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研究生:陳炳常
研究生(外文):Chen, Bing-Chang
論文名稱:P2Y受體在內皮細胞及巨噬細胞訊息傳遞與功能之研究
論文名稱(外文):Studies on the Signal Transduction and Function of P2Y Receptors in Endothelial Cells and Macrophages
指導教授:林琬琬林琬琬引用關係
指導教授(外文):Wan-Wan Lin
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:1999
畢業學年度:87
語文別:中文
論文頁數:299
中文關鍵詞:P2Y受體內皮細胞巨噬細胞訊息傳遞
外文關鍵詞:P2Y receptorendothelial cellsmacrophagessignal transduction
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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
1. Ackermann, E. J., Kempner, E. S. and Dennis, E. A. (1994) Ca2+-independent cytosolic phospholipase A2 from macrophage-like P388D1 cells. Isolation and characterization. J. Biol. Chem. 269, 9227-9233.
2. Akashi, M., Loussararian, A.H., Adelman, D.C., Saito, M. and Koeffler, H.P. (1990) Role of lymphotoxin in expression of interleukin 6 in human fibroblasts. Stimulation and regulation. J. Clin. Invest. 85, 121-129.
3. Allsup, D.J and Boarder, M.R. (1990) Comparison of P2 purinergic receptors of aortic endothelial cells with those of adrenal medulla: evidence for heterogeneity of recepotr subtype and inositol phhosphate response. Mol. Pharmacol. 38, 84-91.
4. Anderson G.D., Hauser S.D., McGarity, K.L., Bremer M.E. and Isakson P.C. (1997) Gregory SA. Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis. J. Clin. Invest. 97, 2673-2679.
5. Anderson, R.J., Breckon, R. and Dixon, B.S. (1991) ATP receptor regulation of adenylate cyclase and protein kinase C activity in cultured renal LLC-PK1 cells. J. Clin. Invest. 87: 1732-1738.
6. Arbibe, L., Vial, D., Rosinski-Chupi, I., Havet, N., Huerre, M., Vargoftig, B. B. and Touqui, L. (1997) Endotoxin induced expression of type II phospholipase A2 in macrophages during acute lung injury in guinea pigs: involvement of TNF- in lipopolysaccharide-induced type II phospholipase A2 synthesis. J. Immunol. 159, 391-400.
7. Arunlakshana, O. and Schild, H.O. (1959) Some quantitative uses of drug antagonists. Br. J. Pharmacol. Chemother. 14, 48-57.
8. Astin, M., Stjemschantz, J. and Selen, G. (1994) Role of nitric oxide in PGF2-induced ocular hyperemia. Exp. Eye Res. 59, 401-407.
9. Aurivillius, M., Hansen, O.C., Lazrek, M.B., Bock, E. and Obrink, B. (1990) The cell adhesion molecule Cell-CAM 105 is an ecto-ATPase and a member of the immunoglobulin superfamily. FEBS Lett. 264, 267-269.
10. Axelrod, J., Burck, R. M. and Jelsema, C. L. (1988) Receptor-mediated activation of phospholipase A2 via GTP-binding proteins: arachidonic acid and its metabolites as second messengers. Trends Neurosci. 11, 117-123.
11. Baeuerle, P.A., and Henkel, T. (1994) Function and activation of NF-B in the immune system. Ann. Rev. Immunol. 12, 141-179.
12. Bailey, S.J. and Hourani, S.M.O. (1994) Different effects of suramin on P2-purinoceptors mediating contraction of the guinea-pig vas deferens and urinary bladder. Br. J. Pharmacol. 112, 219-225.
13. Baldwin, A.S.Jr. (1996) The NF-B and IB proteins: new discoveries and insights. Ann. Rev. Immunol. 14, 649-681.
14. Barker, J. E., Anderson, J., Treasure, T. and Piper, P. J. (1994) Effects of prostaglandins on stimulated release of nitric oxide by angiotensin II from human saphenous vein. Br. J. Pharmacol. 112 (Suppl), 446P.
15. Barnard, E.A., Burnstock, G. and Webb, T.E. (1994) G protein-coupled receptors for ATP and other nucleotides: a new receptor family. Trends Pharmacol. Sci. 15, 67-70.
16. Bauer, M. K. A., Lieb, K., Schulze-Osthoff, K., Berger, M., Gebicke-Haerter, P. J., Bauer, J. and Fiebich, B. L. (1997) Expression and regulation of cyclooxgenase-2 in rat microglia. Eur. J. Biochem. 243, 726-731.
17. Beasley, D. (1997) Phorbol ester and interleukin-1 induce interleukin-6 gene expression in vascular smooth muscle cells via independent pathways. J. Cardiovasc. Pharmacol. 29, 323-330.
18. Beltman, J., McCormick, F. and Cook, S.J. (1996) The selective protein kinase C inhibitor, Ro-31-8220, inhibits mitogen-activated protein kinase phosphatase-1(MKP-1) expression, induces c-Jun expression, and activates Jun N-terminal kinase. J. Biol. Chem. 271, 27018-27024.
19. Benbernou, N., Esnault, S., Shin, H. C. K., Fekkar, H. and Guenounou, M. (1997) Differential regulation of IFN-, IL-10 and inducible nitric oxide synthase in human T cells by cyclic AMP-dependent signal transduction pathway. Immunology 91, 361-368.
20. Berridge, M.J. (1987) Inositol trisphosphate and diacylglycerol: two interacting second messengers. Ann. Rev. Biochem. 56, 159-193.
21. Bertrand, G., Chapal, J. and Loubatieres-Mariani, M.M. (1986) Potentiating synergism between adenosine diphosphate or triphosphate and acetylcholine on insulin secretion. Am. J. Physiol. 251, E416-421.
22. Bertrand, G., Chapal, J. and Loubatieres-Mariani, M.M. and Roye, M. (1987) Evidence for two different P2-purinoceptors on  cells and pancreatic vascular bed. Br. J. Pharmacol. 91, 783-787.
23. Bertrand, G., Chapal, J., Puech, R. and Loubatieres-Mariani, M.M. (1991) Adenosine-5’-O-(2-thiodiphosphate) is a potent agonist at P2 purinoceptors mediating insulin secretion from perfused rat pancreas. Br. J. Pharmacol. 102, 627-630.
24. Bertrand, G., Gross, R., Chapal, J. and Loubatieres-Mariani, M.M. (1989) Difference in the potentiating effect of adenosine triphosphate and ,-methylene-ATP on the biphasic insulin response to glucose. Br. J. Pharmacol. 98, 998-1004.
25. Beukers, M. W., Kerkhof, C.J.M., van Rhee, M.A., Ardanuy, U., Gurgel, C., Widjaja, H., Nickel, P., Ijzerman, A.P. and Soudijn, W. (1995) Suramin analogs, divalent cations and ATPS as inhibitors of ecto-ATPase. Naunyn-Schmiedeberg’s Arch. Pharmacol. 351, 523-528.
26. Beukers, M.W., Pirovano, I.M., van Weert, A., Kerkhof, C.J.M., Ijzerman, A.P. and Soudiji, W. (1993) Characterization of ecto-ATPase on human blood cells. A physiological role in platelet aggregation?. Biochem. Pharmacol. 46, 1959-1966.
27. Beyaert, R., Cuenda, A., Berghe, W., Plaisance, S., Lee, J., Haegeman, G., Cohn, P., and Fiers, W. (1996) The p38 mitogen-activated protein kinase pathway regulates interleukin-6 synthesis in response to tumor necrosis factor. EMBO J. 15, 1914-1923.
28. Blank, V., Kourilsky, P. and Israel, A. (1992) NF-B and related proteins: Rel/dorsal homologies meet ankyrin-like repeats. Trends Biochem. Sci. 17, 135-140.
29. Boarder, M.R. and Hourani, S.M. (1998) The regulation of vascular function by P2 receptors: multiple sites and multiple receptors. Trends Pharmacol. Sci., 19, 99-107.
30. Boarder, M.R., Weisman, G.A., Turner, J.T. and Wilkinson, G.F. (1995) G protein-coupled P2 purinoceptors: from molecular biology to functional responses. Trends Pharmacol. Sci. 16, 133-139.
31. Boeynaems, J.M. and Galand N. (1983) Stimulation of vascular prostacyclin synthesis by extracellular ADP and ATP. Biochem. Biophys. Res. Commun. 112, 290-296.
32. Boeynaems, J.M. and Pearson, J.D. (1990) P2 purinoceptors on vascular endothelial cells: physiological significance and transduction mechnisms. Trends. Pharmacol. Sci. 11, 34-37.
33. Born, G.V.R. and Kratzer, M.A.A. (1984) Source and concentration of extracellular adenosine triphosphate during haemostasis in rats, rabbits and man. J. Physiol. Lond., 354, 419-429.
34. Boutherin-Falson, O., Reuse, S., Dumont, J.E. and Boeynaems, J.-M. (1990) Increased levels of c-fos and c-myc mRNA in ATP-stimulated endothelial cells. Biochem. Biophys. Res. Commun., 172, 306-312.
35. Bouvier, M. (1992) Cross-talk between second messengers. Ann. New York Acad. Sci. 594, 120-129.
36. Boyer, J.L., Lazarowski, E.R., Chen, X. H. and Harden, T.K. (1993) Identification of a P2Y-purinergic receptor that inhibits adenylyl cyclase. J. Pharmacol. Exp. Ther. 267, 1140-1146.
