臺灣博碩士論文加值系統

由於活化內皮細胞中的P2Y受體可釋放出血管放鬆因子，來調控血管平滑肌的作用，促使我們有興趣探討內皮細胞表現何種P2Y受體。因此，我們利用牛肺動脈內皮細胞(CPAE)當做實驗模式，分成四個部分詳加研究。一、牛肺動脈內皮細胞P2Y1和P2Y2受體訊息傳遞之研究。二、P2受體拮抗劑及作用劑對ecto-ATPase活性之影響。三、P2Y受體活化內皮細胞cPLA2訊息傳遞機轉之研究。四、蛋白激C調節內皮細胞P2Y受體活化磷脂C作用機轉之研究。
在CPAE中，共同存在著P2Y1和P2Y2受體，2MeSATP和UTP分別作用在P2Y1和P2Y2受體促進PI水解，使細胞內鈣離子濃度( [Ca2+]i )增加。2MeSATP或UTP具有相加成的作用，而ATP對2MeSATP和UTP二者並不具有相加成的作用。CPAE前處理pertussis toxin (PTX)稍微抑制2MeSATP和UTP誘導IP累積；其抑制程度約15%。短暫(20分鐘)處理phorbol 12-myristate 13-acetate (PMA)不同濃度結果呈現劑量依賴曲線抑制2MeSATP和UTP誘導IP累積，而抑制程度2MeSATP比UTP來的大。綜合以上結果顯示在牛肺動脈內皮細胞中同時具有P2Y1和P2Y2嘌呤受體經由PTX-insensitive G 蛋白活化phospholipase C (PLC)，促進[Ca2+]i增加。
先前研究已證明CPAE具有P2Y1和P2Y2受體，老鼠C6神經膠瘤細胞具有P2Y2受體而RAW 264.7巨噬細胞具有嘧啶受體。所有這些P2受體皆經與G蛋白偶合而活化PI-PLC。而P2受體拮抗劑(PPADS，suramin和reactive blue)及作用劑除對P2受體本身作用外，是否對ecto-ATPase活性具有抑制作用。在CPAE中，suramin完全抑制2MeSATP和UTP引起的PI水解，其pA2值分別為5.5  0.3和4.4  0.4。Reactive blue可將2MeSATP和UTP反應曲線向右移，而PPADS可將2MeSATP曲線向右移約3倍。相反地，PPADS濃度愈高時，UTP反應曲線向左移的情形遞增，而PPADS只稍微抑制ATP的作用。在RAW 264.7巨噬細胞中，suramin和reactive blue完全抑制UTP的反應，其pA2值分別為4.8  0.5和5.8  0.7，但PPADS卻沒有抑制UTP的作用。在老鼠C6神經膠瘤細胞，雖然suramin和reactive blue抑制ATP的反應，但PPADS是加強ATP和UTP的作用。三種P2拮抗劑測試其影響ecto-ATPase的活性，得知三種藥物皆抑制CPAE，C6神經膠瘤細胞和RAW 264.7 巨噬細胞膜上的ecto-ATPase，其IC50值在三種細胞依序是:PPADS為4，4.8和4.7；suramin為4，4.4和>>4；reactive blue為4.5，4.7和4.7。
在探討一些P2作用劑對CPAE ecto-ATPase活性後得知ATPS，-MeATP和AMP-PNP具有抑制ecto-ATPase的活性，其pIC50值分別為5.2，4.5和4.0。在CPAE，-MeATP雖然本身不能引發PI水解，但可將ATP，2-MeSATP和UTP的劑量反應曲線向左移約100-300倍，然而對ATPS和AMP-PNP只有2-3倍。再者，在-MeATP存在之下，PPADS對UTP的加強作用會消失，且稍微具有抑制UTP的反應。從本研究發現PPADS，suramin和reactive blue皆為ecto-ATPase抑制劑。正因它們兼具P2受體拮抗性及ecto-ATPase抑制性的雙重作用，使得它們對核酸作用劑引發PI水解有抑制，加強或沒有影響的複雜結果。對P2Y1，P2Y2和嘧啶受體之拮抗作用而言，reactive blue比suramin強，而PPADS只是一個較弱P2Y1受體拮抗劑。ATPS，-MeATP和AMP-PNP亦為ecto-ATPase的抑制劑，正因如此這三種作用劑之活化受體強度加強，此結果也提供學者發展高選擇性和強效的ecto-ATPase抑制劑的方向。
CPAE給予2MeSATP和UTP會誘導arachidonic acid (AA)的釋放，而此作用會被細胞外無鈣或是methyl arachidonyl fluorophosphate所抑制。PMA本身會增加AA的釋放，同時也加強UTP的反應;但是PMA卻不能增加2MeSATP增加AA的釋放，可能是PMA抑制2MeSATP增加[Ca2+]i的程度比UTP大。Ro 31-8220和staurosporine可抑制2MeSATP，UTP和PMA釋放AA的作用;但Go 6976則對2MeSATP，UTP和PMA的作用沒影響。PMA加強UTP的反應是在PMA前處理1個小時達到最大的加強作用，之後加強作用慢慢下降。在CPAE表現有PKCI、、及四種同功，而PMA前處理4至24小時可將PKCI和 down-regulation。給予PD 098059，會抑制2MeSATP，UTP和PMA誘導ERK的活化、cPLA2磷酸化及AA的釋放。綜合以上結論，P2Y1和P2Y2受體藉由增加[Ca2+]i及經由PKC及ERK活化導致cPLA2磷酸化的雙重作用活化cPLA2，而增加AA的釋放。
