臺灣博碩士論文加值系統

水解磷酸脂 Lysophosphotidic Acid (LPA)與 Sphingosine 1-Phsophate (S1P)均為低分子量之水解磷酸脂(Lysophospholipids)，藉由活化Edg (endothelial differentiation gene)族受器進而調控各種細胞生理活性，其中包括發炎反應的調控。於本研究第一部份中發現S1P或LPA於內皮細胞中各別調控之ICAM-1 mRNA的表現，與之後的單核球與內皮細胞層黏著現象，分別經由S1P1或LPA1受器作用。另一方面，S1P或LPA於內皮細胞中調控之IL-8與MCP-1的mRNA表現，與之後的單核球趨化至內皮細胞層之現象，是經由活化S1P1、S1P3或LPA1、LPA3受器。此外，LPA與S1P同時能夠刺激IL-1b於內皮細胞中的表現，並且有著時間依賴性的現象。藉由前處理IL-1受器抑制劑或是IL-1b中和抗體均能夠明顯的抑制LPA與S1P於內皮細胞中對IL-8與MCP-1的提昇效果。這些結果證實了LPA與S1P於內皮細胞中對於IL-8與MCP-1 mRNA表現的提昇效果至少必須仲介IL-1的表現。此外，在我們先前的研究中發現到LPA1基因剔除斑馬魚胚胎中，淋巴系統之生成受到明顯的影響，進一步的推測LPA很有可能是一種淋巴血管形成因子。我們在本研究中發現到LPA是經由COX-2的活化提昇內皮細胞表現VEGF-C，進而調控在體內或體外形成的管狀構造。此外，這些管狀構造物呈現出淋巴管特異抗原表達。而且，這些淋巴管構造之形成是經由LPA1與LPA3受器活化所達成。結果亦顯示此一調控現象是經由EGFR-transactivation機制所仲介。此外，本研究中也發現S1P能夠提昇TIMP-2及TIMP-3 mRNA之表達而LPA與S1P同時能夠提昇MT1-MMP蛋白質在內皮細胞中的表現量與活性之上升。總而言之，第一部分的研究成果能夠提供我們許多針對發炎反應與動脈硬化症治療新藥的開發，第二部份的成果則是首次提出LPA可能是淋巴血管增生因子，期待做為未來之抗癌症轉移治療提供相關之基礎知識。

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are both low-molecular-weight lysophospholipid (LPL) ligands which are recognized by the endothelial differentiation gene (Edg) family of G protein-coupled receptors. In this study, I demonstrated that the enhancement effects of S1P on intercellular adhesion molecule (ICAM)-1 mRNA, total protein and cell surface expression in human umbilical vein endothelial cells (HUVECs) are mediated through the activation of S1P1. On the other hand, the S1P-dependnet increase in increased interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1 mRNA expression in HUVECs which were mediated by both S1P1 and S1P3. Moreover, S1P1 expressed on endothelial cells mediates the positive regulation of monocytes adhesion and chemotaxis toward the endothelium, whereas S1P3 is only critical the chemoattraction of monocytes by endothelial cells. These findings suggest that S1P1 and S1P3 might be essential receptors for S1P in modulating monocyte-endothelial cell interactions. Furthermore, LPA1 might mediate the enhancement effects of LPA on ICAM-1 mRNA expression and subsequent monocyte/endothelium adhesion. In addition, both LPA1 and LPA3 mediated LPA-enhanced IL-8 and MCP-1 mRNA expression and the subsequent chemoattraction of monocytes toward the endothelium. My study also demonstrated that LPLs increase IL-1 mRNA expression in HUVECs, and the enhancement effects of LPLs on IL-8 and MCP-1 mRNA expressions were at least partially mediated by IL-1. We observed that the knocking-down of LPA1 in zebrafish embyo profoundly affected the lymphatic vessel formation. In the third part of the thesis, results implied that LPA might regulate the lymphangiogenesis process. My data demonstrated that LPA might participate in the regulation of the lymphangiogenesis process. I demonstrated that LPA enhanced vascular endothelial growth factor (VEGF)-C mRNA expression through a cyclooxygenase (COX)-2-dependent mechanism, thereby inducing the endothelial cell tube formation both in vitro and in vivo. This induction of tube formation was possibly stained with the lymphatic vessel marker, prospero-related homeobox gene (prox)-1. LPA1 and LPA3 are required for LPA-induced HUVECs tube formation in vitro, whereas LPA3 mediated mouse endothelial cells tube formation in vivo. These enhancement effects were EGFR transactivation-dependent. Finally, S1P upregulated tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3 mRNA expression and both LPA and S1P stimulated elevations of mt-1-matrix metalloproteinase (MT1-MMP) protein expression and activity elevation in HUVECs in dose- and time-dependent manners, which modulate leukocytes-endothelial cell’s extracellular matrix attachment and subsequent angiogenesis processes. The first half of this thesis provides valid information for possibly developing new therapeutic drugs against LPLs receptors to control the inflammation process and therefore atherosclerosis formation. The second half of study first reports that LPA might be a pro-lymphangiogenic factor, which may provide information for therapeutics against tumor metastasis.