37. Boyer, J.L., Zohn, I.E., Jackson, K.A. and Harden, T.K. (1994) Differential effects of P2-purinoceptor antagonists on phospholipase C- and adenylyl cyclase-coupled P2Y-purinoceptors. Br. J. Pharmacol. 113, 614-620.
38. Briner, V.A. and Kern, F. (1994) ATP stimulates Ca2+ mobilization by a nucleotide receptor in glomerular endothelial cells. Am. J. Physiol. 366, F210-217.
39. Brown, C.A., Patel, V., Wilkinson, G. and Boarder, M.R. (1996) P2 purinoceptor-stimulated conversion of arginine to citrulline in bovine endothelial cells is reduced by inhibition of protein kinase C. Biochem. Pharmacol. 52, 1849-1854.
40. Brown, K., Gerstberger, S., Carlson, L., Franzoso, G., and Siebenlist, U. (1995) Control of IB- proteolysis by site-specific, signal-induced phosphorylation. Science 267, 1485-1488.
41. Buchmuller-Rouiller, Y., Betz-Corradin, S., and Mauel, J. (1992) Differential effect of prostaglandins on macrophage activation induced by calcium ionophore A23187 or IFN-. J. Immunol. 148, 1171-1175.
42. Buell, G., Michel, A.D., Lewis, C., Collo, G. Humphrey, P.P,A., and Surprenant, A. (1996) P2X1 receptor activation in HL60 cells. Blood 87, 2659-2664.
43. Bultmann, R., Driessen, B., Goncalves, J. and Starke, K. (1995) Functional consequences of inhibition of nucleotide breakdown in rat vas deferens: a study with Evans blue. Naunyn-Schmiedebergs Arch. Pharmacol. 351, 555-560.
44. Burnstock, G. (1978) A basis for distinguishing two types of purinergic receptor. In cell membrane receptors for drugs and hormones. A multidiscriplinary apporach, edited by Staub, R.W. and Bolis, L. New York: Raven, P. 107-118.
45. Burnstock, G. and Kennedy, C. (1985) Is there a basis for distinguishing two types of P2-purinoceptors? Gen. Pharmacol. 16, 433-440.
46. Burnstock, G. and Warloand, J.J. (1987) P2-purinoceptors of two subtypes in the rabbit mesenteric artery: reactive blue 2 selectively inhibits responses mediated via the P2Y- but not the P2X-purinoceptor. Br. J. Pharmacol. 90, 383-391.
47. Callery, M.P., Mangino, M.J., Kamei, T. and Flye, M.W. (1990) Interleukin-6 production by endotoxin-stimulated Kupffer cells is regulated by prostaglandin E2. J. Surg. Res. 48, 523-527.
48. Candela, J.L.R. and Garcia-Fernandez, M.C. (1963) Stimulation of secretion of insulin by adenosine-triphosphate. Nature 197, 1210 (Abstract).
49. Caselmann, W.H. (1995) Transactivation of cellular gene expression by hepatitis B viral proteins: a possible molecular mechanism of hepatocarcinogenesis. J. Hepatol. 22 (Suppl 1), 34-37.
50. Castro, E., Tome, A.R., Miras-portugal, M.T. and Rosario, L.M. (1994) Single-cell fura-2 microfluorometry reveals different purinoceptor subtypes coupled to Ca2+ influx and intracellular Ca2+ release in bovine adrenal chromaffin and endothelial cells. Pflugers. Arch. 426, 524-533.
51. Celada, A., Gray, P.W., Rinderknecht, F., and Schreiber, R.D. (1984) Evidence for a interferon- receptor that regulated macrophage tumoricidal activity. J. Exp. Med. 160, 55-74.
52. Chang, K., Hanaoka, K. Kumada, M., and Takuwa, Y. (1995) Molecular cloning and functional analysis of a novel P2 nucleotide receptor. J. Biol. Chem. 270, 26152-26158.
53. Channon, Y.T. and Leslie, C.C. (1990) A calcium-dependent mechanism for associating a soluble arachidonyl-hydrolyzing phospholipase A2 with membrane in the macrophage cell line RAW 264.7. J. Biol. Chem. 265, 5409-5413.
54. Chen J. and Iyengar, R. (1993) Inhibition of cloned adenylyl cyclases by mutant-activated Gi-alpha and specific suppression of type 2 adenylyl cyclase inhibition by phorbol ester treatment. J. Biol. Chem. 268, 12253-12256.
55. Chen, B. C., Chou, C. F. and Lin, W. W. (1998) Pyrimidinoceptor-mediated potentiation of iNOS induction in J774 macrophages: role of intracellular calcium. J. Biol. Chem. 273, 29754-29763.
56. Chen, B.C., Chen, Y.H., and Lin, W.W. (1999) Involvement of p38 mitogen-activated protein kinase in lipopolysaccharide-induced iNOS and COX-2 expression in J774 macrophages. Immunology 97, 124-129.
57. Chen, B.C., Lee, C.M. and Lin, W.W. (1996) Characterization of signaling pathway of P2Y and P2U purinoceptors in bovine pulmonary artery endothelial cells. J. Cardiovasc. Pharmacol., 28, 192-199.
58. Chen, B.C., Lee, C.M. and Lin, W.W. (1996) Inhibition of ecto-ATPase by PPADS, suramin and reactive blue in endothelial cells, C6 glioma cells and RAW 264.7 macrophages. Br. J. Pharmacol. 119, 1628-1634.
59. Chen, B.C., Lee, C.-M., Lee, Y.T. and Lin, W.W. (1996) Characterization of signalling pathways of P2Y and P2U purinoceptors in bovine pulmonary artery endothelial cells. J. Cardiovasc. Pharmacol. 28, 192-199.
60. Chen, B.C., Lin, L.L. and Lin, W.W. (1999) PKC-dependent pathway of ERK activation by P2Y1 and P2Y2 purinoceptors that activate cPLA2 in endothelial cells. Eur. J. Pharmacol.373, 101-110.
61. Chen, Z. J., Parent, L., and Maniatis, T. (1996) Site-specific phosphorylation of IB by a novel ubiquitination-dependent protein kinase activity. Cell 84, 853-862.
62. Chijiwa, T., Mishima, A., Hagiwara, M., Sano, M., Hayashi, K., Inoue. T., Naito, K., Toshioka, T. and Hidaka, H. (1990) Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D phenochromocytoma cells. J. Biol. Chem. 265, 5267-5272.
63. Chiozzi, P., Murgia, M., Falzoni, S., Ferrari, D., and Di Virgilio, F. (1996) Role of the purinergic P2Z receptor in spontaneous cell death in J774 macrophages cultures. Biochem. Biophys. Res. Commun. 218, 176-181.
64. Chuang, D.M. (1989) Neurotransmitter receptors and phosphoinositide turnover. Ann. Rev. Pharmacol. Toxicol., 29, 71-110.
65. Clark, J.D., Lin, L.L., Kriz, R.W., Ramesha, C.S., Sultzman, L.A., Lin, A.Y., Milona, N. and Knopf, J.L. (1991) A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP. Cell 65, 1043-1051.
66. Cohn, Z.A., and Parks, E. (1967) The regulation of pinocytosis in mouse macrophages, Ⅲ. The induction of vesicle formation by nucleotides and nucleotides. J. Exp. Med. 125, 457-466.
67. Communi, D. and Boeynaems, J.M. (1997) Receptors responsive to extracellular pyrimidine nucleotides. Trends Pharmacol. Sci. 18, 83-86.
68. Communi, D., Parmentier, M., and Boeynaems, J.-M. (1996) Cloning, functional expression and tissue distribuction of the human P2Y6 receptor. Biochem. Biophys. Res. Commun. 222, 303-308.
69. Communi, D., Pirotton, S., Parmentier, M., and Boeynaems, J.M. (1995) Cloning and functional expression of a human uridine nucleotide receptor. J. Biol. Chem. 270, 30849-30852.
70. Communi, D., Raspe, E., Pirotton, S. and Boeynaems, J.M. (1995) Coexpression of P2Y and P2U purinoceptors on aortic endothelial cells. Comparison of cell localization and signaling pathways. Circ. Res. 76, 191-198.
71. Connoly, G.P. and Harrison, P.J. (1994) Reactive blue 2 discriminates between responses medicated by UTP and those evoked by ATP or ,-methylene-ATP on rat sympathetic ganglia. Eur. J. Pharmacol. 259, 95-99.
72. Crack, B.E., Beukers, M.C., Mckechnie, K.C.W., Ijzerman, A.P. and Leff, P. (1994) Pharmacological analysis of ecto-ATPase inhibition: evidence for combined enzyme inhibition and receptor antagonism in P2X-purinoceptor ligands. Br. J. Pharmacol. 113, 1432-1438.
73. Crack, B.E., Pollard, C.E., Beukers, M.W., Roberts, S.M., Hurt, S.F., Ingall, A.H., Mckechnie, K.C.W., Ijzerman, A.P. and Leff, P. (1995) Pharmacological and biochemical analysis of FPL 67156, a novel, selective inhibition of ecto-ATPase. Br. J. Pharmacol. 114, 475-481.
74. Cusack, N.J. and Hourani, S. (1991) Design syntheses and pharmacology purinoceptors. Nucleosides Nucleotides 10, 1019-1028.
75. Cusack, N.J. and Hourani, S.M.O. (1982) Specific but non competitive inhibition by 2-alkylthio analogues of adenosine 5''-monophophate and adenosine 5’-triphosphate of human platelet aggregation induced by adenosine 5’-diphosphate. Br. J. Pharmacol. 75, 397-400.
76. Cussack, N. J. (1993) P2 receptor: subclassification and structure-activity relationships. Drug Dev. Res., 28, 244-252.
