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研究生:林晏伃
研究生(外文):Yen-Yu Lin
論文名稱:蛋白磷酸酶2A及蛋白激酶B在卵巢顆粒層細胞中調控蛋白激酶C所誘發的發炎反應
論文名稱(外文):Regulation of PKC-induced inflammation by PP2A and Akt in granulosa cells
指導教授:吳鈺琳
指導教授(外文):Yuh-Lin Wu
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生理學研究所
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:2014
畢業學年度:103
語文別:英文
論文頁數:69
中文關鍵詞:granulosa cellsPKCinflammationPP2AAkt
外文關鍵詞:卵巢顆粒層細胞蛋白激酶C發炎反應蛋白磷酸酶2A蛋白激酶B
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發炎反應在卵巢生理功能中扮演重要的角色,排卵期及黃體裂解過程皆類似發炎的反應。第二型環氧化酵素(COX-2)被廣泛認知為前列腺素E2生成過程中關鍵的速率決定步驟的調控者,能調控卵巢的生理功能,如排卵期及黃體裂解過程, 介白素-8 (IL-8)似乎也參與排卵期的進行。先前研究指出蛋白激酶C (PKC)與發炎反應相關,能促使第二型環氧化酵素及介白素-8的表現增加。蛋白磷酸酶2A (PP2A)為絲胺酸/蘇胺酸磷酸酶,能調節許多細胞功能,許多研究發現蛋白磷酸酶2A的活性可被蛋白激酶C所調控,且蛋白磷酸酶2A能藉由降低NF-B的活性達到調控發炎反應的效果。Akt蛋白激酶為絲胺酸/蘇胺酸激酶,也具有許多調控生物機能的功能。近期許多研究深入探討蛋白激酶C對於PI3K/Akt路徑的活化或者抑制的所扮演的角色,甚至發現到蛋白激酶C能藉由活化蛋白磷酸酶2A來調控PI3K/Akt路徑。然而,蛋白磷酸酶2A及PI3K/Akt路徑在顆粒細胞中對於發炎反應的影響尚未釐清。因此本研究目的為利用蛋白激酶C的促效劑 (PMA)、蛋白磷酸酶2A的抑制劑(okadaic acid)及PI3K的抑制劑(wortmannin)探討在人類及老鼠顆粒細胞中,蛋白磷酸酶2A及Akt是否會影響蛋白激酶C所誘發的發炎反應,並了解其中參與的機制。首先,在人類顆粒細胞株 (KGN細胞株)中,我們發現蛋白激酶C會抑制Akt的磷酸化,進一步探討PI3K/Akt路徑是否參與在蛋白激酶C所誘發的第二型環氧化酵素及介白素-8的表現當中,我們使用PI3K的抑制劑,結果發現加入PI3K的抑制劑後能顯著增加蛋白激酶C所誘發的第二型環氧化酵素和介白素-8的蛋白表現及介白素-8和前列腺素E2的分泌,為了確認Akt的功能,我們使用Akt活化劑(SC79),觀察到加入Akt活化劑後能夠減少蛋白激酶C所誘發的第二型環氧化酵素的表現。然而,給予蛋白磷酸酶2A的抑制劑對於白激酶C所誘發的第二型環氧化酵素的表現並無影響。另外,我們也測試了另一種磷酸酶 (絲裂原活化蛋白激酶;MKP-1),絲裂原活化蛋白激酶同樣對於蛋白激酶C所誘發的第二型環氧化酵素的表現沒有效果。另一方面,我們也想檢測PI3K/Akt路徑及蛋白磷酸酶2A在老鼠顆粒細胞中所扮演的角色。出人意料地,蛋白激酶C會活化Akt的磷酸化,而且,藉由使用PI3K抑制劑及活化劑,我們觀察到加入PI3K抑制劑後對於蛋白激酶C所誘發的第二型環氧化酵素的表現具有抑制的效果,然而給予Akt活化劑則會有促進的現象。接著,我們同樣探討蛋白磷酸酶2A在老鼠顆粒細胞中對於蛋白激酶C所誘發的第二型環氧化酵素中所扮演的角色,發現給予蛋白磷酸酶2A抑制劑後能夠更進一步促進蛋白激酶C所誘發的第二型環氧化酵素的表現及前列腺素E2的分泌。藉由即時定量聚合酶反應法,蛋白磷酸酶2A抑制劑也能夠增加蛋白激酶C所誘發的第二型環氧化酵素核醣核酸(mRNA)的表現。最後,利用免疫螢光法,觀察到加入蛋白磷酸酶2A抑制劑似乎能促進NF-B的轉位(translocation)。因此,我們目前的結果觀察到在人類顆粒細胞株中,PI3K/Akt路徑會抑制蛋白激酶C所誘發的第二型環氧化酵素的表現,但蛋白磷酸酶2A則沒有效果;然而,在老鼠顆粒細胞中顯示PI3K/Akt路徑會促進而蛋白磷酸酶2A則會抑制蛋白激酶C所誘發的第二型環氧化酵素的表現。根據我們的研究,蛋白磷酸酶2A還有可能是透過NF-B來作用,而這也是我們目前仍然在探討的機制。
In the ovary, inflammation plays a critical role to regulate various ovarian functions, including ovulation and luteolysis. Ovulation and luteolysis appear as a confined inflammatory reaction. It has been well-recognized that cyclooxygenase 2 (COX-2), a key rate-limiting regulator in the biosynthesis of prostaglandin E2 (PGE2), is able to regulate ovarian physiological processes such as ovulation and luteolysis; interleukin-8 (IL-8) seems to be involved in ovulation. Previous studies have reported that protein kinase C (PKC) signaling, which is known to be related to inflammation, could induce COX-2 and IL-8 expression. Protein phosphatase 2A (PP2A), a family of serine/threonine