臺灣博碩士論文加值系統

Part-I D9-THC是從大麻植物中萃取出來的精神興奮性物質，有關D9-THC對行為的影響及藥理實驗的報導已有許多詳盡的研究，THC會經由兩種不同型式的cannabinoid receptor而達到其藥理作用，CB1是最先被命名的受體，在腦中大量存在，但在其他部位亦有發現，而CB2主要存在於血液組織系統中，這兩種受體會經由與cannabinoid化合物產生不同生物作用，包括免疫抑制及改變中樞系統的功能。Anandamide (AEA)及2-arachidonyl-glycerol (2-AG) 是最近被鑑定出來的CB受體內生性結合物，在in vitro的實驗中會產生的作用與傳統具有活性的cannabinoid化合物相仿。此外，由於AEA及2-AG的構造與花生四烯酸 (AA) 相仿，它們可能是lipoxygenase及cyclooxygenase的受質並可能經由這兩種酵素代謝成有活性的分子。
在我們的實驗中，是要去探討在鼠類J774巨噬細胞中，cannabinoid的免疫調控作用，我們發現D9-THC及AEA濃度在1-30mM的時候可抑制LPS所引發的nitrite及IL-6生成，而且隨著濃度增加，抑制作用愈明顯。2-AG可減少LPS所引發的IL-6生成，但卻會稍微增加nitrite的生成。在iNOS的誘導現象中,D9-THC、AEA及IMMA具有同樣抑制作用。另外，THC也可抑制LPS引發PGE2合成及COX-2的誘導現象。除此之外，D9-THC、AEA及2-AG可抑制LPS引發的IL-6 mRNA表現。 我們為了更進一步去探討AEA及2-AG可能會產生的代謝物對這些作用的影響，觀察了PGE2-ethanolamide、AA及PGE2的作用。我們發現已報導的AEA會經由COX而產生的代謝物， PGE2-thanolamide，不會影響LPS所引發的nitrite 及IL-6 生成，而AA及PGE2卻有增加LPS所誘導的nitrite生成和抑制IL-6的現象發生。COX的抑制物可抵抗AA的作用，暗示COX的代謝產物可能參與AA的作用路徑中，但它們卻不能影響AEA及2-AG的作用。AEA的回收抑制劑，AM404，可稍微抑制LPS所引起的nitrite及IL-6生成，並且也可促進AEA的抑制作用。
為了確定在鼠類J774 巨噬細胞中是否有CB2受體的存在，我們以RT-PCR的方式偵測發現細胞中只有少量CB2 mRNA的表現，並且cannabinoids不具有之前報導中會經由與CB2受體偶合的Gi蛋白結合而抑制cAMP生成的現象產生，反而發現有促進的作用。此外，CB2的拮抗物，SR144528，也不能拮抗cannabinoid化合物的抑制作用。EMSA的實驗發現D9-THC、AEA及2-AG會抑制LPS誘導的AP-1及NF-IL-6的活化現象。但D9-THC會抑制LPS誘導的NF-kB活化反應，而AEA及2-AG卻不能。總而言之，在我們的實驗中發現在鼠類巨噬細胞中，D9-THC、AEA及2-AG對LPS所引發的抑制作用可能是經由一個與CB受體無關的傳遞路徑。
Part-II
TNF受體家族包含了將近10個人類蛋白，而一個新近發現的蛋白TR2 (或是herpes virus entry mediator)是從cDNA基因庫所得到，它位於染色體1p36.22-36.3，基因經轉錄後可合成具283個胺基酸的signal transmembrane protein，其分子量約30 kDa。TR2主要表現在血液組織系統，特別是淋巴組織如脾臟、胸腺等，並且它與T細胞的活化有關。在我們的實驗中，已成功地表現TR2-ECD-Fc融合性蛋白，並製造了七株單株抗體，(4A12 4D10 3E11 4D12 4B12 5F6 及6A11)。4A12是屬於IgG2a的型式，而其他都是屬於IgG1。我們以RT-PCR的方式來偵測TR2 mRNA的表現，發現在人類T細胞株CEM、B細胞株Ramos、白血球細胞株HL-60及內皮細胞株ECV在靜止態就有TR2 mRNA的表現。ECV細胞以IL-1b (10 ng/ml)處理8小時,而A549細胞以IFN-g (100U/ml)刺激8小時,都可看到TR2 mRNA明顯地增加。其他的細胞株HL-60、CEM U937也會因不同的刺激而增加TR2 mRNA的表現。此外，螢光染色的實驗也可看到相近的結果。總而言之，抗TR2單株抗體是一個有用的工具，可幫助我們了解TR2蛋白在宿主免疫系統的反應，並可偵測在發炎反應時釋放的可溶性TR2蛋白。

Part-I
D9-THC is the major psychoactive component of marijuana. The behavioural and pharmacological actions of D9-THC have been intensively studied. Two subtypes of cannabinoid receptors have been identified and mediate the pharmacological effects of D9-THC; CB1 is expressed primarily although not exclusively in brain, and CB2 is found primarily in cells of myeloid lineage. Both receptors are involved in mediating the diverse biological action of cannabinoid compounds, including immune suppression and alterations in central nervous system function. Anandamide (AEA) and 2-arachidonyl-glycerol (2-AG) were recently identified as endogenous ligands for cannabinoid receptors and in vivo produce effects very similar to those of the classical agonists of the cannabinoid receptor. Furthermore, because of its structural similarities to polyunsaturated fatty acids, AEA and 2-AG could serve as substrate for lipoxygenases and cyclooxygenases that metabolize polyunsaturated fatty acids to potent bioactive molecules.
The objective of present study was to investigate the immunomodulatory effects of cannabinoids on murine J774 macrophages. D9-THC (1-10mM) and AEA (3-30mM) were shown to diminish LPS-induced NO and IL-6 production in a concentration-dependent manner. 2-AG inhibited the production of IL-6 but had little increased effect on NO production. In parallel, D9-THC, AEA and IMMA (a ligand for CB receptors) could inhibit iNOS induction in response to LPS, whereas 2-AG could not. D9-THC also could inhibit LPS-induced PGE2 production and COX-2 induction. Besides, D9-THC, AEA and 2-AG could inhibit LPS-induced IL-6 expression. Furthermore, in order to understand the possible involvement of ligand metabolites on these events, we explore the effects of PGE2-ethanolamide, arachidonic acid (AA) and PGE2, which might be the metabolites of AEA and 2-AG. We found that PGE2-ethanolamide, the reported AEA metabolite, neither influenced the LPS-induced NO nor IL-6 production. On the other hand, AA and PGE2 could increase NO production, but inhibit IL-6 production. COX inhibitors could reverse the effects of AA, suggesting the involvement of COX metabolites in AA response, while they cannot prevent the inhibitory effects of AEA and 2-AG. In addition, AM404, an AEA uptake inhibitor, slightly inhibited LPS-induced NO and IL-6 release, while potentiated the inhibition by AEA.
To characterize CB2 expression in J774 macrophages, we found that only a weak CB2 mRNA expressed and that cannabinoids potentiate cAMP formation rather than inhibition, as predicted from the Gi-coupled CB2 receptor signaling. The CB2 antagonist, SR144528, could not antagonize the inhibitory effects of cannabinoids. Electrophoretic mobility shift assay shows the inhibitory effects of D9-THC, AEA and 2-AG on LPS-induced activation of AP-1 and NF-IL-6. D9-THC could also inhibit LPS-induced NF-kB activation, but AEA and 2-AG could not. All these results suggest that the cannabinoids, D9-THC, AEA and 2-AG, elicit the inhibitory effects on LPS-stimulated macrophages possibly via a cannabinoid receptor -independent pathway.