雖然短時間（20分鐘）前處理PMA可抑制2MeSATP和UTP引發PI水解，在前處理PMA 15小時後其抑制作用消失。相反的，PMA前處理24小時反而會增加2MeSATP和UTP的作用。西方點墨法顯示PMA會快速將PKCI，和同功從細胞質轉移至細胞膜，但PKC不受影響。Go 6976和LY 379196抑制PMA引發P2Y1和P2Y2受體去敏感化的作用。將細胞轉殖PKC-specific antisense oligonucleotide可降低PKCI蛋白表現和抑制PMA降低P2Y受體的作用。RT-PCR方法顯示，給予PMA 4至24小時後可增加P2Y1和P2Y2受體的mRNA的表現。綜合以上結果顯示內皮細胞PKCI具有負回饋抑制P2Y1和P2Y2受體引發PI水解作用；長時間給予PMA則一方面因PKC down-regulation，另一方面因增加P2Y1和P2Y2受體表現反而造成2MeSATP和UTP誘導PI反應增加的現象。
巨噬細胞為宿主防禦外來微生物入侵的第一道防線，在免疫功能上扮演著重要的角色。在巨噬細胞的實驗中將分成五個部分加以探討。一、UTP經活化PKC加強J774巨噬細胞腺酸環化活性之研究。二、嘧啶受體加強J774巨噬細胞iNOS表現之研究：細胞內鈣離子的角色。三、嘧啶受體加強巨噬細胞COX-2表現之研究：PGE2/PKA正向調節iNOS之表現。四、嘧啶受體加強巨噬細胞IL-6釋放之研究：與PGE2之間的交互作用。五、Thapsigargin (TG)加強鼠類腹腔巨噬細胞LPS誘導發炎介質合成作用機轉之研究。
在J774巨噬細胞中，UTP和UDP本身雖然不會影響cAMP的合成，卻皆可產生濃度相關性增加PGE1所導致的cAMP合成。UTP加強cAMP的作用與其增加IP合成及提升[Ca2+]i均與濃度呈現正比例的關係。細胞給予PMA處理，亦可增加PGE1導致cAMP合成的作用。給予staurosporine和Ro 31-8220可抑制UTP的加強作用。細胞前處理PMA 4-24小時亦明顯降低UTP加強PGE1的作用。利用西方點墨法分析PKC同功表現，顯示J774表現PKCI、II、、、、、和同功，而UTP可增加細胞膜上PKCI、II、、、、和的含量；而降低細胞質PKCI、II、、和的含量。此外亦發現J774巨噬細胞表現有可受PKC加強活性之ACII亞型。綜合以上的結果，UTP和UDP經由嘧啶受體加強PGE1活化ACII過程中，PKC的活化是此作用機轉的重要關鍵。
雖然UTP本身不具有增加NO的作用，但是同時給予UTP不同濃度可加強LPS產生NO及iNOS蛋白質的表現。UTP加強的作用可被U73122抑制，表示PI水解下游訊息傳遞參與其中。給予鈣離子螯合劑BAPTA/AM或選擇性CaMK抑制劑KN-93，二者皆抑制UTP的加強作用。PDTC為NF-B抑制劑，可抑制LPS及UTP誘導NO的釋放。Electrophoretic mobility shift assays (EMSA)實驗結果顯示，給予LPS刺激時會活化NF-B及AP-1，而此作用也會被UTP加強；而UTP也會加強LPS誘導IB的磷酸化及分解的作用。UTP活化NF-B，AP-1及引起IB磷酸化及分解作用皆可被KN-93抑制。綜合以上的結果顯示活化CaMK是UTP加強LPS誘導iNOS表現的重要機制。
在J774巨噬細胞中主要表現P2Y6受體亞型，同時加入UTP和LPS反應6個小時後，UTP加強LPS誘導COX-2 mRNA、蛋白的表現和PGE2的釋放明顯的增加，此加強作用的出現比加強NO產生來得早。UTP加強PGE2產生的作用可被U73122，KN-93，Ro 31-8220，Go 6976，PDTC，NS-398和BAPTA/AM抑制。NS-398抑制LPS及UTP增加iNOS表現和NO的釋放，結果更支持細胞內所產生的PGE2具有正向回饋調節iNOS基因的作用。再者，PGE2經由cAMP/PKA增加iNOS的表現可被2’,5’-dideoxyadenosine (AC抑制劑)，KT5720和H-89 (PKA抑制劑)所抑制。細胞外給予PGE2可以活化NFB，且加強LPS誘導NO的釋放。UTP也會增加LPS誘導AA釋放及typeV sPLA2和iPLA2 mRNA的表現。綜合以上的結果，UTP所加強iNOS的表現和NO釋放是需要COX-2-dependent PGE2的生合成，而CaMK及PKC的活化參與UTP加強COX-2表現的作用。
LPS處理8小時後明顯釋放IL-6，UTP隨濃度增加而加強LPS的作用。UTP的加強作用可被U73122，BAPTA/AM，KN-93及PDTC所抑制。利用L-NAME，indomethacin，NS-398和IL-6抗體測試LPS與UTP引發產生發炎媒介物，NO、PGE2和IL-6之間的交互作用。結果顯示PGE2和IL-6之間具有正向回饋互相調節作用，而NO並不會調節PGE2和IL-6的合成。綜合以上結果UTP加強LPS誘導三種發炎物質釋放，在宿主免疫功能扮演著調節的角色。