口試委員會審定書……………………………………….……………………………i
謝辭………………………………...………………………………………………….ii
中文摘要………………………….…………………………………………………..iii
Abstract…………………..……….…………………………………………………..v
Overview of the present study………………………………….………..….…...…..1
Chapter 1: Introduction to Lysophospholipids……………………..………….…..6
1.1 Introduction of Lysophospholipids……………………………….………..7
1.2 Metabolism of LPA and S1P………………………………….……….…..9
1.3 LPLs and G-protein coupled receptors…………………………………..13
1.4 Other Non-GPCR Lysophospholipid Receptors…………………………..15
1.5 Expression and distribution of LPA and S1P receptors…………………...16
1.6 LPLs and Inflammation………………………………….………………..20
1.7 LPLs regulate Angiogenesis and Cardiovascular Development………….26
1.8 The specific aims of present study………………………………………..31
Chapter 2: Expression and Function of the Lysophospholipid Receptors in Human Endothelial Cells and the Regulation of Inflammation-Related Genes...34
2.1 Functions of LPA and S1P receptors.……………………………..……..35
2.2 S1P-induced ICAM-1 mRNA expression is mediated through S1P1, while IL-8 and MCP-1 mRNA expression is mediated through S1P1 and S1P3 in HUVECs…………………………………………………………………………37
2.3 S1P-enhanced adhesive properties of HUVECs toward U937 cells is mediated through S1P1…………………………………….…………………..…39
2.4 S1P-enhanced chemotactic activity of HUVECs toward U937 cells is mediated through S1P1 and S1P3…………………………….…………………..40
2.5 LPA-induced ICAM-1 mRNA expression is mediated through LPA1, while IL-8 and MCP-1 mRNA expression is mediated through LPA1 and LPA3 in HUVECs……………………………………………………………………....…41
2.6 LPA-enhanced adhesive properties of HUVECs toward U937 cells is mediated through LPA1………………………………………………………..…42
2.7 LPA-enhanced chemotactic activity of HUVECs toward U937 cells is mediated through LPA1 and LPA3……….…………………………....………….43
2.8 S1P1 and S1P3 might be key targets for anti-inflammation drug discover...44
2.9 LPA1 and LPA3 might be key targets for anti-inflammation drug discovery…………………………………………………………………………47
2.10 The role of S1P1/S1P3 and LPA1/LPA3 on S1P- and LPA-regulated inflammation-related gene expression in human endothelial cells…………...….49
Chapter 3: Lysophospholipids increase IL-8 and MCP-1 expressions in human umbilical cord vein endothelial cells through an IL-1-dependent mechanism….59
3.1 Role of IL-1 in human endothelial cells……………………………....….60
3.2 IL-1 regulates IL-8 and MCP-1 expression………………………….....….61
3.3 IL-1 mediates LPL-induced IL-8 and MCP-1 mRNA expressions...…….62
3.4 Lysophospholipids increase IL-8 and MCP-1 expressions in human umbilical cord vein endothelial cells through an IL-1-dependent mechanism....63
Chapter 4: LPA induces human endothelial cells to participate in lymphangiogenesis through upregulating VEGF-C expression....……………….70
4.1 Introduction to lymphangiogenesis…………………………………..….71
4.2 Lymphangiogenic factors and Lymphangiogenesis……………....……….71
4.3 LPA and VEGF-C………………………………………………..……..….75
4.4 Specific lymphatic markers…………………………………...………..….76
4.5 LPA and S1P enhance VEGF-C mRNA expression in HUVECs.…….….79
4.6 LPA-induced VEGF-C mRNA expression is mediated through LPA1 and LPA3 in HUVECs………………………………………….………..…………..80
4.7 Blocker of NF-kB, LPA1/LPA3 majorly and COX-2 partially, but not COX-1 suppressed LPA-enhanced VEGF-C mRNA expression in HUVECs....81
4.8 LPA induces lymphatic vessel formation in vitro and in vivo…………....82
4.9 LPA-induced HUVECs tube formation in vitro is mediated through LPA1 and LPA3…………………………………………...…………..…….…………..83
4.10 LPA-induced mouse endothelial cell tube formation in vivo is mediated through LPA1 and LPA3………………………………………………………..83
4.11 LPA and EGFR transactivation…..………………………………………..85
4.12 LPA induces EGFR transactivation in HUVECs in a time-dependent manner……………………………………………………………………………88
4.13 LPA induces EGFR transactivation in HUVECs in a MMP-dependent manner……………………………………………………………………………89
4.14 LPA-induced HUVECs proliferation is mediated through EGFR transactivation..…………………………………………………………...…….. 89
4.15 LPA-induced HUVECs tube formation in vitro is mediated through EGFR transactivation………………………………………………………...……..….. 90
4.16 LPA induces VEGF-C mRNA expression in HUVECs through an EGFR transactivation-depended manner……………………………...…….……...….. 93
4.17 LPA induces VEGF-C mRNA in an EGFR transactivation-depended manner, which contributes to human endothelial cell to participates in lymangiogeneisis process………………………………………………………...……..………….. 94
4.18 Lysophospholipids and MMPs………………………….....………….….. 95
4.19 LPA and S1P enhance MT1-MMP protein expressions in HUVECs…….….................................................................................................. 97
4.20 LPA and S1P enhance MT1-MMP enzymatic activity in HUVECs………99
4.21 S1P enhances TIMP-2 and TIMP-3 mRNA levels in HUVECs…….…. 100
4.22 Lysophospholipids regulate the expression level and activity balance of MMP-2/MT1-MMP/TIMP-2 that modulating the formation and degradation of endothelium ECM in inflammation, thus facilitating inflammation and angiogenesis progression……………………………………………...….….. 101
General Discussion……………………………...…………………………...130
Materials and Methods……………………………...………………………151
References………………………………………………………….…………….162