77. D’Acqisto, F., Iuvone, T., Rombola, L., Sautebin, L., Di. Rosa, M. and Carnuccio. R. (1997) Involvement of NF-B in the regulation of cyclooxgenase-2 protein expression in LPS-stimulated J774 macrophages. FESB Lett. 418, 175-178.
78. Darbon, J.M., Tournier, J.F. Tanber, J.P. and Bayard, F. (1986) Possible role of protein phosphorylation in the mitogenic effect of high density lipoproteins on cultured vascular endothelial cells. J. Biol. Chem. 261, 8002-8008.
79. Davis, P.D., Elliott, L.H., Harris, W., Hill, C.H., Hurst, S.A., Keech, E., Kumar, M.K., Lawton, G., Nixon, J.S., and Wilkinson, S.E. (1992) Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity. J. Med. Chem. 35, 994-1001.
80. Dekker, L.V. and Parker, P.J. (1994) Protein kinase C-a question of specificity. Trends Biochem. Sci. 19, 73-77.
81. Dennis, E.A. (1997) The growing phospholipase A2 superfamily of signal transduction enzymes. Trends Biochem. Sci. 22, 1-2.
82. Dewitt, D. L. (1991) Prostaglandin endoperoxide synthase: regulation of enzyme expression. Biochim. Biophys. Acta. 1083, 121-134.
83. Di Virgilio, F., Bronte, V., Collavo, D., and Zanovello, P. (1989) Responses of mouse lymphocytes to extracellular adenosine 5’-triphosphate (ATP). Lymphocytes with cytotoxic activity are resistant to the permeability effects of ATP. J. Immunol. 143:1995-1960.
84. Di Virgilio, F., Pizzo, P., Zanovello, P., Bronte, V., and Collavo, D. (1990) Extracellular ATP as a possible mediator of cell-mediated cytotoxicity. Immunol. Today 11, 274-277.
85. Diaz-Guerra, M. J.M., Bodelon, O.G., Velasco, M., Whelan, R., Parker, P.J., and Bosca, L. (1996) Up-regulation of protein kinase C- promotes the expression of cytokine-inducible nitric oxide synthase in RAW 264.7 cells. J. Biol. Chem. 271, 32028-32033.
86. Diaz-Meco, M.T., Dominguez, I., Sanz, L., Dent, P., Lozano, J., Municio, M.M., Berra, E., Hay, R.T., Sturgill, T.W., and Moscat, J. (1994) PKC induces phosphorylation and inactivation of IB- in vitro. EMBO J. 13, 2842-2848.
87. Didonato, J. A., Hayakawa, M., Rothwarf, D. M., Zandi, E., and Karin, M. (1997) A cytokine-responsive IB kinase that activates the transcription factor NF-B. Nature 388, 548-554.
88. Drysdale, B.-E., Yapundich, R.A., Shin, M.L., and Shin, H.S. (1987) Lipopolysaccharide-mediated macrophage activation: the role of calcium in the regulation of tumoricidal activity. J. Immunol. 138, 951-956.
89. Dudley, D.T., Pang, L., Decker, S.J., Bridges, A.J. and Saltiel, A.R. (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl. Acad. Sci. USA. 92, 7686-7689.
90. Duyster, J., Schwende, H., Fitzke, E., Hidaka, G. and Kieter, P. (1993) Different roles of protein kinase C- and - in arachidonic acid cascade, superoxide formation and phosphoinositide hydrolysis. Biochem. J. 292, 203-207.
91. Eberhardt, W., Kunz, D. and Pfeilschifter, J. (1994) Pyrrolidine dithiocarbamate differentially affects interleukin 1- and cAMP-induced nitric oxide synthase expression in rat renal mesangial cells. Biochem. Biophys. Res. Commun. 200, 163-170.
92. Edwards, F.A., Gibb, A.J. and Colquhoun, D. (1992) ATP receptor mediated synaptic currents in the central nervous system. Nature 359,144-147.
93. Evans, R.J. and Kennedy, C. (1994) Characterization of P2-purinoceptors in the smooth muscla of the rat tail artery: a comparison between contractile and electrophysiological responses. Br. J. Pharmacol. 113, 853-860.
94. Evans, R.J., Derkach, V. and Surprenant, A. (1992) ATP mediates fast synaptic transmission in mammalian neurons. Nature 357, 503-505.
95. Fischer, B., Boyer, J.L., Hoyle, C.H.V., Ziganshin, A.U., Brizzolara, A.L., Knight, G.E., Zimmet, J., Burnstock, G., Harden, T.K. and Jacobson, K.A. (1993) Identification of potent, selective P2Y-purinoceptor agonists: structure-activity relationships for 2-thioether derivatives of adenosine 5''-triphosphate. J. Med. Chem. 36, 3937-3946.
96. Flodgaard, H. and Klenow, H. (1982) Abundant amounts of diadenosine 5''-5''''''-P1-P4-tetraphosphate are present and releasable, but metabolically inactive in human platelets. Biochem. J. 208, 737-742.
97. Fournier, T., Riches, D. W., Winston, B. W., Rose, D. M., Young, S. K., Noble, P. W., Lake, F. R. and Henson, P. M. (1995) Divergence in macrophage insulin-like growth factor-I (IGF-I) synthesis induced by TNF- and prostaglandin E2. J. Immunol. 155, 2123-2133.
98. Frantz, B., Nordby, E., Bren, G., Steffan, N., Paya, C., Kincaid, R., Tocci, M., O’Keefe, S., and O’Neill, E. (1994) Calcineurin acts in synergy with PMA to inactivate IB/MAD3, an inhibitor of NF-B. EMBO J. 13, 861-870.
99. Fredholm, B.B., Abbracchio. M.P., Burnstock. G., Daly, J.W., Harden, T.K., Jacobson, K.A., Leff, P. and Williams, M. (1994) Nomenclature and classification of purinoceptros. Pharmacol. Rev. 46, 143-156.
100. Fredholm, B.B., Abbrachio, M.P., Burnstock, G., Dubyak, G.R., Harden, T.K., Jacobson, K.A., Schwabe, U. and Williams, M. (1997) Towards a revised nomenclature for P1 and P2 receptors. Trends Pharmacol. Sci. 18, 79-82.
101. Fredholm, B.B., Burnstock, G., Harden, T.K. and Spedding, M. (1996) Receptor nomenclature. Drug. Dev. Res. 39, 461-466.
102. Fujihara, M., Connolly, N., Ito, N. and Suzuki, T. (1994) Properties of protein kinase C isoforms (II, , and ) in a macrophage cell line (J774) and their roles in LPS-induced nitric oxide production. J. Immunol. 152, 1898-1906.
103. Gallucci, S., Provenzano, C., Mazzarelli, P., Flavia, S. and Bartoccioni, E. (1997) Myoblasts produce IL-6 in response to inflammatory stimuli. Int. Immunol. 3, 267-27.
104. Gaumond, F., Fortin, D., Stankova, J. and Rola-Pleszcynski, M. (1997) Differential signaling pathways in platelet-activating factorinduced proliferation and interleukin-6 production by rat vascular smooth muscle cells. J. Cardio. Pharmacol. 30, 169-175.
105. George, J.S., Bernard, W.A., Wayne-Albers, R., Perry, B.M. (1995) Basic Neurochemistry, 5th. Raven Press, New York. p. 409.
106. Geppert, T.D., Whitehurst, C.E., Thompson, P., and Beutler, B. (1994) Lipopolysaccharide signal activation of tumor necrosis factor biosynthesis through the ras/raf-1/MEK/MAPK pathway. Mol. Med. 1, 93-103.
107. Goet''z, K., Da Prada, M. and Pletscher, A. (1971) Adenine-, guanine- and uridine-5''-phosphonucleotides in blood platelets and storage organelles of various species. J. Pharmacol. Exp. Ther. 178, 210-215.
108. Goldring, C.E.P., Reveneau, S., Algarte, M, and Jeannin, J.-F. (1996) In vivo footprinting of the mouse inducible nitric oxide synthase gene: inducible protein occupation of numerous sites including Oct and NF-IL6. Nucleic Acids Res. 24, 1682-1687.
109. Goodman, R., Stevens, T.M., Mantegna, L.R., Kidd, P.R., Harris, R.R. and Kerr, J.S. (1991) Phospholipase A2 (PLA2) activity in bovine pulmonary artery endothelial cells. Agents Actions 34, 113-116.
110. Gordon, E.L., Pearon, J.D., Dickson, E.S., Moreau, D. and Slakey, L.L. (1989) The hydrolysis of extracellular adenine nucleotides by arterial smooth muscle cells. Regulation of adenosine production at the cell surface. J. Biol. Chem. 264, 18986-18995.
111. Goss, J.A., Mangino, M.J., Callery, M.P. and Flye, M.W. (1993) Prostaglandin E2 downgulates kupffer cell production of Il-1 and IL-6 during hepatic regulation. Am. J. Physiol. 264, G601-C608.
112. Graeve, L., Baumann, M. and Heinrich, P.C. (1993) Interleukin-6 in autoimmune diseases. Clin. Invest. 71, 664-671
113. Greco, N., Tandon, NN., Jackson, BW., and Jamieson, A.(1992) Low structural specificity for nucleotide triphosphates as an antagonists of ADP-induced platelet activation. J. Biol. Chem. 267, 2966-2970.
114. Griese, M., Gobran, L.J. and Rooney, S.A. (1991) A2 and P2 purine receptor interactions and surfactant secretion in primary cultures of type II cells. Am. J. Physiol. 261, L140-147.