Part-II
The tumor necrosis factor receptor (TNFR) superfamily consists of approximately 10 characterized members of human proteins. A newly identified member, TR2 (or herpes virus entry mediator) from a search of an expressed sequence tag data base is encoded by a single gene, which maps to chromosome 1p36.22-36.3, and the TR2 open reading frame sequence encodes a 283-amino acid single transmembrane protein (30 kDa). TR2 is expressed mainly in hemopoietic tissues, particularly in lymphoid tissues such as spleen and thymus, and is involved in T cell activation. In this study, we have successfully expressed TR2-ECD-Fc fusion protein and generated seven monoclonal antibodies (4A12, 4D10, 3E11, 4D12, 4B12, 5F6 and 6A11). One antibody is IgG2a isotype and the others are IgG1 type. TR2 mRNAs, as detected by RT-PCR, are normaly expressed in human T-cell line CEM, B-cell line Ramos, peripheral blood mononuclear cells (PBMC), leukocyte cell line HL-60 and endothelial cell line ECV. TR2 mRNA expression could be induced by various stimuli in T-cell line CEM, monocyte cell line U937 leukocyte, cell line HL-60, endothelial cell line ECV and pulmonary A549 epithelial cells. ECV cells treated with IL-1b (10 ng/ml) for 8 hr and A549 cells treated with IFN-g (100 U/ml) for 8hr expressed greater amount of TR2 mRNA. In parallel, the immunostaining of TR2 in both cell lines was increased after cytokine stimulation. In conclusion, the antibodies for TR2 are useful tools to understand the role of TR2 in host immune response and to detect the presence of soluble TR2 during various inflammatory diseases.

第一部分：
中文摘要……………………………………………………………..1
英文摘要……………………………………………………………..3
緒言…………………………………………………………………..5
材料及方法………………………………………………………….17
結果………………………………………………………………….27
討論………………………………………………………………….36
圖表………………………………………………………………….43
參考文獻……………………………………………………………65
第二部分：
中文摘要…………………………………………………………….80
英文摘要…………………………………………………………….81
緒言………………………………………………………………….82
材料及方法………………………………………………………….86
結果………………………………………………………………….96
討論………………………………………………………………...100
圖表………………………………………………………………...104
參考文獻…………………………………………………………...117

Part-I
參考文獻
Adcock, I.M. (1997) Transcription factors as activators of gene transcription: AP-1 and NF-kappa B. Monaldi Archives for Chest Disease. 52:178-186.
Akira, S. and Kishimoto, T. (1997) NF-IL6 and NF-kB in cytokine gene regulation. Adv. Immunol. 65: 1-10.
Axelrod, J. and Felder, C.C. (1998) Cannabinoid receptors and their endogenous agonist, anandamide. Neurochem. Res. 23: 575-581.
Baeuerle, P.A. and Henkel, T. (1994) Function and activation of NF-kB in the immune system. Ann. Rev. Immunol. 12:141-179.
Baldwin, A.S.Jr. (1996) The NF-kB and IkB proteins: new discoveries and insights. Ann. Rev. Immunol. 14: 649-681.
Beltramo, M., Stella, N., Calignano, A., Lin, S.Y., Makriyannis, A. and Piomelli, D. (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science. 277:1094-10947.
Berdyshev, E.V., Boichot, E., Germain, N., Allain, N., Anger, J.-P. and Lagente, V. (1997) Influence of fatty acid ethanolamides and D9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. Eur.. J. Pharmacol. 330: 231-240.
Bisogno, T., Sepe, N., Melck, D., Maurelli S., De Petrocellis, L. and Di Marzo, V. (1997) Biosynthesis, release and degradation of the novel endogenous cannabimimetic metabolite 2-arachidonoylglycerol in mouse neuroblastoma cells. Biochem. J. 322:671-677.
Blanchard, DK., Newton, C., Klein, TW., Stewart, WE 2d. and Friedman, H. (1986) In vitro and in vivo suppressive effects of delta-9-tetrahydrocannabinol on interferon production by murine spleen cells. Int. J. Immunopharmacol. 8: 819-824.
Bouaboula, M., Poinot-Chazel, C., Bourrie, B., Canat, X., Calandra, B., Rinaldi-Carmona, M., Le Fur, G. and Casellase, P. (1995) Activation of mitogen-activated protein-kinases by stimulation of the central cannabinoid receptor CB1. Biochem. J. 312: 637-641.
Brown, K., Gerstberger, S., Carlson, L., Franzoso, G. and Siebenlist, U. (1995) Control of IkB-a proteolysis by site-specific, signal-induced phosphorylation. Science 267: 1485-1488.
