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研究生:曾惠苹
研究生(外文):Hui-Ping Tseng
論文名稱:LPS誘導老鼠巨噬細胞十號介白素基因表現之調控
論文名稱(外文):Regulation of Interleukin-10 Gene Expression by Lipopolysaccharide in RAW264.7 Cells
指導教授:張文昌張文昌引用關係
指導教授(外文):Wen-Chang Chang
學位類別:碩士
校院名稱:國立成功大學
系所名稱:藥理學研究所
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:2002
畢業學年度:90
語文別:中文
論文頁數:84
中文關鍵詞:老鼠巨噬細胞十號介白素酯多糖體
外文關鍵詞:RAW264.7LPSInterleukin-10
相關次數:
  • 被引用被引用:2
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  • 下載下載:112
  • 收藏至我的研究室書目清單書目收藏:0
摘要
十號介白素(Interleukin-10, IL-10)是體內的一種細胞激素,具有抑制發炎反應及細胞免疫反應的功能。它主要是由T細胞、B細胞、單核白血球及巨噬細胞所製造分泌。研究顯示人類IL-10啟動區的基因多型性與一些癌症及嚴重的自體免疫疾病,例如:紅斑性狼瘡,類風濕性關節炎等有密切關係。已有研究報導指出在老鼠巨噬細胞株RAW264.7中,Lipopolysaccharide (LPS)可以透過啟動區上的Sp1 binding site誘導IL-10 基因表現,且LPS處理後並不影響Sp1結合至DNA的能力,因此,我們想要探討LPS是如何透過Sp1來活化IL-10基因表現。首先利用一系列接上不同長度IL-10啟動區的報告基因來分析,藉由分析各段從5’端段切的啟動區,我們發現-122至-66區域及-422至-363區域是LPS誘導IL-10啟動區活性的重要位置。再利用gel shift來確認啟動區蛋白質結合情形,結果顯示Sp1結合至-122/ -49區域及C/EBPβ結合至-422/-363區域。進一步探討LPS是經由哪些訊息傳遞路徑來調控IL-10基因表現,以及MAPK是否參與其中,於是利用藥理性抑制劑觀察細胞處理過後的反應情形。實驗結果得知,個別處理ERK,JNK及p38 MAPK抑制劑U0126,SP600125及SB203580皆能抑制LPS誘導之IL-10蛋白質表現。接著再利用轉染方式將ERK2, JNK及p38的dominant negative mutants (分別為K52R ERK2 , pcDNA3.1-JNK, dn p38) 送入細胞,使其大量表現,結果皆能抑制LPS誘導之IL-10啟動區活性,由此可推論LPS是透過MAPK pathways來調控IL-10基因表現。我們想要進一步探討MAPK下游的轉錄因子,例如:c-Jun、c-Fos、ATF-2、Elk-1等,是否有參與在IL-10基因表現的調控,結果發現LPS可以促進RAW264.7細胞c-Jun表現量增加並呈現dose-dependent現象,且overexpression c-Jun可以促進IL-10啟動區活性表現。而利用不同長度啟動區報告基因來分析c-Jun的作用點,結果顯示是在轉錄啟動點前66 bp即可被c-Jun活化,這段區域並不包含LPS response elements —122/-66 bp及-422/-363 bp,所以c-Jun應該不參與LPS調控IL-10基因表現。綜合以上實驗結果,LPS誘導IL-10基因表現,是透過MAPK pathways與C/EBP b以及Sp1共同調控。
Abstract
Interleukin-10 (IL-10), a pleiotropic cytokine that inhibits inflammatory and cell-mediated immune response, is produced by a variety of cell types including T cells, B cells and monocytes/macrophages. Polymorphisms in human IL-10 promoter have been identified that correlate with the severity of multiple autoimmune disorders such as lupus, rheumatoid arthritis and various cancers. It is reported that lipopolysaccharide (LPS) could induce IL-10 gene expression through Sp1 binding site at IL-10 promoter in mouse macrophage cell line RAW264.7. But this result is not able to completely explain whole mechanism because DNA binding activity of Sp1 was not altered by LPS treatment. In this study, we want to identify the regulation mechanisms involved in LPS-induced expression of IL-10. First, we constructed a series of luciferase vectors bearing various lengths of IL-10 promoter. Analysis of the 5’ deletion mutants revealed that two DNA sequences between —122 to —66 bp and —422 to —363 bp are sufficient for induction of the IL-10 promoter in