為了瞭解巨噬細胞活化過程中鈣離子加強發炎媒介物合成所扮演的角色，我們更進一步利用鼠類腹腔巨噬細胞給予TG或UTP探討鈣離子加強LPS誘導NO、TNF、PGE2和IL-6釋放的作用機轉。雖然LPS本身不能誘導NO的釋放，但可促進TNF、PGE2和IL-6的釋放。TG可持續性增加鼠類腹腔巨噬細胞[Ca2+]i，且具有加強LPS誘導NO、TNF、PGE2和IL-6的釋放。雖然鼠類腹腔巨噬細胞主要表現P2Y6受體，UTP結合至P2Y6受體後可增加PI水解及快速短暫地增加[Ca2+]i，但UTP不具有類似TG加強LPS的作用。實驗亦發現細胞內鈣離子是長時間誘導上述四種基因表現訊息過程中所必須存在的一個必要因子。TG之加強作用可被KN-93，PDTC，PD 098059，SB 203580和BAPTA/AM所抑制。進一步研究NO、TNF、PGE2和IL-6之間的相互調節作用。結果顯示TNF具有正向調節NO、PGE2和IL-6的合成作用，PGE2和IL-6有相互正向調節作用，而PGE2正向調節NO的合成，但抑制TNF的釋放。綜合以上的結果，TG持續性增加[Ca2+]i，經由CaMK，ERK，p38 MAPK及NF-B而促進鼠類腹腔巨噬細胞增加發炎煤介物質；雖然UTP只是短暫增加[Ca2+]i但不具有加強LPS的作用。

The actions of ATP and other nucleotides on the endothelium and macrophages are mediated by P2 purinoceptors. We have shown that P2Y1 and P2Y2 purinoceptors coexist in bovine pulmonary artery endothelium (CPAE), while 2MeSATP (P2Y1 receptor agonist) and UTP (P2Y2 receptor agonist) induce phosphoinositide (PI) turnover and Ca2+ mobilization. At maximal concentrations, the IP responses to 2MeSATP and UTP were additive, whereas those to ATP and either 2MeSATP or UTP were not. Pretreatment with pertussis toxin (PTX) slightly inhibited 2MeSATP- and UTP-stimulated IP generation by 15%. Short-term treatment of the cells with phorbol 12-myristate-13-acetate (PMA) resulted in a dose-dependent inhibition of 2MeSATP-induced IP formation greater and more sensitive than that induced by UTP. Together these results suggest that both P2Y1 and P2Y2 purinoceptors are expressed in bovine pulmonary artery endothelial cells and are coupled to phospholipase C (PLC) activation and Ca2+ mobilization through pertussis toxin-insensitive G proteins.
Previous studies have shown that CPAE have P2Y1 and P2Y2 receptors, rat C6 glioma cells have P2Y2 receptors and mouse RAW 264.7 cells have pyrimidinoceptors, all of which are coupled to PI-PLC. The dual actions of PPADS, suramin and reactive blue as antagonists and ecto-ATPase inhibitors, and actions of some P2 receptor agonists as also ecto-ATPase inhibitors of receptor subtypes were studied in these three cell types. In CPAE, suramin competitively inhibited the PI responses induced by 2MeSATP and