Burnette-Curley, D., Marciano-Cabral, F., Fischer-Stenger, K. and Cabral, G.A. (1993) Delta-9-tetrahydrocannabinol inhibits cell contact-dependent cytotoxicity of Bacillus Calmette-Guerin -activated macrophages. Int. J. Immunopharmacol. 15: 371-382.
Cabral, G. A., Mishkin, E. M., Marciano-Cabral, F., Coleman, P., Harris, L. and Munson, A. E. (1986) Effect of delta-9-tetrahydrocannabinol on herpes simplex virus type 2 vaginal infection in the guinea pig. Proc. Soc. Exp. Biol. 182: 181-186.
Coffey, M., Peters-Golden, M., Fantone, JC 3d. and Sporn PH. (1992) Membrane association of active 5-lipoxygenase in resting cells. Evidence for novel regulation of the enzyme in the rat alveolar macrophage. J. Biol. Chem. 267(1): 570-576
Coffey, R.G., Yamamoto, Y., Snella, E. and Pross, S. (1996) Tetrahydrocannabinol inhibition of macrophage nitric oxide production. Biochem. Pharmacol. 52: 743-751.
De Petrocellis, L., Orlando, P. and Di Marzo, V. (1995) Anandamide, an endogenous cannabinomimetic substance, modulates rat brain protein kinase C in vitro. Biochem. Mol. Biol. Int. 36: 1127-1133.
Derocq, J.M., Bouaboula, M., Marchand, J., Rinaldi-Carmona, M. and Casellas, S.P. (1998) The endogenous cannabinoid anadamide is a lipid messenger activting cell growth via a cannabinoid receptor-independent pathway in hematopoietic cell lines. FEBS Lett. 425: 419-425.
Devane, W.A., Dyzarz III, F.A., Johnson, M.R., Melvin, L.S. and Howlett, A.C. (1988) Determination and characterisation of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34: 605-613.
Devane, W.A., Hanus, L., Breuer, A., Pertwee, R.G., Stevenson, L.A., Griffin, G., Gibson, D., Mandelhaum. A., Etinger, A. and Mechoulam, R. (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258: 1946-1949.
Di Marzo, V., De Petrocellis, L., Sepe, N. and Buono, A. (1996) Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18 neuroblastoma cells. Biochem. J. 316 (Pt 3):977-984
Di Marzo, V., De Petrocellis, L., Sugiura, T. and Waku K. (1996) Potential biosynthetic connections between the two cannabimimetic eicosanoids, anandamide and 2-arachidonoyl-glycerol, in mouse neuroblastoma cells. Biochem.Biophys.Res.Commun. 227: 281-288.
Di Marzo, V. and Deutsch, DG. (1998) Biochemistry of the endogenous ligands of cannabinoid receptors. Neurobiol. Disea.(6 Pt B):386-404.
Di Marzo, V., Fontana, A., Cadas, H., Schinelli, S., Cimino, G., Schwartz, JC. and Piomelli, D. (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372: 686-691.
Di Marzo, V. (1998) Endocannabinoids and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochim. Biophys. Acta. 1392: 153-175.
Edgemond, W.S., Hillard, C.J., Falck, J.R., Kearn, C.S. and Campbell, W.B. (1998) Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anadamide): their affinities for cannabinoid receptors and pathways of inactivation. Mol. Pharmacol. 54: 180-188.
Facci, L. Dal Toso, R.., Romanello, S., Buriani, A., Skaper, SD. and Leon A. (1995) Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide.Proc. Nat. Acad. Sci.USA 92: 3376-3380.
Fan, P. (1995) Cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons. J. Neurophysiol. 73: 907-910.
Felder, C.C., Briley, E.M., Axelrod, J., Simpson, J., Mackie, K.and Devane, W. (1993) Anandamide, an endogenous cannabimetic eiconsanoid, binds to the cloned human cannabinoid receptor and stimulates receptor mediated signal transduction. Proc. Natl. Acad. Sci. USA 90: 7656-7660.
Felder, C.C., Joyce, K.E., Briley, E.M., Mansouri, J. and Mackie, K. (1995) Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol. Pharmacol. 48: 443-450.
