腎絲球間質細胞為一群包圍在腎絲球微血管網叢內的特殊細胞群，在正常生理功能中它扮演協助腎絲球調節過濾液平衡，結構上則提供腎絲球體支持以及與其它鄰近細胞交互作用。過去研究指出在慢性腎臟疾病致病進程中，受到許多細胞激素(例如:腫瘤壞死因子;TNF-alpha)刺激之下，腎絲球間質細胞會表現許多發炎相關蛋白以及細胞黏附蛋白分子，而這樣的反應將吸引更多免疫球細胞的黏附、浸潤，進而導致更嚴峻的發炎反應。之前的研究已經證實在慢性腎臟疾病中，腫瘤壞死因子(TNF-alpha)表現量增加，並且進而刺激腎絲球間質細胞表現細胞黏附蛋白分子vascular cell adhesion molecule-1 (VCAM-1)。然而，在TNF-alpha刺激之下表現VCAM-1的訊號傳遞路徑，以及與免疫球細胞的黏附作用之機轉至今仍待進一步研究。在本論文中，針對人類腎絲球間質細胞，探討TNF-alpha如何透過訊號傳遞路徑調控VCAM-1表現。利用西方墨點轉漬法以及RT-PCR分析，我們發現TNF-的確可以誘發VCAM-1蛋白質和mRNA表現，以及活化MAPKs (ERK1/2, p38 MAPK, JNK1/2)與轉錄因子AP-1和NF-kappaB;並且在transactivation路徑中可以活化c-Src, EGFR, PI3K/Akt, PKC, c-Jun的磷酸化，然而當我們前處理上述訊號路徑蛋白激酶的個別藥理性抑制劑，可以發現磷酸化的情形以及VCAM-1的表現都會受到明顯抑制。因此，我們推論TNF-刺激人類腎絲球間質細胞透過活化MAPKs以及EGFR transactivation路徑誘導VCAM-1表現，並且MAPKs(p38 MAPK與JNK1/2)和AP-1的活化作用亦會受到transactivation路徑的調控。另一方面在TNF-的作用之下，透過細胞膜上專一性受體TNFR1，接著活化受體輔助蛋白TRAF2與IKK形成聚合體，之後促進IkappaB分解，進而使得活化態的NF-kappaB進入細胞核中參與VCAM-1基因的調控。同時當細胞轉染(Transfection) p38, JNK2, c-Src, EGFR, Akt, c-Jun, c-Fos以及p65的siRNA後，可以發現個別明顯抑制了TNF-alpha所調控VCAM-1表現。為了進一步探討這樣的調控機轉，我們利用promoter luciferase assay與免疫螢光染色技術，在前處理相關訊號路徑蛋白基酶的藥理性抑制劑後，可以發現分別抑制luciferase activity以及p65轉錄因子進入細胞核。此外透過免疫沉澱法(co-IP)以及染色質免疫沉澱分析(ChIP assay)同步證實，轉錄因子AP-1與NF-B以及p300等，對於TNF-作用之下調控VCAM-1的重要性。
TNF-alpha誘發VCAM-1表現之外，同時也增加單核白血球(monocyte)與腎絲球間質細胞之間黏附作用，而這樣的作用也可以受到anti-VCAM-1、anti-ICAM-1、U0126、SB202190、SP600126、genistein、PP1、AG1478、LY294002、GF109203X、Rottlerin、Tanshinone IIA、Bay11-7082以及GR343等藥理性抑制劑所抑制。根據我們的實驗結果顯示，TNF-誘導人類腎絲球間質細胞表現VCAM-1，過程透過兩個獨立的訊號調控路徑。首先，透過活化c-Src、EGFR transactivation、PI3K/Akt、PKC、JNK和AP-1來達成。除此之外，藉由細胞膜上受體TNFR1及其受體輔助蛋白TRAF2與IKK形成聚合體來活化NF-kappaB路徑。並且轉錄因子AP-1與NF-B都可以和p300交互作用，協同調控VCAM-1表現。本篇論文對於慢性腎臟發炎疾病中，在人類腎絲球間質細胞上，TNF-alpha調控VCAM-1的表現以及單核白血球黏附作用提供了更新且更完整的訊號調控機轉，希望對於腎臟發炎相關致病機轉以及未來臨床治療研究提供參考方向。