UTP, with pA2 values of 5.5  0.3 and 4.4  0.4, respectively. Reactive blue produced shifts to the right of the 2MeSATP and UTP curves. PPADS caused a 3 fold right shift of the 2MeSATP curve. In contrast, a dose-dependent shift to the left of the UTP curve and a weak inhibition of the ATP response were seen with PPADS. In RAW 264.7 cells, suramin and reactive blue, but not PPADS, competitively inhibited the UTP response, with pA2 values of 4.8  0.5 and 5.8  0.7, respectively. In C6 glioma cells, although suramin and reactive blue inhibited the ATP response, a potentiation effect on ATP and UTP responses was seen with PPADS. The ecto-ATPase inhibitory activity of these three receptor antagonists was determined. All three inhibited ecto-ATPase present in CPAE, C6 and RAW 264.7 cells, with IC50 values of 4, 4.8 and 4.7 for PPADS, 4, 4.4 and > > 4 for suramin, and 4.5, 4.7 and 4.7 for reactive blue.
With respect to the action of P2 receptor agonists on ecto-ATPase, we show that the P2 receptor agonists, ATPS, ,-MeATP and AMP-PNP, inhibit the ecto-ATPase of CPAE, with pIC50 values of 5.2, 4.5 and 4.0, respectively. In CPAE, ,-MeATP does not induce PI turnover, left-shifted the agonist-concentration effect curves for ATP, 2MeSATP and UTP by approximate 100-300 fold, while those for ATPS and AMP-PNP were only shifted approximately 2-3 fold. Moreover, in the presence of ,-MeATP, not only was the potentiation effect of PPADS on the UTP response lost, but a slight inhibition of the UTP response by PPADS was also seen. This study indicates that PPADS, suramin and reactive blue are ecto-ATPase inhibitors. This property, combined with their antagonistic selectivity for receptor subtypes, can result in inhibition of, potentiation of, or lack of effect on agonist-mediated PI responses. Reactive blue is a more potent antagonist than suramin on P2Y1, P2Y2and pyrimidinoceptors, and PPADS is a weak antagonist for P2Y1 receptors. That the action of ATPS, ,-MeATP and AMP-PNP as ecto-ATPase inhibitors account for their high agonist potency, and also provide information for the development of ecto-ATPase inhibitors of high selectivity and potency.
