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研究生:陳冠勳
研究生(外文):Kuan-Hsun Chen
論文名稱:探討15-keto-PGE2於人類巨噬細胞中對介白素10的影響
論文名稱(外文):The effects of 15-keto-PGE2 on IL-10 production in human macrophages
指導教授:莊立民莊立民引用關係
指導教授(外文):Lee-Ming Chuang
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:58
中文關鍵詞:第2型糖尿病介白素1015-keto-PGE2巨噬細胞過氧化氫受體γ
外文關鍵詞:15-keto-PGE2Interleukin-10PPARγTHP-1 cellmacrophage
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第2型糖尿病現今已成為威脅全人類健康的一種疾病,目前第2型糖尿病已被廣泛的認為與肥胖所導致的輕微慢性發炎有關,此種發炎的特徵在於脂肪組織中出現大量巨噬細胞及其所分泌的炎症性細胞激素。介白素10是一種多功能性的細胞激素,可借由抑制炎症性的細胞激素來調控免疫及發炎反應,在脂肪組織中的巨噬細胞所釋放的介白素10可結抗發炎反應,並且保護脂肪細胞免於傷害。在本篇研究中,藉由PMA所誘導分化的人類巨噬細胞,吾人發現15-keto-PGE2 可誘使抗發炎的介白素10之生成,但不會誘使發炎反應的細胞激素生成。而15-keto-PGE2主要是藉由PI3K/AKT/GSK-3β的訊息傳遞途徑來誘使介白素10之生成。15-keto-PGE2 可藉由增強轉錄因子CREB及Sp1對於介白素10 promoter的結合能力來調控介白素10,除此之外,15-keto-PGE2 也經由過氧化氫受體γ之途徑來調控介白素10。綜合以上,這些結果開拓了15-keto-PGE2於調控抗發炎上之重要角色,以及增強了前列腺素代謝反應在免疫反應調控上之重要性。
Type 2 diabetes (T2D) mellitus is currently one of the main health treats for humans. It is now broadly accepted that low-grade chronic inflammation associated with obesity leads to the onset of type 2 diabetes. Obesity-associated inflammation is characterized by an increased abundance of macrophages in adipose tissue along with the production of inflammatory cytokines. Interleuikin-10 (IL-10) is a pleiotropic cytokine that mediate immune and inflammatory responses by inhibiting the synthesis of pro-inflammatory cytokines. IL-10 secreted from macrophages in adipose tissue may counteract the inflammatory effects and protect adipose tissue from injuring. In this study, by using PMA-differentiated THP-1 macrophages, we demonstrated that 15-keto-PGE2 could induce the anti-inflammatory cytokine IL-10 production, but not the pro-inflammatory cytokines (TNF-α, IL-6 and IL-12). The capacity of 15-keto-PGE2 to elevate IL-10 expression level was mediated through PI3K/AKT/GSK-3β signaling pathway. 15-keto-PGE regulated IL-10 promoter activation by increasing the binding activities of transcription factors, CREB and Sp1. Furthermore, 15-keto-PGE2 also induced IL-10 production through partial PPARγ-dependent pathway. Taken together, these findings explore the crucial role of 15-keto-PGE2 in anti-inflammatory effect and enforce the importance of PGE2 catabolism in the immune response.
謝誌 I
中文摘要 II
Abstract III
Table of contents IV
Introduction 1
I. Obesity, insulin resistance and Type 2 Diabetes 2
II. Inflammation – linked obesity to Type 2 Diabetes 3
The main origin of the systemic inflammatory response is located in adipose tissue 3
The infiltration of macrophage causes local inflammation in adipose tissue 5
III. Peroxisome proliferator-activated receptors (PPARs) 8
Macrophage PPARγ is a crucial regulator of inflammation and insulin resistance 9
IV. Anti-inflammatory cytokine - Interleukin-10 (IL-10) 11
V. Prostaglandins (PGs) 12
Prostaglandin E2 and its metabolites 13
Materials and methods 15
Reagents 15
Cell culture 15
Prepare whole cell extraction 15
Western blot analysis 16
RNA isolation and Real-Time PCR 17
Enzyme-Linked Immunosorbent Assay (ELISA) 18
Chromatin Immunoprecipitation (ChIP) Assay 18
Statistical Analysis 19
Results 20
PMA induced differentiation of human THP-1 cells 20
15-keto-PGE2 induced the anti-inflammatory cytokine IL-10 mRNA and protein levels in human THP-1 derived macrophages 20
Differential effects of 15-keto-PGE2 and other PPARγ agonists on IL-10 production in human THP-1 cells 21
15-keto-PGE2 stimulated IL-10 expression through PPARγ-dependent pathway 22
The effect of 15-keto-PGE2 on IL-10 production was mediated by PI3K/AKT pathway 22
Role of MAPK family in the 15-keto-PGE2 activated IL-10 production 23
Transcription factors binding to the IL-10 promoter in situ 24
Conclusion and Discussion 26
PPARγ ligands in immune regulation 26
Prostaglandin and its receptor on the cytokine regulation 28
Transcriptional control of IL-10 production 28
Our findings in drug discovery for the Type 2 diabetes mellitus therapy 30
Figures and Tables 31
FIG. 1 Characterization of human THP-1 derived macrophages. 31
FIG. 2 15-keto-PGE2 up-regulates the anti-inflammatory cytokine IL-10, but not pro-inflammatory cytokines in human THP-1 cells. 32
FIG. 3 15-keto-PGE2 induces IL-10 mRNA and protein expression in a dose- and time-dependent manner in human THP-1 derived macrophages. 33
FIG. 4 Effects of different PPARγ agonists on the IL-10 production by THP-1 cells. 34
FIG. 5 Effect of 15-keto-PGE2 on IL-10 production is mediated through PPARγ-dependent pathway. 35
FIG. 6 Effect of 15-keto-PGE2 on IL-10 production is mediated through PI3K/AKT but not PKA signaling pathway. 37
FIG. 7 Role of MAPK family in the 15-keto-PGE2 activated IL-10 production 39
FIG. 8 Activation of CREB and Sp1 binding at the IL-10 promoter by 15-keto-PGE2 in THP-1 derived macrophages. 41
FIG. 9 Proposed model for regulation of IL-10 production by 15-keto-PGE2 42
Supplemental Data 43
Figure S1. Effects of different PPARγ agonists in various dose on the IL-10 production by THP-1 derived macrophages. 43
Figure S2. The expression of PTGR-2 during THP-1 derived macrophage differentiation. 44
Table 1. Nucleotide sequence of the promoter region of hIL-10 gene 45
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