115. Grimble, R.F. (1990) Nutrition and cytokine action. Nutr. Res. Rev. 3, 193-210.
116. Gross, V., Zhang, B., Geng, Y., Villiger, P.M. and Lotz, M. (1994) Regulation of interleukin-6 (IL-6) expression: evidence for a tissue-specific role for protein kinase C. J. Clin. Immunol. 13, 310-320.
117. Grynkiewicz, G., Poenie, M. and Tsien, R.M. (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J. Biol. Chem. 260, 3440-3450.
118. Guan, Z., Baier, L.D., and Morrison, A.R. (1997) p38 mitogen-activated protein kinase down-regulates nitric oxide and up-regulates prostaglandin E2 biosynthesis stimulated by interleukin-1. J. Biol. Chem. 272,8083-8089.
119. Habib, A., Bernard, C., Tedgui, A. and Maclouf, J. (1994) Evidence of cross-talks between inducible nitric oxide synthase and cyclooxygenase II in rat peritoneal macrophages. Abstracts of the 9th International Conference on Prostaglandins and Related Compounds. Florence (Italy) June. 6-10, 57.
120. Handler, J.A., Danilowicz, R.M. and Eling, T.E. (1990) Mitogenic signaling by epidermal growth factor (EGF), but not platelet-derived growth factor, requires arachidonic acid metabolism in Balb/c 3T3 cells. J. Biol. Chem. 265, 3669-3673.
121. Harden, T.K., Boyer, J.L. and Nicholas, R.A. (1995) P2-purinergic receptors: subtype-associated signaling responses and structure. Ann. Rev. Pharmacol. & Toxicol. 35, 541-579.
122. Henning, R.H., Duin, M., Den Hertog, H.A. and Nelemans, A. (1993) Characterization of P2-purinoceptor mediated cyclic AMP formation in mouse C2C12 myotubes. Br. J. Pharmacol. 110, 133-138.
123. Hepler, J.R., Earp, H.S. and Harden, T.K. (1998) Long-term phorbol ester treatment down-regulates protein kinase C and sensitizes the phosphoinositide signaling pathway to hormone and growth factor stimulation: evidence for a role of protein kinase C in agonist-induced desensitization. J. Biol. Chem., 263, 7610-7619.
124. Hibbs, J.B. Jr. (1991) Synthesis of nitric oxide from L-arginine: a recently discovered pathway induced by cytokines with antitumour and antimicrobial activity. Res. Immunol. 142, 565- 569.
125. Hinson, R.M., Wiolliams, J.A. and Shacter, E. (1996) Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2. Proc. Natl. Acad. Sci. USA 93, 4885-4890.
126. Hirano, T., Yasukawa, K., Harada, H., Taga, T., Watanabe, Y., Matsuda, T., Kashiwamura, S., Nakajima, K., Koyama, K., Iwamatsu, A., Tsunasawa, S., Sakiyama, F., Matsui, H., Takahara, Y., Taniguchi, T. and Kishimoto, T.(1986) Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324, 73-76.
127. Hourani, S.M.O. and Chown, J.A. (1989) The effects of some possible inhibitors of ectonucleotidases on the breakdown and pharmacological effects of ATP in the guinea-pig urinary bladder. Gen. Pharmacol. 20, 413-416.
128. Hoyle, C.H.V. (1990) Pharmacological activity of adenine dinucleotides in the periphery: possible receptor classes and transmitter function. Gen. Pharmacol. 21, 827-831.
129. Huang, A., Payette, P., Abdullah, K., Cromlish, W.A. and Kennedy, B.P. (1996) Functional identification of the active-site nucleophile of the human 85-kDa cytosolic phospholipase A2. Biochemistry 35, 3712-3721.
130. Hug, H. and Sarre, T.F. (1993) Protein kinase C isoenzymes: divergence in signal transduction? Biochem. J. 291, 329-343.
131. Humphries, R.G., Robertson, M.J. and Leff, P. (1995) A novel series of P2T purinoceptor antagonists: definition of the role of ADP in arterial thrombosis. Trends Pharmacol. Sci. 16, 179-181.
132. Inoue, R. and Brading, A.F. (1990) The properties of the ATP-induced depolarization and current in signal cells isolated from the guinea-pig urinary bladder. Br. J. Pharmacol. 100, 619-625.
133. Iwabuchi, K., Hatakeyama, S., Takahashi, A., Ato, M., Okada, M., Kajino Y., Kajino, K. I., Ogasawara, K., Takami, K., Nakagawa, H. and Onoe, K. (1997) Csk overexpression reduces several monokines and nitric oxide productions but enhances prostaglandin E2 production in response to lipopolysaccharide in the macrophage cell line J774A.1. Eur. J. Immunol. 27, 742-749.
134. Iyengar, R. (1993) Molecular and functional diversity of mammalian Gs-stimulated adenylyl cyclases. FASEB J. 7, 768-775.
135. Jacobowitz, O. and Iyengar, R. (1994) Phorbol ester-induced stimulation and phosphorylation of adenylyl cyclase 2. Proc. Nat. Acad. Sci. USA 91, 10630-10634.
136. Jaken, S. (1996) Protein kinase C isozymes and substrates. Curr. Opinion Cell Biol. 8, 168-173.
137. Janosch, P., Schellerer, M., Seitz, T., Reim, P., Eulitz, M., Brielmeier, M., Kolch, W., Sedivy, J.M., and Mischak, H. (1996) Characterization of IB kinases. IB- is not phosphorylated by Raf-1 or protein kinase C isozymes, but is a casein kinase II substrate. J. Biol. Chem. 271, 13868-13874.
138. Jeon, Y. J., Yang, K.-H., Pulaski, J. T. and Kaminski, N. E. (1996) Attenuation of inducible nitric oxide synthase gene expression by 9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor-B/Rel activation. Mol. Pharmacol. 50, 334-341.
139. Jiang, C., Ting, A.T. and Seed, B. (1998) RRAP-r agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82-86.
140. Jin, J., Rao Dasari, V., Sistare, F.D. and Kunapuli, S.P. (1998) Distribution of P2Y receptor subtypes on haematopoietic cells. Br. J. Pharmacol., 123, 789-794.
141. Johansson, J., Curstedt, T. and Robertson, B. (1994) The proteins of the surfactant system. Eur. Respir. J. 7, 372-391.
142. Jun, C.D., Choi, B.M., Ryn, H., et al., (1994) Synergistic cooperation between phorbol ester and IFN- for induction of nitric oxide synthesis in murine peritoneal macrophages. J. Immunol. 153, 3684-3690.
143. Kamijo, R., Harada, H., Matsuyama, T., Bosland, M., Gerecitano, J., Shapiro, D., Le, J., Koh, S.I., Kimur, T., Green, S.J., Mak, T.W., Taniguchi, T., and Vilcek, J. (1994) Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science 263, 1612-1615.
144. Katada, T., Gilman, A.G., Watanabe, Y., Bauer, S. and Jakobs, K.H. (1985) Protein kinase C phosphorylates the inhibitory guanine-nucleotide-binding regulatory component and apparently suppresses its function in hormonal inhibition of adenylyl cyclase. Eu. J. Biochem. 151, 431-437.
145. Kawabe, J., Iwami, G., Ebina, T., Ohno, S., Katada, T., Ueda, Y., Homcy, C.J. and Ishikawa, Y. (1994) Differential activation of adenylyl cyclase by protein kinase C isoenzymes. J. Biol. Chem. 269, 16554-16658.
146. Keenedy, C. and Leff, P. (1995) How should P2x Purinoceptors be classified pharmacologically? Trends. Pharmacol. Sci. 16, 168-174.
147. Kelm, M. Feelisch, M., Spahr, R., Piper, H.M., Noack, E. and Schrader, J. (1988) Quantitative and kinetic characterization of nitric oxide and EDRF released from cultured endothelial cells. Biochem. Biophys. Res. Commun. 154, 236-244.
148. Keppler, D., Rudiger, J. and Decker, K. (1970) Enzymatic determination of uracil nucleotides in tissues. Anal. Biochem. 38, 105-114.
149. King, B.F., Townsend-Nicholson, A. and Burnstock, G. (1998) Metabotropic receptors for ATP and UTP: exploring the correspondence between native and recombinant nucleotide receptors. Trends Pharmacol. Sci. 19, 506-514.
150. Knowles, R.G., and Moncada, S. (1994) Nitric oxide synthases in mammals. Biochem. J. 298, 249-258.
151. Koide, M., Kawahara, Y., Nakayama, I., Tsuda, T. and Yokoyama, M. (1993) Cyclic AMP-elevating agents induce an inducible type of nitric oxide synthase in cultured vascular smooth muscle cells. J. Biol. Chem. 268, 24959-24966.
152. Kozawa, O., Suzuki, A. and Uematsu, T. (1997) Basic fibroblast growth factor induces interleukin-6 synthesis in osteoblasts: autoregulation by protein kinase C. Cell Signal. 9, 463-468.
153. Kozawa, O., Suzuki, A., Kaida, T., Tokuda, H. and Uematsu, T. (1997) Tumor necrosis factor-a autoregulates interleukin-6 synthesis via activation of protein kinase C. J. Biol. Chem. 272, 25099-25104.
154. Kozawa, O., Suzuki, A., Shinoda, J., Ozaki, N., Oiso, Y. and Uematsu, T. (1997) Involvement of phospholipase D activation in endothelin-1-induced release of arachidonic acid in osteoblast-like cells. J. Cell. Biochem. 64, 376-381.