Exposure of CPAE to 2MeSATP and UTP led to the release of arachidonic acid (AA), a response which was abolished by the removal of extracellular Ca2+ and methyl arachidonyl fluorophosphonate. PMA itself not only stimulated AA release but also played a permissive role in the response to UTP. However, PMA failed to enhance the AA response induced by 2MeSATP, probably due to greater attenuation of the [Ca2+]i increase caused by 2MeSATP than UTP. Inhibition of PKC with Ro 31-8220 and staurosporine, but not with Go 6976, reduced the AA response of 2MeSATP, UTP and PMA. PMA-induced potentiation of the UTP response reached a maximum after a 1 h preincubation, then declined and eventually lost its effect when the preincubation lasted up to 8 h. Among the PKC isoforms present in endothelial cells, I and  could be down-regulated by treatment with PMA for 4-24 h. PD 098059 inhibited extracellular signal-regulated protein kinase activation, cytosolic phospholipase A2 phosphorylation and AA release caused by 2MeSATP, UTP and PMA. Taken together, our results demonstrate that P2Y1 and P2Y2 receptors mediate AA release by activating cytosolic phospholipase A2 through an elevation of [Ca2+]i and PKC-, extracellular signal-regulated protein kinase-dependent phosphorylation.
Although short-term (20 min) pretreatment of cells with PMA attenuated 2MeSATP- and UTP-induced PI breakdown, this inhibition was lost after 15 h. Preincubation with PMA for 24 h, on the contrary, potentiated 2MeSATP and UTP responses. Western blot analysis showed that treatment of CPAE with PMA resulted in a rapid translocation of PKC isoform I,  and , but not , from the cytosol to the membrane fraction. Pretreatment of Go 6976 (an inhibitor of conventional PKC,  and ) and LY 379196 (a selective PKC inhibitor) dose-dependently inhibited the PMA-mediated desensitization. Transfection of PKC-specific antisense oligonucleotide reduced PKCI protein level and inhibited PMA-mediated PI reduction. RT-PCR analysis showed that PMA treatment for 4-24 h up-regulated P2Y1 and P2Y2 receptors at the mRNA levels. The down-regulation of PKCI and enhanced P2Y receptor expression together might contribute to the late PI enhancing effect of PMA. These results suggest that PKCI may exert a negative feedback regulation on endothelial P2Y1 and P2Y2 receptor-mediated PI turnover. The down-regulation of PKCI and enhanced P2Y receptor expression together might contribute to the late PI enhancing effect of PMA.
We have investigated the effects of nucleotide analogues on cyclic AMP formation in mouse J774 macrophages and the mechanisms involved. UTP and UDP induced concentration-dependent potentiation of prostaglandin E1 (PGE1)-induced cyclic AMP formation. The cyclic AMP potentiation effect of UTP correlated with increased [Ca2+]i and IP formation over the same concentration range. Exposure of cells to PMA also increased PGE1 stimulation of cyclic AMP levels, and the UTP-induced potentiation of cyclic AMP formation was inhibited by either staurosporine or Ro 31-8220. Pretreatment of cells with PMA for 4-24 h resulted in marked attenuation of UTP-stimulated cyclic AMP potentiation. Analysis of J774 cells by Western blotting with antibodies specific for different PKC isoforms shows the presence of the I,II, , , , ,  and  isoforms. Moreover, UTP significantly increased the level of PKCI, II, , , ,  and  immunoreactivity in the membrane fraction and decreased the cytosolic reactivity of PKCII, ,  and . Immunoblot studies also indicate the presence of type II AC. These results indicate that PKC is required for the potentiation of AC activity by macrophage pyrimidinoceptors, which exhibit a higher specificity for UTP and UDP than for ATP.
