臺灣博碩士論文加值系統

排卵乃是生殖過程中極為重要的一環，因此該過程本應受到相當嚴密的調控。卵巢過度刺激症候群之發生則是由於在排卵過程中一些因子的過量產生所導致而成為常見的促性腺激素治療的併發症。由於排卵的過程與發炎反應之相關性，會引起發炎的因子在此病變中可能佔有其重要性。另一卵巢病變，常發生於接近停經年齡或者已停經的婦女身上的卵巢顆粒層細胞癌，有假說提出人類卵巢顆粒層細胞的癌化可能是由於卵巢受到過度刺激所導致。在調控卵巢功能的細胞介素當中，介白素-1b已被指出是許多癌症的重要指標因子且能調控其他促進發炎反應的因子之表現，例如介白素-8以及第二型環氧酵素這兩個在癌症過程中的重要因子，進而影響卵巢功能。另一方面，非固醇類抗發炎藥物例如NS-398，除了已知抗發炎之功能外，也被指出能做為具有潛力的抗癌症治療方式。因此本篇論文在於探討NS-398這個藥物在人類卵巢顆粒層細胞中對於介白素-1所引起介白素-8與第二型環氧酵素之影響。我們發現NS-398不僅沒有抑制介白素-8與第二型環氧酵素之表現量，反而具有促進之效果。而我們也發現NS-398對於介白素-8與第二型環氧酵素蛋白質穩定度並不具任何效果。為了釐清NS-398是透過何種訊息傳遞路徑來進行介白素-8與第二型環氧酵素表現量之調控，我們利用了MAPK，PKA，PKC以及NF-kB 的抑制劑阻斷這些訊息路徑，結果發現MAPK與NF-kB可能是調控路徑，於是我們進一步研究NS-398對於MAPK磷酸化以及NF-kB轉移至細胞核內的影響，根據結果推測NF-kB才是主要之訊息路徑。此外，我們也發現介白素-8對於人類卵巢顆粒層細胞具有促進其增生的效果；而NS-398與介白素-1b的共同刺激能抑制細胞循環中的調控因子p21waf-1/cip-1與p27kip-1之表現量。綜而言之，在人類卵巢顆粒層細胞中，NS-398能夠促進由介白素-1b所引發之介白素-8與第二型環氧酵素之表現，並且可能主要經由NF-kB訊息路徑進行此調控；增加之介白素-8則能促進人類卵巢顆粒層細胞之增生，另外NS-398與介白素-1�猁漲@同刺激可能透過抑制細胞循環中的調控因子p21waf-1/cip-1與p27kip-1之表現量而影響人類卵巢顆粒層細胞之細胞週期。

The process of ovulation is the key event for reproduction and therefore should be well-regulated. Ovarian hyperstimulation syndrome (OHSS), which results from excess production of some factors during ovulation, has been recognized as a dramatic complication of gonodotrophin therapy. Since ovulation has been proposed to be associated with inflammatory responses, inflammatory factors may be implicated in the occurrence of OHSS. In addition, ovarian granulosa cell tumor (GCT) is most commonly found in women between peri- and post-menopausal ages; therefore a hypothesis arises that ovarian hyperstimulation may lead to carcinogenesis of granulosa cells, which are implicated in sex hormone and growth factor production during ovarian development. Among the multiple cytokines that regulate ovarian functions, interleukin (IL)-1b is about the best-known one that have been characterized as an indicator of several cancers and could mediate the expression of other pro-inflammatory factors, such as IL-8 and cyclooxygenase 2 (COX)-2, which in turn participate in the process of ovulation. On the other hand, non-steroidal anti-inflammatory drugs (NSAIDs), for example NS-398, in addition to its traditional anti-inflammatory feature, it has also been proposed as a potential option to retard cancer development. Here we presented that, instead of attenuating the inflammatory response, NS-398 further enhanced IL-1b-induced COX-2 and IL-8 mRNA and protein expression as well as IL-8 secretion in human granulosa KGN cell line. We also examined on whether NS-398 would enhance the protein stability of COX-2 and IL-8 and we found that NS-398 did not have post-translational effect, indicating that NS-398 may act mostly at the transcriptional level. To evaluate what signaling pathways are involved in the enhancement effect by NS-398, we pretreated KGN cells with inhibitors of MAPK (ERK, JNK, p38) as well as NF-kB before the inclusion of IL-1b in the absence or presence of NS-398. Inhibition of MAPKs and NF-kB significantly reduced NS-398-mediated enhancement on IL-1b-induced COX-2 and IL-8 expression. We also found that NS-398 could promote IL-1b-mediated NF-kB p65 translocation from cytosol into nucleus but have no effect on MAPK phosphorylation. These results suggest that NS-398 may augment IL-1b-induced COX-2 and IL-8 expression through NF-kB signal pathways. In addition, IL-8 appeared to increase proliferation of KGN cells according to the alamarBlue assay. NS-398 combined with IL-1b could reduce p21waf-1/cip-1 and p27kip-1 expression, which are regulators of cell cycle. In conclusion, our data identify a novel role of NS-398 that it could amplify IL-1b-induced COX-2 and IL-8 expression possibly through an NF-kB signal pathway; the increase of IL-8 secretion may contribute to proliferation of granulosa tumor cells and NS-398 combined with IL-1b might mediate cell cycle through down-regulating p21waf-1/cip-1 and p27kip-1 expression.