155. Kozawa, O., Suzuki, A., Tokuda, H., Kaida, T. and Uematsu, T. (1997) Protein kinase C activation by interleukin (IL)-1 limits IL-1-induced IL-6 synthesis in osteoblast-like cells: involvement of phosphatidylcholine-specific phospholipase C. J. Cell Biochem. 67, 103-111.
156. Kozawa, O., Suzuki, A., Tokuda, H., Kaida, T. and Uematsu, T. (1998) Interleukin-6 synthesis induced by prostaglandin E2: cross-talk regulation by protein kinase C. Bone 22, 355-360.
157. Kozawa, O., Tokuda, H., Kaida, T., Matsuno, H. and Uematsu, T. (1997) Thrombin regulates interleukin-6 synthesis through phosphatidylcholine hydrolysis by phospholipase D in osteoblasts. Arch. Biochem. Biophys. 345, 10-15.
158. Kristhal, O.A., Marchenko, S.M., Obukhov, A.G. and Volkova, T.M. (1988) Receptors for ATP in rat sensory neurones: the structure-function relationship for ligands. Br. J. Pharmacol. 95, 1057-1062.
159. Kunapuli, S.P. (1998) Multiple P2 receptor subtypes on platelets: a new interpretation of their function. Trends Pharmacol. Sci. 19, 391-394.
160. Kunz, D., Muhl, H., Walker, G. and Pfeilschifter, J. (1994) Two distinct signaling pathways trigger the expression of inducible nitric oxide synthase in rat renal mesangial cells. Proc. Natl. Acad. Sci. USA 91, 5387-5391.
161. Kurihara, K., Hosoi, K. and Ueha , T. (1992) Characterization of ecto-nucleoside triphosphatase on A-431 human epidermoidal carcinoma cells. Enzyme 46, 213-220.
162. Kuroda, A., Sugiyama, E., Taki, H., Mino, T. and Kobayashi, M. (1997) Interleukin-4 inhibits the gene expression and biosynthesis of cytosolic phospholipase A2 in lipopolysaccharide stimulated U937 macrophage cell line and freshly prepared adherent rheumatoid synovial cells. Biochem. Biophy. Res. Comm. 230, 40-43.
163. Lai, J.-H., and Tan, T.-H. (1994) CD28 signaling causes a sustained down-regulation of IB which can be prevented by the immunosuppressant rapamycin. J. Biol. Chem. 269, 30077-30080.
164. Lambrecht, G., Friebe, T., Grimm, U., Windscheif, U., Bungardt, E., Hilderbrandt, C., Baumert, H., Spatz-kumbel, G. and Mutschler, E. (1992) PPADS, a novel functionally selective antagonist of P2 purinoceptor-mediated responses. Eur. J. Pharmacol. 217, 217-219.
165. Lapointe, M.C., and Isenovic, E. (1999) IL-1 regulation of inducible nitric oxide synthase and cyclooxygenase-2 involves the p42/p44 and p38 MAPK signal pathways in cardiac myocytes. Hypertension. 31, 276-282.
166. Larsson, P. K. A., Claesson, H.-E. and Kennedy, B. P. (1998) Multiple splice variants of the human calcium-independent phospholipase A2 and their effect on enzyme activity. J. Biol. Chem. 273, 207-214.
167. Lazarowski, E.R. and Harden, T.K. (1994). Identification of a uridine nucleotide-selective G-protein-linked receptor that activates phospholipase C. J. Biol. Chem. 269, 11830-11836.
168. Lazarowski, E.R., Homolya, L., Boucher, R.C. and Harden, T.K. (1997) Direct demonstration of mechanically induced release of cellular UTP and its implication for uride nucleotide receptor activation. J. Biol. Chem., 272, 24348-24354.
169. Lazarowski, E.R., Watt, WC., Stutts, M.J., Boucher, R.C., Harden, T.K. (1995) Pharmacological selectivity of the cloned human P2U-purinoceptor: potent activation by diadenosine tetraphosphate. Br. J. Pharmacol. 116, 1619-1627.
170. Lee, F. S., Hagler, J., Chen, Z. J., and Maniatis, T. (1997) Activation of the IB kinase complex by MEKK1, a kinase of the JNK pathway. Cell 88, 213-222.
171. Lee, F. S., Peters, R. T., Dang, L. C., and Maniatis, T. (1998) MEKK1 activates both IB kinase  and IB kinase . Proc. Natl. Acad. Sci. US A 95, 9319-9324.
172. Lee, J.C., Layton, J.T., McDonnell, P.C., Gallagher, T.F., Kumar, S., Green, D., McNulty, D., Blumenthal, M.J., Heys, J.R., Landvatter, S.W., Strickler, J.E., McLaughlin, M.M., Siemerns, I.R., Fisher, S.M., Livi, G.P., White, J.R., Adams, J.L., and Young, P.R. (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739-746.
173. Leslie, C.C. (1997) Properties and regulation of cytosolic phospholipase A2. J. Biol. Chem. 272, 16709-16712.
174. Levesque, L., Dean, N. M., Sasmor, D.H. and Crooke, S.T. (1997) Antisense oligonucleotides targeting human protein kinase C- inhibit phorbol ester-induced reduction of bradykinin-evoked calcium mobilization in A549 cells. Mol. Pharmacol. 51, 209-216.
175. Li, H. Oehrlein, S.A. Walleerath, T., Ihrig-Biedert, I., Wohlfart, P., Ulshfer, T., Jessen, T., Herget, T., Forstermann, U. and Kleinert, H. (1998) Activation of protein kinaseC and/or  enhances transcription of the human endothelial nitric oxide synthase gene. Mol. Pharmacol. 53, 630-637.
176. Libermann, T.A. and Baltimore, D. (1990) Activation of interleukin-6 gene expression through the NF-B transcription factor. Mol. Cell Biol. 10, 2327-2344.
177. Lin, L.L., Lin, A. and Knopf, J. (1992) Hormonal regulation of cPLA2. Proc. Natl. Acad. Sci. USA 89, 6147-6151.
178. Lin, L.L., Wartmann, M., Lin, A.Y., Knopf, J.L., Seth, A. and Davis, R.J. (1993) cPLA2 is phosphorylated and activated by MAP kinase. Cell 72, 269-278.
179. Lin, S.H. and Guidotti, G. (1989) Cloning and expression of a cDNA coding for a rat liver plasma membrane ecto-ATPase. The primary structure of the ecto-ATPase is similar to that of the human biliary glycoprotein I. J. Biol. Chem. 264, 14408-14414.
180. Lin, W. W. and Chen, B. C. (1997) Involvement of protein kinase C in the UTP-mediated potentiation of cyclic AMP accumulation in mouse J774 macrophages. Br. J. Pharmacol. 121, 1749-1757.
181. Lin, W. W. and Chen, B. C. (1998) Pharmacological comparison of UTP- and thapsigargin-induced arachidonic acid release in RAW 264.7 macrophages. Br. J. Pharmacol. 123, 1173-1181.
182. Lin, W. W. and Lee, Y. T. (1996) Pyrimidinoceptor-mediated activation of phospholipase C and phospholipase A2 in RAW 264.7 macrophages. Br. J. Pharmacol. 119, 261-268.
183. Lin, W. W., Chang, S. H. and Wu, M. L. (1998) Lipoxygenase metabolites as mediators of UTP-induced intracellular acidification in mouse RAW 264.7 macrophages. Mol. Pharmacol. 53, 313-321.
184. Lin, W.W. (1994) Heterogeneity of nucleotide receptors in NG108-15 neuroblastoma and C6 glioma cells for mediating phosphoinositide turnover. J. Neurochem. 62, 536-542.
185. Lin, W.W. (1997) Priming effects of lipopolysaccharide on UTP-induced arachidonic acid release in RAW 264.7 macrophages. Eur. J. Pharmacol. 321, 121-127.
186. Lin, W.W. and Chen, B.C. (1998) Distinct PKC isoforms mediated the activation of cPLA2 and adenylyl cyclase by phorbol ester in RAW 264.7 macrophages. Br. J. Pharmacol., 125, 1601-1609.
187. Lin, W.W. and Chen, B.C. (1998) Pharmacological comparison of UTP- and thapsigargin-induced arachidonic acid release in mouse RAW 264.7 macrophages. Br. J. Pharmacol. 123, 1173-1181.
188. Lin, W.W. and Chuang, D.M. (1992) Regulation of bradykinin-induced phosphoinositide turnover in cultured cerebellar astrocytes: possible role of protein kinase C. Neurochem. Int., 21, 573-579.
189. Lin, W.W. and Chuang, D.M. (1994) Different signal trandsuction pathways are coupled to the nucleotide receptor and the P2Y receptor in C6 glioma cells. J. Pharmacol. Exp. Ther. 269, 926-931.
190. Lin, W.W. and Lee, Y.T. (1996) Pyrimidinoceptor-mediated activation of phospholipase C and phospholipase A2 in RAW 264.7 macrophages. Br. J. Pharmacol. 119, 261-268.
191. Lin, W.W., and Chen B.C. (1998) Pharmacological comparison of UTP- and thapsigargin-induced arachidonic acid release in mouse RAW 264.7 macrophages. Br. J. Pharmacol.123, 1173-1181.
192. Lin, W.W., and Chen, B.C. (1997) Involvement of protein kinase C in the UTP-mediated potentiation of cyclic AMP accumulation in mouse J774 macrophages. Br. J. Pharmacol. 121, 1749-1757.