Felder, C.C., Nielsen, A., Briley, E.M., Palkovits, M., Priller, J., Axelrod, J., Nguyen, D.N., Richardson, J.M., Riggin, R.M., Koppel, G.A., Paul, S.M. and Becker, G.W. (1996) Isolation and measurement of the endogenous cannabinoid receptor agonist, anandamide in brain and peripheral tissues of human and rat. FEBS Lett. 393: 231-235.
Felder, C.C. and Glass, M. (1998) Cannabinoid receptors and their endogenous agonists. Annu. Rev. Pharmacol. Toxicol. 38: 179-200.
Feng, L., Sun, W., Xia, Y. and Tang, WW., Chanmugam, P., Soyoola, E. and Wilson, CB. (1993) Cloning two isoforms of rat cyclooxygenase: differential regulation of their expression. Arch. Biochem.Biophys. 307: 361-368
Finaldi-Carmona, M., Barth, F., Millan, J., Derocq, J. and Bouaboula, M. (1998) SR144528, a potent and selective antagonist of the CB2 receptor. Symposium on Cannabinoids, 1: 11. Burlington, VT: J. Pharmacol. Exp. Ther.284: 644-650
Fisher-Stenger, K., Dove Pettit, D. A. and Cabral, G. A. (1993) D9-tetrahydrocannabinol inhibition of tumor necrosis factor-alpha: suppression of post-translational events. J. Pharmacol. Exp. Ther. 267: 1558-1565.
Friedman, H., Shivers, S.and Klein, T.W. (1994) Drugs of abuse and the immune system. Immunotoxicology and immunopharmacology. 2nd ed. Raven Press, New Youk, NY. pp.303-322.
Fu, JY., Masferrer JL., Seibert, K., Raz, A. and Needleman, P. (1990) The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J. Biol. Chem. 265: 16737-16740
Galiegue, S., Mary, S., Marchand, J., Dussossoy, D., Carriere. D., Carayon, P., Bouaboula, M., Shire, D., Le Fur, G. and Casellas, P. (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur. J. Biochem. 232(1) : 54-61
Gerard, C.M., Mollereau, U.C., Vassart, G. and Parmentier, M. (1991) Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem. J. 279: 129-134.
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.
Graeve, L., Baumann, M. and Heinrich, P.C. (1993) Interleukin-6 in autoimmune diseases. Clin. Invest. 71: 664-671
Grimble, R.F. (1990) Nutrition and cytokine action. Nutr. Res. Rev. 3: 193-210.
Grinspoon, L. Bakalar, JB. and Doblin, R. (1995) Marijuana, the AIDS wasting syndrome, and the U.S. government. New England Journal of Medicine. 333(10): 670-671
Habib, A., Creminon, C., Frobert, Y., Grassi, J., Pradelles, P. and Maclouf J. (1993) Demonstration of an inducible cyclooxygenase in human endothelial cells using antibodies raised against the carboxyl-terminal region of the cyclooxygenase-2. J. Biol. Chem.268: 23448-23455.
Hampson, A.J., Hil, W.A.G., Zan-Phillips, M., Makriyannis, A., Leung, E., Egien, R.M. and Bornheim. L.M. (1995) Anadamide hydroxylation by brain lipoxygenase: metabolite structures and potencies at the cannabinoid receptor. Biochem. Biophys. Acta 1259: 173-179.
Hembree, W. C., Nahas G., Zeidenberg, P. and Huang, H. F. S. (1979) Changes in human spermatozoa associated with high dose marihuana smoking, in Marihuana: Biological Effects, Analysis, Cellular responses, Reproduction and Brain. (Nahas G. G. and Paton W. D. M., eds.) Pergamon, New York, 429-439.
Hillard, G.J. and Campbell, W.B. (1997) Biochemistry and pharmacology of arachidonylethanolamide, a putative endogenous cannabinoid. J. Lipid Res. 38: 2383-2398.
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: 4885-4892.
Inoue, H., Yokoyama, C., Hara, S., Tone, Y. and Tanabe, T. (1995) Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells:Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element. J. Biol. Chem. 270: 24965-24971.