Figures
Fig. 1……………….…………………………………………………………………33
Fig. 2……………….…………………………………………………………………50
Fig. 3……………….…………………………………………………………………51
Fig. 4……………….…………………………………………………………………52
Fig. 5……………….…………………………………………………………………53
Fig. 6……………….…………………………………………………………………54
Fig. 7……………….…………………………………………………………………55
Fig. 8……………….…………………………………………………………………56
Fig. 9……………….…………………………………………………………………57
Fig. 10………………...………………………………………………………………58
Fig. 11……………….…………..……………………………………………………66
Fig. 12……………….…………………..……………………………………………67
Fig. 13…………..….…………………………………………………………………69
Fig. 14……....……….………………………………………………………………104
Fig. 15…………….……………………………………………....…………………105
Fig. 16…………….…………………………………………………………………106
Fig. 17…………….……....…………………………………………………………107
Fig. 18…………….…………………………………………………………………108
Fig. 19…………….…………………………………………………………………109
Fig. 20…………….…………………………………………………………………110
Fig. 21……………….………………………………………………………………111
Fig. 22…………….…………………………………………………………………112
Fig. 23…………….…………………………………………………………………113
Fig. 24…………….…………………………………………………………………114
Fig. 25…………….…………………………………………………………………115
Fig. 26…………….…………………………………………………………………116
Fig. 27…………….…………………………………………………………………117
Fig. 28…………….…………………………………………………………………119
Fig. 29…………….…………………………………………………………………120
Fig. 30…………….…………………………………………………………………121
Fig. 31……………….………………………………………………………………122
Fig. 32……………….………………………………………………………………123
Fig. 33…………….…………………………………………………………………124
Fig. 34…………….…………………………………………………………………126
Fig. 35…………….…………………………………………………………………127
Fig. 36……………….………………………………………………………………128
Fig. 37…………….…………………………………………………………………129
Fig. 38…………….…………………………………………………………………149

Tables
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