193. Lin, W.W., Chen, B.C., Hsu, Y.W., Lee, C.M. and Shyue, S.K. (1999) Modulation of iNOS induction by PGE2 in macrophages: distinct susceptibility in murine J774 and RAW 264.7 macrophages. Prostaglandins Lipid Mediators (in press).
194. Lorsbach, R.B., Murphy, W.J., Lowenstein, C.J., Snyder, S.H., and Russell, S.W. (1993) Expression of the nitric oxide synthase gene in mouse macrophages activated for tumor cell killing. Molecular basis for the synergy between interferon- and lipopolysaccharide. J. Biol. Chem. 268, 1908-1913.
195. Lowenstein, C.J., Alley, E.W., Raval. P., Snowman, A.M., Snyder, S.H., Russell, S.W., and Murphy, W.J. (1993) Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon  and lipopolysaccharide. Proc. Natl. Acad. Sci. USA 90, 9730-9734.
196. Lustig, K.D., Erb, L., Landis, D.M., Hicks-Taylor, C.S., Zhang, X., Sportiello, M.G. and Weisman, G.A (1992) Mechanisms by which extracellular ATP and UTP stimulate the release of prostacyclin from bovine pulmonary artery endothelial cells. Biochem. Biophys. Acta 1134, 61-72.
197. MacMicking, J., Xie, Q-W. and Nathan, C. (1997) Nitric oxide and macrophage function. Annu. Rev. Immunol. 15, 323-350.
198. Margolis, R.N., Schell, M.J., Taylor, S.I., and Hubbard, A.L. (1990) Hepatocyte plasma membrane Ecto-ATPase (pp120/HA4) is a substrate for tyrosine kinase activity of the insulin receptor. Biochem. Biophys. Res. Commun. 166, 562-566.
199. Marotta, P., Sautebin, L. and Rosa, M. D. (1992) Modulation of the induction of nitric oxide synthase by eicosanoids in the murine macrophage cell line J774. Br. J. Pharmacol. 107, 640-641.
200. Martin, C.A. and Dorf, M.E. (1990) Interleukin-6 production by murine macrophage cell lines P388D1 and J774A.1: stimulation requirements and kinetics. Cell. Immunol.128, 555-568.
201. Martin, E., Nathan, C., and Xie, Q-W. (1994) Role of interferon regulatory factor 1 in induction of nitric oxide synthase. J. Exp. Med. 180, 977-984.
202. Martin, K.A., Kertesy, S.B. and Dubyak, G.B. (1997) Down-regulation of P2U-purinergic nucleotide receptor messenger RNA expression during in vitro differentiarion of human myeloid leukocytes by phorbol esters or inflammatory activators. Mol. Pharmacol. 51, 97-108.
203. Martin, W., Cusack, N.J., Carleton, J.S. and Gordon, J.L. (1985) Specificity of P2-purinoceptor that mediates endothelium-dependent relaxation of the pig aorta. Eur. J. Pharmacol. 108, 295-299.
204. Martiny-Baron, G., Kazanietz, M.G., Mischak, H., Blumberg, P.M., Kochs, G., Hug, H., Marme, D. and Schachtele, C. (1993) Selective inhibition of protein kinase C isozymes by the indolocarbazole Go 6976. J. Biol. Chem, 268, 9194-9197.
205. Matsuno, M., Kozawa, O., Suzuki, A., Tokuda, H., Kaida, T., Matsuno, H., Niwa, M. and Uematsu, T. (1998) Involvement of protein kinase C activation in endothelin-1-induced secretion of interleukin-6 in osteoblast-like cells. Cell Signal 10, 107-111.
206. Matsuoka, I., Zhou, Q., Ishimoto, H. and Nakanishi, H. (1995) Extracellular ATP stimulates adenylyl cyclase and phospholipase C through distinct purinoceptors in NG108-15 cells. Mol. Pharmacol. 47, 855-862.
207. Mattila, P.S., Ullman, K.S., Fiering, S., Emmel, E.A., McCutcheon, M., Crabtree, G.R., and Herzenberg, L.A. (1990) The actions of cyclosporin A and FK506 suggest a novel step in the activation of T lymphocytes. EMBO J. 9, 4425-4433.
208. Mayer, R.J. and Marshall, L.A. (1993) New insights on mammalian phospholipase A2(s); comparison of arachidonoyl-selective and -nonselective enzymes. FASEB J. 7, 339-348.
209. Mercurio, F., Zhu, H., Murray, B. W., Shevchenko, A., Bennett, B. L., Li, J. W., Young, D. B., Barbosa, M., Manning, A. M., and Rao, A. (1997) IKK-1 and IKK-2:cytokine-activated IB kinases essential for NF-B activation. Science 278, 860-866.
210. Miller, B. W., Baier, L. D. and Morrison, A. R. (1997) Overexpression of protein kinase C- isoform increases cyclooxygenase-2 and inducible nitric oxide synthase. Am. J. Physiol. 273, C130-136.
211. Mochly-Rosen, D. and Gordon, A.D. (1998) Anchoring proteins for protein kinase C: a means for isozyme selectivity. FASEB J. 12, 35-42.
212. Moncada, S., Grhglewski, R., Bunting, S. and Vane, J.R. (1976) An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263, 663-665.
213. Moncada, S., Palmer, R.M.J., and Higgs, E.A. (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43, 109-142.
214. Mons, N. and Cooper D.M.F. (1995) Adenylate cyclases: critical foci in neuronal signaling. Trends Neurosci. 18, 536-542.
215. Morimoto, B. H. and Koshland, D. E. (1994) Conditional activation of cAMP signal transduction by protein kinase C. The effect of phorbol esters on adenylyl cyclase in permeabilized and intact cells. J. Biol. Chem. 269, 4065-4069.
216. Motte, S., Pirotton, S. and Boeynaems, J.M. Heterogeneity of ATP receptors in aortic endothelial cells. Involvement of P2Y and P2U receptors in inositol phosphate response. Circ. Res. 72, 504-510.
217. Muller-Decker, K. (1989) Interruption of TPA-induced signals by an antiviral and antitumoral xanthate compound: inhibition of a phospholipase C-type reaction. Biochem. Biophys. Res. Commun. 162, 198-205.
218. Mullet, D., Fertel, R.H., Kniss, D., and Cox, G.W. (1997) An increase in intracellular cyclic AMP modulates nitric oxide production in IFN--treated macrophages. J. Immunol. 158, 897-904.
219. Murakami, M., Shimbara, S., Kambe, T., Kuwata, H., M. Winstead, V., Tischfield, J. A. and Kudo, I. (1998) The functions of five distinct mammalian phospholipase A2s in regulating arachidonic acid release. Type IIA and type V secretory phospholipase A2s are functionally redundant and act in concert with cytosolic phospholipase A2. J. Biol. Chem. 273, 14411-14423.
220. Murayama, T., Kajiyama, Y., and Nomura, Y. (1990) Histamine-stimulated and GTP-binding proteins-mediated phospholipase A2 activation in rabbit platelets. J. Biol. Chem. 265, 4290-4295.
221. Naraba, H., Murakami, M., Matsumoto, H., Shimbara, S., Ueno, A., Kudo, I. and Oh-Ishi, S. (1998) Segregated coupling of phospholipase A2, cyclooxygenases, and terminal prostanoid synthases in different phases of prostanoid biosynthesis in rat peritoneal macrophages. J. Immunol. 160, 2974-2982.
222. Nathan, C. (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J. 6, 3051-3064.
223. Nathan, C., and Xie, Q.-W.(1994) Regulation of biosynthesis of nitric oxide. J. Biol. Chem. 269, 13725-13728.
224. Nathan, C.F. (1987) Secretory products of macrophages. J. Clin. Invest. 79, 319-326.
225. Nathan, C.F. and Hibbs J. Jr. (1991) Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr. Opin. Immunol. 3, 65-70.
226. Naumann, M., and Scheidereit, C. (1994) Activation of NF-B in vivo is regulated by multiple phosphorylations. EMBO J. 13, 4597-4607.
227. Nemenoff, R.A., Winitz, S., Qian, N.X., Van Putten, V., Johnson, G.L. and Heasley, L.E. (1993) Phosphorylation and activation of a high molecualr weight form phospholipase A2 by p42 microtubule-associated protein 2 kinase and protein kinase C. J. Biol. Chem. 268, 1960-1964.
228. Nishizuka, T. (1986) Studies and perspectives of protein kianse C. Science 233, 305-312.
229. Nishizuka, Y. (1984) The role of protein kinase C in cell surface signal transduction and tumor promotion. Nature 308, 693-698.
230. Nishizuka, Y. (1986) Studies and perspective of protein kinase C. Science 233, 305-312.
231. Nishizuka, Y. (1992) Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258, 607-614.
232. Nishizuka, Y. (1995) Protein kinase C and lipid signaling for sustained cellular responses. FASEB J, 9, 484-496.
233. Norris, J. L. and Manley, J. L. (1992) Selective nuclear transport of the Drosophila morphogen dorsal can be established by a signaling pathway involving the transmembrane protein Toll and protein kinase C. Gen. Dev. 6, 1654-1667.
234. North, R.A. and Barnard, E.A. (1997) Nucleotide receptors. Curr. Opin. Neurobiol. 7, 346-357.
235. Nuttle, LC., and Dubyak, GR. (1994) Differential activation of cation channels and non-selective pores by macrophage P2Z purinergic receptors expressed in Xenopus oocytes. J. Biol. Chem. 269, 13988-13996.
236. O’Connor, S.E., Dainty, I.A. and Leff, P. (1991) Further subclassification of ATP receptors based on agonist studies. Trends Pharmacol. Sci. 12, 137-141.