INDEX 1
Abstract 3
中文摘要 6
CHAPTER 1: INTRODUCTION 8
1. INFLAMMATION AND OVARIAN FUNCTIONS 8
2. GRANULOSA CELL TUMOR OVARIAN AND OVARIAN HYPERSTIMULATION SYNDROME 10
3. INTERLEUKIN-1 13
4. INTERLEUKIN-8 15
5. CYCLOOXYGENASE-2 18
6. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) 21
7. OBJECTIVE 24
CHAPTER 2: MATERIALS AND METHODS 26
1. CHEMICALS AND REAGENTS 26
2. CELL CULTURE 27
3. WESTERN BLOT 28
4. PROTEIN STABILITY DETECTION 30
5. REVERSE TRANSCRIPTION PCR 30
6. QUANTITATIVE REAL-TIME PCR 34
7. IL-8 ENZYME LINKED IMMUNOSORBENT ASSAY 36
8. PGE2 ENZYME LINKED IMMUNOSORBENT ASSAY 37
9. CELL PROLIFERATION ASSAY 39
10. EXTRACTION OF NUCLEAR AND CYTOSOLIC PROTEINS 39
11. STATISTICAL ANALYSIS 40
CHAPTER 3: RESULTS 41
1. NS-398 enhanced IL-1b-induced COX-2 and IL-8 expression in human ovarian granulosa cells 41
2. NS-398 increased IL-1b-induced IL-8 secretion in ovarian granulosa cells but effectively inhibited PGE2 production 41
3. NS-398 had no effect on COX-2 and IL-8 protein stability 42
4. NS-398 promoted IL-1b-mediated COX-2 and IL-8 mRNA expression 43
5. NS-398-potentiated IL-1b-mediated COX-2 and IL-8 expression might be through NF-kB signaling pathway 43
6. IL-8 promoted proliferation of ovarian granulosa cells 45
7. IL-1b combined with NS-398 attenuated expression of two cell cycle regulators -- p21waf-1/cip-1 and p27kip-1 45
CHAPTER 4: DISCUSSION 47
CHAPTER 5: REFERENCES 52
FIGURES AND FIGURE LEGENDS 63
Figure 1. Augmentation of IL-1b-induced COX-2 and IL-8 expression by NS-398 in KGN ovarian granulosa cells. 65
Figure 2. Enhancement of IL-1b-induced IL-8 secretion by NS-398. 66
Figure 3. Effective inhibition of PGE2 production by NS-398. 67
Figure 4. No effect of NS-398 on COX-2 and IL-8 protein stability at post-translational stage. 69
Figure 5. Increase of IL-1b-induced COX-2 and IL-8 mRNA expression by NS-398. 73
Figure 6. Attenuation of NS-398-enhanced IL-1b-induced COX-2 and IL-8 expression and secretion by MAPK and NF-kB inhibitors. 76
Figure 7. No involvement of PKA or PKC in NS-398-enhanced IL-1b-induced COX-2 expression. 78
Figure 8. No enhancement on the IL-1b-induced MAPK phosphorylation by NS-398. 81
Figure 9. Promotion of IL-1b-induced NF-kB p65 tranlocation by NS-398. 84
Figure 10. Proliferation of KGN cells induced by IL-8. 86
Figure 11. Decrease of cell cycle regulator p21waf-1/cip-1 and p27kip-1 by combined treatment of IL-1b and NS-398. 88
ACKNOWLEDGEMENT 89

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