Iwabuchi, K., Hatakeyama, S. and Takahashi, A. (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: 742-747.
Jeon, Y.J., Yang, K.-H., Pulaski, J.T. and Kaminski, N.E. (1996) Attenuation of inducible nitric oxide synthase gene expression by D9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor-kB/Rel activation. Mol. Pharmacol. 50: 334-341
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.
Kaminski, N.E., Koh, W.S., Lee, M., Yang, K.H. and Kessler, F.K. (1994) Suppression of the humoral immune response by cannabinoids is partially mediated through inhibition of adenylate cyclase by a pertussis toxin-sensitive G-protein coupled mechanism. Biochem. Pharamcol. 48: 1899-1908.
Klein, T.W., Newton, C.and Friedman, H. (1994) Resistance to Legionella-pneumophila suppressed by the marijuana component, tetrahydrocannabino. J. Infect. Dis. 169: 1177-1179.
Kujubu DA., Reddy, ST., Fletcher, BS. and Herschman HR. (1993) Expression of the protein product of the prostaglandin synthase-2/TIS10 gene in mitogen-stimulated Swiss 3T3 cells. J. Biol.Chem. 268: 5425-5430.
Laviolette, M., Carreau, M., Coulombe, R., Cloutier, D., Dupont, P., Rioux J. and Braquet P. (1988) Metabolism of arachidonic acid through the 5-lipoxygenase pathway in normal human peritoneal macrophages. J. Immunol. 141 (6): 2104-2109.
Lee, M., Yang, KH. and Kaminski NE. (1995) Effects of putative cannabinoid receptor ligands, anandamide and 2-arachidonyl-glycerol, on immune function in B6C3F1 mouse splenocytes. J. Pharmacol. Exp.Ther. 275: 529-536
Lorsbach, RB., Murphy, WJ., Lowenstein, CJ., Snyder, SH. and Russell SW. (1993) Expression of the nitric oxide synthase gene in mouse macrophages activated for tumor cell killing. Molecular basis for the synergy between interferon-gamma and lipopolysaccharide. J. Bio.Chem. 268: 1908-1913.
Lowenstein, CJ., Alley, EW., Raval, P., Snowman, AM., Snyder, SH., Russell, SW. and Murphy WJ. (1993) Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc. Natl. Acad. Sci. USA 90: 9730-9734.
Mackie, K., Lai, Y., Westenbroek, R. and Mitchell, R. (1995) Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AT20 cells transfected with rat brain cannabinoid receptors. J. Neurosci. 15: 6552-6561.
MacMicking, J., Xie, QW. and Nathan, C. (1997) Nitric oxide and macrophage function. Annu. Rev. Immunol. 15: 323-350.
Marletta, MA., Yoon, PS., Iyengar, R., Leaf, CD. and Wishnok JS. (1988) Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate. Biochemistry. 27: 8706-8711.
Marotta, P., Sautebin, L. and DiRosa, M. (1992) Modulation of the induction of nitric oxide synthase by eicosanoids in the murine macrophage cell line J774. Br. J. Pharmacol. 197: 640-646.
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.
Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C. and Bonner, T.I. (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346: 561-564.
Matsusaka, T., Fujikawa, K., Nishio, Y., Mukaida, N., Matsushima, K., Kishimoto, T. and Akira, S. (1990) Transcription factors NF-IL6 and NF-kB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc. Natl. Acad. Sci. USA 90: 10193-10199.
Mechoulam R (1986) Interview with Prof. Raphael Mechoulam, codiscoverer of THC. Int. J. Addictions. 21 (4-5): 579-587
Mechoulam, R. Ben-Shabat, S., Hanus, L., Ligumsky, M., Kaminski, NE. Schatz, AR., Gopher, A., Almog, S., Martin, BR. and Compton DR. (1995) Identification of an endogenous 2-monoglyceride, present in canine gut,that binds to cannabinoid receptors. Biochem.Pharmacol. 50: 83-90.
Morahan, P.S., Klykken, P.C., Smith, S.H., Harris, L.S. and Munson, A.E. (1979) Effects of cannabinoids on host resistance to Listeria monocytogenes and herpes simplex virus. Infect. Immun. 23: 670-674.