phosphatases, regulates many cellular functions. Lots of evidences have implicated that PP2A activity could be regulated by PKC and it may down-regulate the NF-B activity to modulate the inflammation. Akt, a serine/threonine kinase has also been widely implicated in many diverse biological processes. Substantial studies have explored the effect of PKC on PI3K/Akt signaling pathway to activate or inhibit PI3K/Akt cascade and PKC could even regulate PI3K/Akt by activating PP2A. However, the role of PP2A and PI3K/Akt signaling pathway in the inflammatory cascade in granulosa cells remains mostly unclear. Thus, the aim of this study was to clarify whether and how PP2A and PI3K/Akt signaling pathway may affect PKC-induced inflammation in human and rat granulosa cells by using PKC activator phorbol 12-myristate 13-acetate (PMA), PP2A inhibitor okadaic acid and PI3K inhibitor wortmannin. First, in KGN human granulosa cells, we found that PMA could inhibit Akt phosphorylation. In order to determine PI3K/Akt signaling pathway involved in PMA-induced COX-2 and IL-8 expression, we used PI3K inhibitor and discovered that wortmannin could significantly enhance PMA-induced COX-2 and IL-8 expression as well as PGE2 and IL-8 secretion. In addition, by using Akt activator SC79, we also observed that SC79 could attenuate PMA-induced COX-2 expression. However, okadaic acid had no effect on PMA-induced COX-2 expression. We also monitored another phosphatase, MAPK phosphatase-1 (MKP-1) and MKP-1 did not affect PMA-induced COX-2 expression. On the other hand, we also endeavored to examine the role of PI3K/Akt signaling pathway and PP2A in rat granulosa cells. Surprisingly, PMA could activate Akt phosphorylation. In addition, by using wortmannin and SC79, we noted a suppression effect of wortmannin and an enhancement effect of SC79 on PMA-induced COX-2 expression. We also found that okadaic acid could further enhance PMA-induced COX-2 expression and PGE2 secretion. With real-time PCR, we revealed that okadaic acid could increase PMA-induced COX-2 mRNA expression. However, PMA had no effect on PP2A phosphorylation. At last, with immunofluorescence, we observed that okadaic acid seems to enhance PMA-induced NF-B translocation. Thus, our current findings suggest that PI3K/Akt signaling pathway appears to inhibit PKC-induced COX-2 expression in KGN human granulosa cells but PP2A had no effect; while PI3K/Akt signaling pathway seems to enhance but PP2A is able to attenuate the PKC-induced COX-2 expression in rat granulosa cells. We are currently on the way to clarify the regulation manners of NF-B by PP2A in relation to COX-2 expression.