237. O’Sullivan, M. G., Chilton, F. H., Huggins, E. M. and McCall, C. E. (1992) Lipopolysaccharide priming of alveolar macrophages for enhanced synthesis of prostanoids involves induction of a novel prostaglandin H synthase. J. Biol. Chem. 267, 14547-14550.
238. Ogle, C.K., Guo, X., Szczur, K., Hartmann, S. and Ogle, J.D. (1994) Production of tumor necrosis factor, interleukin-6 and prostaglandin E2 by LPS-stimulated rat bone marrow macrophages after thremal injury: effect of indomethacin. Inflammation 18, 175-185.
239. Ohno, S., Kawasaki, H., Imajoh, S. and Suzuki, K. (1987) Tissue-specific expression of three distinct types of rabbit protein kinase C. Nature 325, 161-166.
240. Okajima, F., Tokumitsu, Y., Kondo, Y. and Ui, M. (1987) P2-purinergic receptors are coupled to two signal transduction systems leading to inhibition of cAMP generation and to production of inositol trisphosphate in rat hepatocytes. J. Biol. Chem. 262, 13483-13490.
241. Orellana, S., Solski, P.A. and Brown, J.H. (1987) Guanosine 5’-O-(thiotriphosphate)-dependent inositol triphosphate formation in membranes is inhibited by phorbol ester and protein kinase C. J. Biol. Chem. 262, 1638-1643.
242. Osipchuk, Y. and Cahalan, M. (1992) Cell-to-cell spread of calcium signals mediated by ATP receptors in mast cells. Nature 359, 241-244.
243. Pace, J.L., Russell, S.W., Torres, B.A., Johnson, H.M., and Gray, P.W. (1983b) Recombinant mouse interferon- induces the priming step in macrophage activation for tumor cell killing J. Immunol. 130, 2011-2013.
244. Pace, J.L., Russell, S.W., Schreiber, R.D., Altmann, A., and Katz, D.H. (1983a) Macrophage activation: priming activity from a T-cell hybridoma is attributable to interferon-. Proc. Natl. Acad. Sci. USA 80, 3782-3786.
245. Paglin, S., Roy, R. and Polgar, P. (1993) Characterization of hormonally regulated and particulate-associated phospholipase A2 from bovine endothelial cells. J. Biol. Chem. 268, 11697-11702.
246. Pang, L. and Hoult, J. R. (1997) Repression of inducible nitric oxide synthase and cyclooxygenase-2 by prostaglandin E2 and other cyclic AMP stimulants in J774 macrophages. Biochem. Pharmacol. 53, 493-500.
247. Park, Y.C., Jun, C.D., Kang, H.S., Kim, H.D., Kim, H.M., and Chung, H.T. (1996) Role of intracellular calcium as a priming signal for the induction of nitric oxide synthesis in murine peritoneal macrophages. Immunology 87, 296-302.
248. Parr, C.E., Sullivan, D.M., Paradiso, A.M., Lazarowski, E.R., Burch, L,H., Olsen, J.C., Erb, L., Weisman, G.A., Boucher, R.C. and Turner, J.T. (1994) Cloning and expression of human P2U nucleotide receptor, a target for cystic fibrosis pharmacotherapy. Pro. Natl. Acad. Sci. USA 91, 3275-3279.
249. Patel, P., Brown, C. and Boarder, M.R. (1996a) Protein Kinase C isoforms in bovine aortic endothelial cells : role in regulation of P2Y- and P2U-purinoceptor-stimulated prostacyclin release. Br. J. Pharmacol. 118, 123-130.
250. Patel, V., Brown, C., Goodwin, A., Wilkie, N. and Boarder, M.R. (1996b) Phosphorylation and activation of p42 and p44 mitogen-activated protein kinase are required for the P2 purinoceptor stimulation of endothelial prostacyclin production. Biochem. J. 320, 221-226.
251. Paul, A., Pendreigh, R.H., and Plevin, R. (1995) Protein kinase C and tyrosine kinase pathways regulate lipopolysaccharide-induced nitric oxide synthase activity in RAW 264.7 murine macrophages. Br. J. Pharmacol. 114, 482-488.
252. Pintor, J., Torres, M., Castro, E. and Miras-Portugal, M.T. (1991) Characterization of diadenosine tetraphossphate (AP4A) binding sites in cultured chromaffin cells: evidence for a P2Y site. Br. J. Pharmacol. 103, 1980-1984.
253. Pirotton, S., Lecomte, M., Robaye, B., DeMolle, D., Van Coevorden, A., Nairn, A.C. and Boeynaems, J.M. (1990) P2-purinergic receptors on vascular endothelial cells: Transduction mechanisms. Ann. NY Acad. Sci. 603, 480-483.
254. Pison, U., Max, M., Neuendank, A., Weissbach, S. and Pietschmann, S. (1994) Host defence capacities of pulmonary surfactant: evidence for “non-surfactant” functions of the surfactant system. Eur. J. Clin. Invest. 24, 586-599.
255. Post, S.R., Jacobson, J.P. and Insel, P.A. (1996) P2 purinergic receptor agonists enhance cAMP production in Madin-Darby canine kidney epithelial cells via an autocrine/paracrinemechanism. J. Biol. Chem. 271, 2029-2032.
256. Pruimboom, W.M., van Dijk., J. A.P.M., Tak, C.J.A.M., Garrelds, I., Bonta, I.L., Wilson, P.J.H. and Zijlstra, F.J. (1994) Interaction between cytokines and eicosanoids: a study using human peritoneal macrophages. Immunol. Lett. 41, 255-260.
257. Purkiss, J.R., West, D., Wilkes, L.C., Scott, C., Yarrow, P., Wilkinson, G.F. and Boarder, M.R. (1994) Stimulation of phospholipase C in cultured microvascular endothelial cells from human frontal lobe by histamine, endotheilin and purinoceptor agonists. Br. J. Pharmacol. 111, 1041-1046.
258. Purkiss, J.R., Wilkinson, G.F. and Boarder, M.R. (1994) Different regulation of inositol 1,4,5-trisphosphate by co-existing P2Y-purinoceptors and nucleotide receptors on bovine aortic endothelial cells. Br. J. Pharmacol. 111, 723-728.
259. Qiu, Z.H., De Carvalho, M.S. and Leslie, C.C. (1993) Regulation of phospholipase A2 activation by phosphorylation in mouse peritoneal macrophages. J. Biol. Chem. 268, 24506-24513.
260. Quinn, M.T., Parathasarathy, S. and Steinberg, D. (1988) Lysophosphatidylcholine: a chemotactic factor for human monocytes and its potential role in atherogenesis. Proc. Natl. Acad. Sci. USA 85, 2805-2809.
261. Raddassi, K., Petit, J. F. and Lemaire, G. (1993) LPS-induced activation of primed murine peritoneal macrophages is modulated by prostaglandins and cyclic nucleotides. Cell. Immunol. 149, 50-64.
262. Ralveic, V. and Burnstock, G. (1996) Discrimination by PPADS between endothelial P2X- and P2U-purinoceptors in the rat isolated mesenteric bed. Br. J. Pharmacol. 118, 428-434.
263. Regnier, C.H., Song, H.Y., Gao, X. Goeddel, D.V., Cao, Z., and Rothe, M. (1997) Identification and characterization of an IB kinase. Cell 90, 373-383.
264. Ridley, S.H., Sarafield, S.J., Lee, J.C., Bigg, H.F., Cawston, T.E., Taylor, D.J., DeWitt, D.L., and Saklatvala, J. (1997) Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J. Immunol. 158, 3165-3173.
265. Roco, L.P., and Meltzer, M.S. (1978) Macrophage activation for tumor cytotoxicity: development of macrophage cytotoxic activity requires completion of sequence of short-lived intermediary reactions. J. Immunol. 121, 2035-2042.
266. Rodriguez del Castillo, A., Torres, M., delicado, E.G.and Miras-Portugal, M.T. (1988) Subcellular distribution studies of diadenosine polyphosphates-AP4A and AP5A-in bovine adrenal medulla: presence in chromaffin granules. J. Neurochem. 51, 1696-1703.
267. Rola-Pleszczynski, M. and Stankova, J. (1992) Leukotriene B4 enhances interleukin-6 (IL-6) production and IL-6 messenger RNA accumulation in human monocytes in vitro: transcriptional and posttranscriptional mechanisms. Blood 80, 1004-1011.
268. Rooney, S.A. (1990) Type II cell purinoceptors and surfactant section. Prog. Respir. Res. 25, 127-135.
269. Rougier, F., Cornu, E., Praloran, V. and Denizot, Y. (1998) IL-6 and IL-8 production by human bone marrow stromal cells. Cytokine 10, 93-97.
270. Sa, G. and Fox, P.L. (1994) Basic fibroblast growth factor-stimulated endothelial cell movement is mediated by a pertussis toxin-sensitive pathway regulating phospholipase A2 activity. J. Biol. Chem. 269, 3219-3225.
271. Salvemini, D., Korbut, R., Anggard, E., and Vane., J. (1990) Immediate release of a nitric oxide-like factor from bovine aortic endothelial cells by Escherichia coli lipopolysaccharide. Proc. Natl. Acad. Sci. USA 87, 2593-2597.
272. Salvemini, D., Misko, T. P., Masferrer, J. L., Seibert, K., Currie, M. G. and Needleman, P. (1993) Nitric oxide activates cyclooxygenase enzymes. Proc. Natl. Acad. Sci. USA 90, 7240-7244.