response to LPS. Gel shift assay was used to identify potential regulators of these LPS response elements. The results showed that Sp1 bound to the promoter region of —122 to —49 bp and C/EBP b bound to —422 to —363 bp. To understand the signal transduction pathway that leads to the promoter activation, we investigated MAPK activations by using their specific inhibitors. Our data demonstrated that ERK, JNK, p38 inhibitors, U0126, SP600125 and SB203580, respectively inhibited LPS-induced protein expression in a dose dependent manner. Overexpression of ERK2, JNK and p38 dominant negative mutants, K52R ERK2, pcDNA3.1-JNK and dn p38 respectively inhibited LPS-induced promoter activity of IL-10 gene. The downstream factor followed by MAPK pathways was then studied. In RAW264.7 cells, LPS induced the expression of c-Jun in a time dependent manner and overexpression of c-Jun increased the activity of IL-10 promoter. To determine the c-Jun response element in the IL-10 promoter, a series promoter constructs were used. A comparison of luciferase activities revealed that c-Jun response element located between positions —66 to +64, and there was no LPS response element residing in this region. This result suggested that the c-Jun was not involved in LPS-induced IL-10 gene expression. Taken together, MAPK signaling pathways and transcription factors Sp1 and C/EBP b may play functional roles in regulation of murine IL-10 gene expression.
目錄
中文摘要…………………………………………………………………….1
英文摘要…………………………………………………………………….3
圖目錄……………………………………………………………………….5
縮寫指引……………………………………………………………………..7
第一章緒論…………………………………………………………………8
第二章實驗材料及方法
來源……………………..…………………………………………………. .11
實驗方法…………………………………………………………………….16
第三章實驗結果
第一節 LPS誘導IL-10 gene表現增加之情形
(一) LPS促使IL-10 mRNA表現增加之情形………………………..……37
(二) LPS促使IL-10 蛋白質表現增加之情形……………………….…….37
第二節 LPS誘導IL-10 啟動區活性增加之情形
(一)LPS對IL-10啟動區5’段段切建構之報告基因的影響………………38
(二)LPS對IL-10啟動區Sp1 site點突變之報告基因的影響…………….39
(三)IL-10啟動區-122 bp至-49 bp的核蛋白結合狀況……………………39
(四)IL-10啟動區-422 bp至-363 bp的核蛋白結合狀況………………….40
(五)LPS對IL-10啟動區C/EBP site點突變之報告基因的影響………….41
(六) LPS對IL-10啟動區C/EBP site及Sp1 site雙突變之報告基因的影響……………………………………………………………………….41
第三節 LPS誘導IL-10 基因表現之訊息傳遞路徑
(一)LPS誘導MAPKs活化之情形…………………………………………42
(二)MEK抑制劑U0126對LPS誘導IL-10表現增加之影響…………….42
(三)JNK抑制劑SP600125對LPS誘導IL-10表現增加之影響…………43
(四)p38抑制劑SB203580對LPS誘導IL-10表現增加之影響………….43
(五)ERK2, JNK及p38的dominant negative mutants對LPS調控
IL-10啟動區活性之影響……………………………………………44
第四節 探討c-Jun在LPS誘導IL-10 基因表現中扮演的角色
(一)LPS活化c-Jun表現情形……………………………………………….45
(二)c-Jun overexpression對IL-10啟動區活性之影響…………………….45
第四章 討論…………………………………………………………...…..46
第五章 參考文獻……………………………………………………...…..51
附圖. ………………………………………………………..………...…..…59
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