Tumor necrosis factor-alpha (TNF-alpha), a potent pro-inflammatory cytokine, is significantly increased in the kidneys with inflammatory renal diseases. TNF-alpha-induced inflammatory response on renal glomerular resident cells, such as mesangial cells, are involved in a range of kidney disorders. Vascular cell adhesion molecule-1 (VCAM-1), which belongs to immunoglobulin superfamily, is one kind of adhesion molecules participating in the process of PMN transmigration. Up-regulation of VCAM-1 expression has been shown in glomerular mesangial cells to pro-inflammatory mediators such as TNF-alpha and IL-1. The expression of VCAM-1 enhances the interaction of PMN with glomerular resident cells, and strongly linked to the severity of kidney inflammatory diseases.
In glomerular resident cells, TNF-alpha can induce expression of adhesion molecules and then attract leukocytes adhesion. However, the mechanisms underlying TNF-alpha-induced VCAM-1 expression in human renal glomerular mesangial cells (HRMCs) remain unclear. Western blot, RT-PCR, and THP-1/monocytes adhesion analyses showed that in HRMCs, TNF-alpha induced VCAM-1 mRNA and protein expression in a time-dependent manner, which were attenuated by the inhibitors of c-Src (PP1), EGF receptor (AG1478), PI3K (LY294002), PKC (GF109203X, Ro31-8220 and rottlerin), MEK1/2 (U0126), p38 MAPK (SB202190) and JNK (SP600125), or transfection with siRNA of c-Src, EGFR, Akt, p38 MAPK, JNK2, c-Jun, c-Fos and p65. These results suggest that c-Src-dependent EGFR transactivation participates in VCAM-1 expression induced by TNF-alpha. Accordingly, TNF--stimulated phosphorylation of p38 MAPK and JNK was inhibited by pretreatment with PP1, AG1478, LY294002, GF109203X, rottlerin, SB202190, or SP600125. TNF-alpha induced VCAM-1 expression was blocked by selective inhibitors of AP-1 (tanshinone IIA) and NF-B (Bay11-7082). Moreover, TNF-alpha-stimulated activation of VCAM-1 promoter activity was blocked by these selective inhibitors.
In this study we investigated the effect of TNF- on expression of VCAM-1 in human renal glomerular mesangial cells. These findings indicated that TNF-alpha induced VCAM-1 expression at the transcriptional and translational levels, which were mediated through two independent pathways. First, TNF-alpha activated c-Src-dependent EGFR transactivation, PI3K/Akt, PKC, JNK, and c-Jun/AP-1 signaling pathways in HRMCs. In addition, TNF-alpha-stimulated TNFR1 induced association of TRAF2, which promoted recruitment with IKK resulting in NF-kappaB activation and VCAM-1 expression. These results provide new insights into the mechanisms of TNF-alpha action which may be therapeutic value in kidney diseases.

目 錄 (Contents)
論文指導教授推薦書. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .i
論文口試委員審定書. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ii
國家圖書館授權書. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .iii
長庚大學博碩士紙本論文著作授權書. . . . . . . . . . . . . . . . . . . . . . . . . .iv
誌謝. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .v縮寫表. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vi抑制劑表. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .viii中文摘要 (Abstract in Chinese）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix英文摘要 (Abstract in English) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi緒論 (Introduction) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Specific aims. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30材料跟方法 (Materials and Methods) . . . . . . . . . . . . . . . . . . . . . . . . . .32實驗結果 (Results) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41

PART I: Involvement of MAPKs and transcription factors (NF-B and
AP-1) in TNF--induced VCAM-1 Expression in Human Renal Mesangial Cells (HRMCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41

PART II: TNF--induced VCAM-1 Expression via c-Src-dependent, EGFR transactivation, PI3K/Akt, PKC linking to AP-1 in Human Renal Mesangial Cells (HRMCs) . . . . . . . . . . . . . . 49

圖表 (Figures and Legends) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .60
討論 (Discussion）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .106
參考文獻 (References) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112

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