273. Sands, W.A., Clark, J.S., and Liew, F.Y. (1994) The role of a phosphatidylcholine-specific phospholipase C in the production of diacylglycerol for nitric oxide synthesis in macrophages activated by IFN- and LPS. Biochem. Biophys. Res. Commun. 199, 461-466.
274. Sato, K., Okajima, F. and Kondo, Y. (1992) Extracellular ATP stimulates three different receptor-signal transduction systems in FRTL-5 thyroid cells. Activation of phospholipase C, and inhibition and activation of adenylate cyclase. Biochem. J. 283, 281-287.
275. Schievella, A.R., Regier, M.K., Smith, W.L. and Lin, L.L. (1995) Calcium-mediated translocation of cytosolic phospholipase A2 to the nuclear envelope and endoplasmic reticulum. J. Biol. Chem. 270, 30749-30754.
276. Schouten, G.J., Vertegaal, A.C.O., Whiteside, S.T. Israel, A., Toebes, M., Dorsman, J.C., van der Eb. A.J., and Zantema, A. (1997) IB is a target for the mitogen-activated 90 kDa ribosomal S6 kinase. EMBO J. 16, 3133-3144.
277. Schreck, R. Rieber, P., and Baeuerle, P. A. (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-B transcription factor and HIV-1. EMBO J. 10, 2247-2258.
278. Schreck, R., Meier, B., Mannel, D.N., Droge, W., and Baeuerle, P.A. (1992) Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J. Exp. Med. 175, 1181-1194.
279. Sehgal, P.B., Walther, Z. and Tamm, I. (1987) Rapid enhancement of 2-interferon/B-cell differentiation factor BSF-2 gene expression in human fibroblasts by diacylglycerols and the calcium ionophore A23187. Proc. Natl. Acad. Sci. USA 84, 3663-3667.
280. Seifert, R. and Schultz, G. (1989) Involvement of pyrimidinoceptors in the regulation of cell functions by uridine and by uracil nucleotides. Trends Pharmacol. Sci. 10, 365-369.
281. Serkkola, E. and Hurme, M. (1993) Activation of NF-B by cAMP in human myeloid cells. FEBS Lett. 334, 327-330.
282. Severn, A., Wakelam, M.J.O., and Liew, F.Y. (1992) The role of protein kinase C in the induction of nitric oxide synthesis by murine macrophages. Biochem. Biophys. Res. Commun. 188, 997-1002.
283. Shirakawa, F. and Mizel, S. B. (1989) In vitro activation and nuclear translocation of NF-B catalyzed by cyclic AMP-dependent protein kinase and protein kinase C. Mol. Cell. Biol. 9, 2424-2430.
284. Siebenlist, U., Franzoso, G., and Brown, K. (1994) Structure, regulation and function of NF-B. Ann. Rev. Cell Biol. 10, 405-455.
285. Sippel, C.J., Suchy, F.J., Ananthanarayanan, M. and Perlmutter, D.H. (1990) The rat liver ecto-ATPase is also a canalicular bile acid transport protein. J. Biol. Chem. 268, 2083-2091.
286. Smith, J.A.M., Webb, C., Holford, J. and Burgess, G.M. (1995) Signal transduction pathways for B1 and B2 bradykinin receptors in bovine pulmonary artery endothelial cells. Mol. Pharmacol. 47, 525-534.
287. Smith, R.J., Sam, L.M., Justen, J.M., Bundy, G.L., Bala, G.A., and Bleasdale, J.E. (1990) Receptor-coupled signal transduction in human polymorphonuclear neutrophils: effects of a novel inhibitor of phospholipase C-dependent processes on cell responsiveness. J. Pharmacol. Exp. Ther. 253, 688-697.
288. Sodhi, A., and Kumar, R. (1994) Int. J. Immunolpathol. Pharmacol. 7, 65-77.
289. Somers, S.D., Weiel, J.E., Hamilton, T.A., and Adams, D.O. (1986). Phorbol esters and calcium ionophore can prime murine peritoneal macrophage for tumor cells destruction. J. Immunol. 136, 4199-4205.
290. Sowa, G., and Przewlocki, R. (1994) cAMP analogues and cholera toxin stimulate the accumulation of nitrite in rat peritoneal macrophage cultures. Eur. J. Pharmacol. 266, 125-129.
291. Spangelo, B.L., Isakson, P.C., and MacLeod, R.M. (1990) Production of interleukin-6 by anterior pituitary cells is stimulated by intracellular adenosine 3’,5’-monophosphate and vasoactive intestinal peptide. Endocrinology 127, 403-409.
292. Spriggs, D.R., Deutsch, S. and Kufe, D.W. (1991) Genomic structure, induction, and production of TNF-a. In The Cytokine Handbook. ed. Thompson, A.W. pp.1-34. London: Academic Press.
293. Stadler, J., Racic, M. S., Billiar, T. R., Curran, R. D., Mcintyre, L. A., Georgescu, H. I., Simmons, R. L. and Evans., C. H. (1991) Articular chondrocytes synthesize nitric oxide in response to cytokines and lipopolysaccharide. J. Immunol. 147, 3915-3920.
294. Steffan, N.M., Bren, G.D., Frantz, B., Tocci, M.J., O’Neill, E.A., and Paya, C.V. (1995) Regulation of IB phosphorylation by PKC- and Ca2+-dependent signal transduction pathways. J. Immunol. 155, 4685-4691.
295. Stratman, N. C., Carter, D. B. and Sethy, V. H. (1997) Ibuprofen: effect on inducible nitric oxide synthase. Brain Res.-Mol. Brain Res. 50, 107-112.
296. Streb, H., Irvine, R.F., Berridge, M.J. and Schulz, I. (1983) Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature 306, 67-69.
297. Sugiyama, K. (1971) Calcium-dependent histamine release with degranulation from isolated rat mast cells Jpn. J. Pharmacol. 84, 165-173.
298. Sumi, M., Kiuchi, K., Ishikawa, T., Ishii, A., Hagiwara, M., Nagatsu, T., and Hidaka, G. (1991) The newly synthesized selective Ca2+/calmodulin dependent protein kinase II inhibitor KN-93 reduces dopamine contents in PC12h cells. Biochem. Biophys. Res. Commun. 181, 968-975.
299. Sunahara, R.K., Dessauer, C.W. and Gilman, A.G. (1996) Complexity and diversity of mammalian adenylyl cyclases. Ann. Rev. Pharmacol. Toxicol. 36, 461-480.
300. Sung, S.J., and Silverstein, S.C. (1985) Inhibition of macrophage phagocytosis by methylation inhibitors. J. Biol. Chem. 260, 546-554.
301. Surprenant, A., Rassendren, F., Kawashima, E., North, R. A., and Buell, G. (1996) The cytolytic P2Z receptor for extracellular ATP indentified as a P2X receptor (P2X7). Science 272:735-738.
302. Tada, S., Okajima, F., Mitsui, Y., Kondo, Y. and Ui, M. (1992) P2 purinoceptor-mediated cyclic AMP accumulation in bovine vascular smooth muscle cells. Eur. J. Pharmacol. 227, 25-31.
303. Taussig, R. and Gilman, A.G. (1995) Mammalian membrane-bound adenylyl cyclas
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1. 李鎡堯,〈國內人工生殖科技之現況〉,《月旦法學雜誌》,第二期,1995年6月,頁6-8。
2. 郭碧照,李茂盛,〈護理措施對不孕症接受生殖科技治療婦女社會心理反應與壓力感受之效果探討〉,《護理雜誌》,第39卷第1期,1992年3月,頁95-105。
3. 林芳玫,〈新科技是傳統的幫兇:代理孕母與母親身份的問題化〉,《騷動》,第2期,1996年10月,頁48-51。
4. 李鎡堯,〈談人工授精〉,《健康世界》,第49期,1980年1月,頁16-18。
5. 李震山,〈從憲法保障生命權及人性尊嚴之觀點論人工生殖〉,《月旦法學雜誌》,第2期,1995年6月,頁18-25。
6. 李從業,張昇平,陳嘉琦,〈不孕夫妻的困擾程度、壓力感受及因應策略的比較〉,《護理研究》,第5卷第5期,1997年10月,頁425-437。
7. 李宇宙,〈人工代母與現代醫學倫理〉,《應用倫理研究通訊》,第5期,1998年1月,頁32-36。
8. 張碧芬,〈試管嬰兒技術的倫理考量〉,《護理雜誌》,第42卷第3期,1995年9月,頁30-36。
9. 孫效智,〈代理孕母的倫理與法律問題〉,《應用倫理研究通訊》,第4期,1997年10月,頁8-11。
10. 陳美伶,〈人工生殖子女婚生地位之認定〉,《月旦法學雜誌》,第2期,1995年6月,頁25-37。
11. 陳惠馨,〈人工生殖技術對親屬法的衝擊〉,《高雄律師會訊》,1996年12月,第1卷第12期,頁29-40。
12. 楊友仕,〈生殖科技之新進展(一):從「試管嬰兒」談起〉,《健康世界》,新版第46期,1989年10月,頁49-50。
13. 楊友仕,〈生殖科技之新進展(三)----「禮物」?「嬰兒」!〉,《健康世界》,新版第49期,1990年2月,頁94-96。
14. 楊友仕,〈生殖科技之新進展(四)----神奇的輸卵管︰談輸卵管內胚胎植入術〉,《健康世界》,新版第50期,1990年2月,頁27-29。
15. 楊友仕,〈生殖科技之新進展(五)----從冰箱裡走出來的娃娃︰談「冷凍胚胎」〉,《健康世界》,新版第51期,1990年3月,頁26-29。
 
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