Acknowledgement ……………………………………………………………………i
Abstract……………………………………………………………………iii
中文摘要……………………………………………………………………v
Index ……………………………………………………………………vii
Chapter 1. Introduction………………………………………………………………1
1-1. Hormones and ovarian functions…………………………………………1
1-2. Inflammation and ovarian physiology……………………………1
1-3. Cyclooxygenase (COX)-2 in ovarian physiology…………2
1-4. Protein Kinase C (PKC) signaling pathway in ovarian physiology………3
1-5. Significance of protein phosphatase 2A (PP2A) in inflammation………4
1-6. Significance of MAPK phosphatase-1 (MKP-1) in inflammation……………5
1-7. Significance of PI3K/Akt pathway in inflammation…………………6
1-8. Objectives………………………………………………………………7
Chapter 2. Materials and methods……………………………………………………9
2-1. Chemicals and reagents…………………………………………………………………9
2-2. Cell culture…………………………………………………………………11
2-3. Rat granulosa cell collection………………………………………12
2-4. Preparation of the whole cell lysates and western blotting ………………………………………………………………12
2-5. Measurement of PGE2 and IL-8 by enzyme-linked immunosorbent assay (ELISA) ………………………………………………………………14
2-6. Real-time PCR……………………………………………………………14
2-7. Determination of cell viability………………………………………16
2-8. Immunofluorenscence………………………………………………………17
2-9. Evaluation of COX2 promoter activity ………………………17
2-10. Statistical analysis………………………………………………………………18
Chapter 3. Results…………………………………………………………………19
3-1. Up-regulation of PKC-induced COX-2 and IL-8 protein expression, PGE2 and IL-8 secretion by PI3K inhibitor wortmannin in KGN human ovarian granulosa cells…………………………………………………………19
3-2. Inhibition of PMA-induced COX-2 expression by Akt activator (SC79) in KGN human ovarian granulosa cells ……………………………………20
3-3. Cytotoxic effect of Akt activator SC79 and PI3K inhibitor wortmannin in KGN human ovarian granulosa cells ……………………………………20
3-4. The significance of PP2A in PKC-induced COX-2 expression in KGN human ovarian granulosa cells …………20
3-5. Inhibitory effect of PI3K inhibitor (wortmannin) and up-regulatory effect of Akt activator (SC79) on PMA-induced COX-2 expression in rat granulosa cells……………………21
3-6. No effect of MKP-1 on PKC-induced COX-2 expression and PGE2 secretion in rat granulosa cells ……22
3-7. Up-regulatory effect of PP2A inhibitor okadaic acid on PMA-induced COX-2 expression in rat granulosa cells ………………………………23
3-8. Up-regulation effect of PP2A inhibitor okadaic acid on PMA-induced COX-2 mRNA expression in rat granulosa cells………………………23
3-9. Inhibition of PKC-mediated COX-2 expression by PP2A activation in rat granulosa cells…………………………………………24
3-10. Inhibition of PKC-induced COX-2 promoter activity by PP2A activation in rat granulosa cells……………24
3-11. No effect of PKC activation on PP2A phosphorylation in rat granulosa cells……………………………………24
3-12. Up-regulation effect of PP2A inhibitor on PMA-induced NF-B nuclear translocation in rat granulosa cells……………………………25
3-13. Further decrease of PP2A activation-reduced PKC-modulated COX-2 expression by Akt activation and inhibitory effect of Akt inhibition on PP2A inhibition-induced PKC-modulated COX-2 expression in rat granulosa cells……………………………25
Chapter 4. Discussion………………………………………………………………27
Chapter 5. References………………………………………………………………32
Figures and figure legends…………………………………………………………42
Figure 1. Up-regulation of COX-2 protein expression by hCG, FSH and PKC activator PMA in human and rat granulosa cells…………………………………………………………44
Figure 2. COX2 up-regulation via PKC cascade by PMA…… 45
Figure 3. Inhibition of Akt phosphorylation by PMA in human granulosa cells……………………………………………………………46
Figure 4. Up-regulation of PMA-mediated COX-2 and IL-8 protein expression, PGE2 and IL-8 secretion by PI3K inhibition in human granulosa cells…………………………………………………48
Figure 5. Inhibition of PMA-induced COX-2 expression by Akt activation in human granulosa cells…………………………………………49
Figure 6. Cytotoxic effect of Akt activator SC79 and PI3K inhibitor wortmannin in human granulosa cells………………………………………………………………51
Figure 7. Significance of MKP-1 and PP2A in PKC-induced COX-2 expression in human granulosa cells………………………………53
Figure 8. Up-regulation of Akt phosphorylation by PMA in rat granulosa cells………………………………………………………………54
Figure 9. Inhibition of PMA-induced COX-2 expression by PI3K inhibition in rat granulosa cells. ……………………………………55
Figure 10. Up-regulation of PMA-mediated COX-2 expression by Akt activation in rat graulosa cells……………56
Figure 11. No effect of MKP-1 on PKC-induced COX-2 expression and PGE2 secretion in rat granulosa cells………58
Figure 12. Up-regulation effect of PP2A inhibition on PMA-induced COX-2 expression and PGE2 secretion in rat granulosa cells……………60
Figure 13. Up-regulation effect of PP2A inhibition on PMA-induced COX-2 mRNA expression in rat granulosa cells………………………61
Figure 14. Up-regulation of PKC-induced COX-2 promoter activity by PP2A inhibition in rat granulosa cells……………62
Figure 15. Inhibition of PKC-mediated COX-2 expression by PP2A activation in rat granulosa cells……………………………………………………………63
Figure 16. Inhibition of PKC-induced COX-2 promoter activity by PP2A activation in rat granulosa cells ………64
Figure 17. No effect of PKC activation on PP2A phosphorylation in rat granulosa cells…………………………65
Figure 18. Up-regulation effect of PP2A inhibition on PMA-induced NF-B nuclear translocation in rat granulosa cells ………………………………………………………67
Figure 19. Further decrease of PP2A activation-reduced PKC-modulated COX-2 expression by Akt activation and inhibitory effect of Akt inhibition on PP2A inhibition-induced PKC-modulated COX-2 expression in rat granulosa cells……………………………………………………………68
Figure 20. Working model of the roles of PP2A and Akt in PKC-mediated inflammation of human and rat granulosa cells ……………………………………69
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