NO production, as assessed by nitrite accumulation, followed by the induction of iNOS was increased in J774 cells after overnight treatment with the bacterial product, lipopolysaccharide (LPS). Although UTP alone had no effect, stimulation of J774 cells with a combination of UTP and LPS resulted in a potentiated increase in nitrite levels. In parallel, the amount of iNOS protein induced by LPS was also potentiated by UTP treatment. The UTP potentiating effect was attenuated by a PI-PLC inhibitor, U73122, suggesting involvement of the downstream signaling pathways of PI turnover. Furthermore, the UTP-induced potentiation was abolished by BAPTA/AM or KN-93 (a selective inhibitor of Ca2+/calmodulin-dependent protein kinase, CaMK). In the presence of KN-93, the UTP potentiation of iNOS protein induction was also lost. Pyrrolidine dithiocarbamate (PDTC, 3-30 M), an inhibitor of NF-B, caused a concentration-dependent reduction in the nitrite response to LPS and UTP. In electrophoretic mobility shift assays, LPS produced marked activation of NF-B and AP-1, which was potentiated by UTP. In accordance with the activation of NF-B, the LPS-induced degradation of IB as well as the phosphorylation of IB were also increased by UTP. Moreover, the UTP-potentiated activation of NF-B and AP-1, degradation and phosphorylation of IB were inhibited by KN-93. Taken together, these data demonstrate that nucleotides, especially UTP, can potentiate the LPS-induced activation of NF-B and AP-1, and of iNOS induction via a CaMK-dependent pathway, and suggest that the UTP-dependent up-regulation of iNOS may constitute a novel element in the inflammatory process.
In J774 macrophages predominantly expressing P2Y6 receptors, the simultaneous addition of UTP and LPS increases PGE2 release and this occurs after 6 h of stimulation, earlier than the NO potentiation seen after 24 h of stimulation. UTP-induced increased PGE2 release was demonstrated by a concomitant increase in COX-2 mRNA and protein expression, and was decreased by inhibitors specific for PI-PLC, CaMK, PKC, NF-B or COX-2. NS-398 reduced LPS plus UTP-elicited iNOS induction and nitrite accumulation, supporting for the positive regulation of iNOS gene expression by endogenous PGE2. Moreover, the cAMP/PKA-dependent up-regulation of iNOS expression mediated by PGE2 was drawn from the inhibitory effects of 2’,5’-dideoxyadenosine, KT5720 and H-89. Exogenous PGE2 induced NF-B activation and potentiated nitrite accumulation in response to LPS. In addition to COX-2 induction, basal AA release and steady-state mRNA levels of type V sPLA2 and iPLA2 were also increased in the presence of UTP; the LPS-induced increase in iPLA2 activity was also potentiated by UTP. Taken together, we conclude that UTP-mediated iNOS potentiation and NO formation are dependent on COX-2-dependent PGE2 biosynthesis, and that CaMK and PKC activation are two key steps required for the UTP enhancement of COX-2 induction.
In this study we found that the amount of IL-6 release in response to LPS stimulation was greatly enhanced in the presence of UTP. The UTP-enhanced IL-6 production exhibited a concentration-dependent manner and occurred after 8 h treatment with LPS. RT-PCR analysis indicated that the steady state level of IL-6 mRNA induced by LPS was apparently increased upon UTP co-addition. The potentiation effect of UTP was inhibited by the treatment with U73122, BAPTA/AM, KN-93 or PDTC. To understand the cross-regulation among NO, PGE2 and IL-6, all of which are dramatically induced after LPS stimulation, the effects of L-NAME, indomethacin, NS-398 and IL-6 antibody were tested. The results revealed the positive regulation between PGE2 and IL-6 synthesis. Taken together, these results reinforce the role of UTP as a regulatory element in the inflamed sites by demonstrating the capacity of this nucleotide to potentiate LPS-induced release of inflammatory mediators.
