臺灣博碩士論文加值系統

在醫療用藥開發上，調控免疫和發炎相關藥物的篩選是十分重要的。在已知的轉錄因子中，NF-IL6和NF-kappaB在免疫發炎反應、細胞增生、分化、癌化……等生理過程中扮演了關鍵性的角色，著眼於這些生理反應的重要性，我們建立了以NF-IL6和NF-kappaB這兩個轉錄因子為導向的藥物篩檢系統，應用於找尋中草藥內可以調控免疫發炎反應的有效成分。在系統建構上，我們已經成功的挑選出能穩定保有NF-IL6和NF-kappaB蟲螢光酵素報導基因的小鼠巨噬細胞株(RAW264.7)，來應用於中草藥活性物質的篩選。在實驗的過程中，我們發現到穀精草的正丁醇萃取物能有效的刺激巨噬細胞株中NF-IL6和NF-kappaB的活化。另一方面，之前實驗室發現在人類腎臟上皮細胞株(HEK293)中前列腺素E1 (PGE1)可以造成NF-IL6的活化，為了瞭解此一現象的生理意義及分子調控機轉，我們設計了一系列的實驗來研究，發現到前列腺素E1活化NF-IL6的過程可能經由PKA的調控而不是讓NF-IL6本身蛋白質表現量增加或是促使NF-IL6轉進細胞核這類的動作來調控。除此之外，PGE1還可能會透過NF-IL6來造成IL-6 mRNA轉錄程度的增加。

The screening for drugs in regulating the host immune and inflammatory response is important for the therapeutical purpose. Among the known transcription factors, NF-IL6 and NF-kappaBplay pivotal roles in various physiological events such as the inflammatory response, immunity, differentiation, proliferation, tumorgenesis, and numerous other cellular responses. Hence, NF-IL6- and NF-kappaB-based drug screening systems were constructed in our laboratory for the screening of lead components from Chinese herbs for the regulation of immune and inflammatory responses. The p3X-NIL-Lucneo or p4X-NkB-Lucneo stably transfected RAW264.7 cell clones were generated and used for screening of corresponding agonists from various traditional Chinese herbs. We found that the n-butanol layer of Gu Jing Cao could significantly induce the luciferase activity of RAWNFkB cells as well as RAWNFIL6 cells compared with that of untreated cells. In previous studies, we have demonstrated that PGE1 could mediate NF-IL6 activation in HEK293 cells. In this study, we further demonstrate that PGE1-mediated NF-IL6 activation in HEK293 might be controlled by a PKA-dependent manner. The induction of luciferase activity in HEK293 cells was not dependent on the NF-IL6 gene expression or nuclear translocation. Interestingly, the IL-6 mRNA was increased after treatment of PGE1 possibly via the activation of NF-IL6.

中文摘要 1
ABSTRACT 2
CONTENT 3
TABLE CONTENT 6
FIGURE CONTENT 7
APPENDIX CONTENT 8
I. INTRODUCTION 9
PART I: CONSTRUCTION OF A TF-BASED DRUG SCREENING SYSTEM 9
ABOUT THE DRUG SCREENING SYSTEM 10
Drug screening based on regulation of transcription 10
Transcription factors control transcription process 11
The application of reporter genes on TF-based screening system 11
Molecular targets on TF-based screening system 12
USING NF-IL6 AND NF-kB AS DRUG SCREENING TARGET 15
Pivotal roles of NF-IL6 and NF-kB in physiology 15
NUCLEAR FACTOR OF INTERLEUKIN-6 (NF-IL6) 15
The structure features of NF-IL6 and other C/EBP family members 16
The physiological function of NF-IL6 16
The regulation of NF-IL6 18
NUCLEAR FACTOR OF KAPPA B (NF-kB) 20
The structure features of NF-kB family 21
The physiological functions of NF-kB 22
The signal transduction leading to NF-kB activation 23
Roles of NF-IL6 and NF-kB in host immune response 24
THE STRATEGY OF DRUG SCREENING 25
Screening on the treasure of traditional Chinese medicine 26
Clinical application of compounds isolated from Chinese herbs 27
PARTⅡ: THE MOLECULAR MECHANISM OF PROSTAGLANDIN E1 -MEDIATED NF-IL6 ACTIVATION 29
THE PROPERTIES OF PROSTAGLANDINS 29
The biochemical properties and biosynthesis of prostaglandins 29
The physiological function of prostaglandins 31
The signal transduction underlying prostaglandin-mediated process 35
Preliminary results of constructed NF-IL6-based drug screening system 39
MATERIALS AND METHODS 41
PART I: MATERIALS 41
1. CELL LINES 41
2. REAGENTS 41
3. EQUIPMENTS 42
4. PRIMERS 42
5. PLASMIDS AND VECTOR 42
PART II: METHODS 43
1. CELL CULTURE 43
2. TRANSFECTION 44
3. ELECTROPORATION 44
4. SELECTION OF STABLY TRANSFECTED CELLS 45
5. DRUG TREATMENT 46
6. LUCIFERASE ASSAY 47
7. WESTERN BLOTTING 48
8. FLUORESCENCE IMMUNOSTAINNING 49
9. SUBCELLULAR FRACTIONATION 50
10. SEMI-QUANTITIVE RT-PCR 51
11. SITE-DIRECTED MUTAGENESIS 52
12. AUTO-SEQUENCING 53
13. CONSTRUCION OF PHOSPHORYLATION-SITE MUTANTS 53
Ⅲ.RESULT 54
PART I: CONSTRUCTION OF A TF-BASED DRUG SCREENING SYSTEM 54
1. NF-IL6 BASED DRUG SCREENING SYSTEM IN RAW264.7 54
The induction of NF-IL6 by other stimulants 55
The effect of traditional Chinese herbs on the activation of NF-IL6 56
2. NF-kB BASED DRUG SCREENING SYSTEM IN RAW264.7 57
The responses to traditional Chinese herbs 57
PARTⅡ: THE MOLECULAR MECHANISM OF PGE1-MEDIATED NF-IL6 ACTIVATION 59
The up-regulation of NF-IL6 activtiy by PGE1 59
PGE1 does not change the protein level of NF-IL6 59
PKA may involve in the pathway of PGE1-mediated NF-IL6 activation 60
PGE1 did not induce nuclear localization of NF-IL6 61
Activated NF-IL6 may regulate its downstream gene, IL-6 62
IV. DISCUSSION 63
PART I: CONSTRUCTION OF A TF-BASED DRUG SCREENING SYSTEM 63
Staurosporine may mediate physiological and pharmaceutical function through NF-IL6 63
The role of NF-kB and NF-IL6 in LPS-induced inflammatory responses 64
Future developments and applications on these drug screening systems 65
PARTⅡ: THE MOLECULAR MECHANISM OF PGE1-MEDIATED NF-IL6 ACTIVATION 67
Does NF-IL6 really mediate IL-6 gene expression? 67
What’s the receptor of PGE1? 68
Further finding of PGE1-mediated kinase phosphorylation site on NF-IL6 69
PGE1-mediaed NF-IL6 activation may play an important role in chronic inflammation 69
V. REFERENCE 71

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