應................................. 39
二、專一性PDE4抑制劑Rolipram抑制發炎反應.............................. 39
三、IBMX和Rolipram透過PKA的訊息路徑來抑制發炎反應.........40
四、IBMX誘導促進mRNA降解的調控蛋白KSRP表現.................. 41
五、Rolipram誘導促進mRNA降解的調控蛋白KSRP表現..............42
陸、討論................................................................................................... 43
柒、參考文獻............................................................................................45
捌、圖表....................................................................................................50
PART II
目錄

目錄......................................................................................................1
中文摘要..............................................................................................5
英文摘要..............................................................................................7
縮寫表..................................................................................................8
壹、 前言
一、 ROS (Reactive oxygen species)
1. ROS的產生與生理意義................................................................9
2. ROS與細胞凋亡.......................................................................... 11
3. ROS與細胞老化...........................................................................13
4. ROS調控NFκB............................................................................14
二、 p66shc
1. shc (Src homology collagen-like) 家族........................................15
2. p66shc............................................................................................16
3. p66shc在細胞中的分佈...............................................................17
4. p66shc促進ROS及細胞凋亡之機制.........................................18
三、 PIN1 (Protein interacting with NIMA (never in mitosis A) 1)
1. PIN1...............................................................................................19
2. PIN1與p65...................................................................................20
?、實驗目的....................................................................................21
參、實驗材料
1. 細胞株...........................................................................................22
2. 細胞培養.......................................................................................22
3. 酵素...............................................................................................22
4. 試劑...............................................................................................22
5. 引子...............................................................................................23
6. 質體...............................................................................................23
7. Marker........................................................................................... 23
8. Kit...................................................................................................23
肆、實驗方法
一、細胞培養
1. Cell line HEK- 293 細胞繼代 (Subculture)................................ 25
2. 細胞冷凍.......................................................................................25
3. 細胞解凍.......................................................................................26
4. Seeding...........................................................................................26
二、 大量表現p66shc及突變株與其質體建構
1. RNA純化 (RNA extraction)........................................................26
2. 反轉錄反應 (Reverse Transcription, RT)....................................27
3. 聚合?連鎖反應 (Polymerase chain reaction, PCR)...................27
4. 大量表現p66shc及其突變株之質體的建構流程......................28
5. 質體DNA轉染(Transfection)-短暫轉染(transient transfection) 29
6. Luciferase 活性測定......................................................................29
7. 蛋白質定量....................................................................................29
8. Hoechst 33342 stain和數據統計..................................................30
9. SA-β-Galactosidase staining...........................................................30
伍、結果
一、p66shc 抑制NFκB的活性.......................................................32
二、 p66shc Ser 36對NFκB活性的影響.......................................32
三、 p66shc Ser 36對NFκB下游iNOS活性的影響....................33
四、 p66shc促進NFκB的活性與ROS無關.................................33
五、 p66shc促進H2O2誘導之細胞凋亡........................................33
六、 PIN 1與p66shc參與H2O2誘導細胞凋亡之途徑.................34
七、 p66shc參與H2O2誘導細胞老化之途徑................................34
八、 PIN 1參與H2O2誘導細胞老化之途徑..................................35
陸、討論
一、 p66shc對於NFκB的調控................................................... ...36
二、 p66shc 和PIN 1參與ROS誘導之細胞凋亡與細胞老化....37
柒、參考文獻.....................................................................................39
捌、圖表...............................................................................................45
玖、附圖...............................................................................................55
PART I
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