To understand the role of calcium priming and/or potentiation of macrophage activation, we investigated the effects of thapsigargin and UTP on the induction of NO, TNF, PGE2 and IL-6 synthesis in murine peritoneal macrophages. While LPS alone did not induce NO release, it increased TNF-, PGE2 and IL-6 release. Thapsigargin, which sustainedly increased [Ca2+]i, time-dependently potentiated LPS-induced TNF, PGE2 and IL-6 release and primed the cells for NO formation. In peritoneal macrophages predominantly expressing P2Y6 receptors, UTP stimulated PI turnover transiently increased [Ca2+]i, but did not elicit potentiation and priming effects as TG. TG—induced potentiation of mediator release was decreased by KN-93, PDTC, PD 098059 and SB 203580. The effects of BAPTA/AM also indicate the requirement of long-term and sustained increase in [Ca2+]i for TG priming and LPS-induction of these four inflammatory mediators. To understand the cross-regulation among NO, TNF, PGE2 and IL-6, the effects of L-NAME, sTNFR, IL-6 antibody, NS-398 and indomethacin were tested. The results revealed that TNF up-regulates NO, PGE2 and IL-6 synthesis; PGE2 up-regulate NO synthesis but down-regulate TNF release; and PGE2 and IL-6 mutually regulate each other. Taken together, these results suggest that events associated with long-term increased [Ca2+]i, such as the activation of CaMK, ERK and p38 MAPK, contribute to the activation of murine peritoneal macrophages.

縮寫表………………………………………………………………….1
中文摘要……………………………………………………………….4
英文摘要………………………………………………………………11
拮抗劑一覽表…………………………………………………………19
第一章緒論………………………………………………………20
第二章 P2Y受體在內皮細胞訊息傳遞及功能之研究
2-1牛肺動脈內皮細胞P2Y1和P2Y2受體訊息傳遞之研究……36
Characterization of signaling pathways of P2Y1 and P2Y2 purinoceptors in bovine pulmonary endothelial cells
2-2 P2受體拮抗劑及作用劑對ecto-ATPase活性之影響………56
Effects of P2 purinoceptor antagonists and agonists on
ecto-ATPase activity
2-3 P2Y受體活化內皮細胞cPLA2訊息傳遞機轉
之研究………………………………………………………….87
Signal transduction of P2Y receptor-mediated activation
of cytosolic phospholipase A2 in endothelial cells
2-4 蛋白激C調節內皮細胞P2Y受體活化磷脂C作用
機轉之研究…………….……………………………………..111
Regulatory roles of PKC isoforms in P2Y receptor-induced inositol phosphate formation in endothelial cells
第三章P2Y受體在巨噬細胞訊息傳遞及功能之研究
3-1 UTP經活化PKC加強J774巨噬細胞腺酸環化活性
之研究…………………………………………………………127
Involvement of protein kinase C in the UTP-mediated potentiation of adenylyl cyclase activity in macrophages
3-2 嘧啶受體加強J774巨噬細胞iNOS表現之研究：細胞
內鈣離子的角色………………………………………………150
Pyrimidinoceptor potentiation of macrophage inducible nitric oxide synthase induction: role of intracellular calcium
3-3 嘧啶受體加強巨噬細胞COX-2表現之研究：PGE2/PKA
正向調節iNOS之表現………………………………………..181
Pyrimidinoceptor potentiation of macrophage cyclooxygenase 2 induction: positive feedback on iNOS induction via PGE2/PKA signaling
3-4 嘧啶受體加強巨噬細胞IL-6釋放之研究：與PGE2
之間的交互作用………………………………………………212
Pyimidinoceptor Potentiation of macrophage IL-6 release: cross interaction with COX-2 dependent PGE2 production
3-5 Thapsigargin加強鼠類腹腔巨噬細胞LPS誘導發炎介
質合成作用機轉之研究………………………………………229
Potentiation effects of thapsigargin on LPS-induced inflammatory mediator formation in mouse peritoneal macrophages
第四章結論……………………………………………………………252
參考文獻………………………………………………………………255
發表著作………………………………………………………………298

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