Munro, S., Thomas, KL. and Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids Nature 365 (6441):61-65.
Nakano, Y., Pross, SH. and Friedman H. (1992) Modulation of interleukin 2 activity by delta 9-tetrahydrocannabinol after stimulation with concanavalin A, phytohemagglutinin, or anti-CD3 antibody. Proc. Soc. Exp. Biol. Med. 201: 165-168.
Nathan C (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J .6: 3051-3064.
Newton, C.A., Klein, T.W. and Friedman, H. (1994) Secondary immunity to Legionella-pneumophila and Th1 activity are suppressed by delta-9-tetrahydrocannabinol injection. Infect. Immun. 62: 4015-4020.
O'Sullivan, MG., Chilton, FH., Huggins, EM, Jr. and McCall, CE. (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.
Poli V. ( 1998) The role of C/EBP isoforms in the control of inflammatory and native immunity functions. J. Bio. Chem. 273: 29279-29282.
Pross, S., Nakano, Y., Smith, J., Widen, R., Rodriguez, R., Newton, C. and Friedman, H. (1992) Suppressive effect of tetrahydrocannabinol on specific T cell subpopulations in the thymus. Thymus 19: 97-104.
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: 50-54.
Ralph P, Ho, M-K., litcofsky, PB. and Springer, TA. (1983) Expression and induction in vitro of macrophage differentiation antigens on murine cell lines. J. Immunol. 130:108-113.
Raschke, WC, Baird, S, Ralph, P. and Nakoinz I. (1978) Functional macrophages cell lines trasformed by Abelson leukemia. Cell 15:261-267.
Richardson, C. and Emery P. (1996) The clinical implications of inhibition of the inducible form of cyclo-oxygenase. Drug Safety. 15: 249-260
Rinaldi-Carmona, M., Barth, F., Millan, J., Derocq, JM., Casellas, P., Congy, C., Oustric, D., Sarran, M.., Bouaboula, M., Calandra, B., Portier, M., Shire, D., Breliere ,JC. and Le Fur, GL. (1998) SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol.. Exp. Ther. 284 (2): 644-650
Rinaldi-Carmona, M., Barth, F., Heaulme, M., Shire, D., Calandra, B., Congy, C., Marginez, S., Maruani, J., Neliat, G., Caput, D., Ferrara, P., Soubrie, P., Breliere, J.C. and Fur, G.L. (1994) SR141716A, a potent and selective antagonist of the braine cannabinoid receptor. FEBS Lett. 350: 240-244.
Schatz, A.R., Lee, M., Condie, R.B., Pulaski, J.T. and Kaminski, N.E. (1997) Cannabinoid receptors CB1 and CB2: a characterization of expression and adenylate cyclase modulation within the immune system. Toxicol. Appl. Pharmacol. 142: 278-287.
Schmid, H.H., Schmid, P.C. and Natarajan, V. (1996) The N-acylation-phosphodiesterase pathway and cell signalling. Chem. Phys. Lipids 80: 133-142.
Schwarz, H., Blanco, F.J. and Lotz, M. (1994) Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte-proliferation and induces apoptosis. J. Neuroimmunol. 55: 107-115.
Seibert, K. and Masferrer, JL. (1994) Role of inducible cyclooxygenase (COX-2) in inflammation. Receptor. 4: 17-23.
Shimizu, H., Mitomo, K., Watanabe, T., Okamoto, S.I. and Yamamoto, K.I. (1990) Involvement of a NF-kB like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol. Cell. Biol. 10: 561-65.
Siebenlist, U., Franzoso, G. and Brown, K. (1994) Structure, regulation and function of NF-kB. Ann. Rev. Cell Biol. 10: 405-455.
Sirois, J. and Richards, JS. (1993) Transcriptional regulation of the rat prostaglandin endoperoxide synthase 2 gene in granulosa cells. Evidence for the role of a cis-acting C/EBP beta promoter element. J. Biol.Chem.268: 21931-21938.
Slipetz, DM., O'Neill, GP., Favreau, L., Dufresne, C., Gallant M., Gareau,Y., Guay, D., Labelle, M. and Metters, KM. (1995) Activation of the human peripheral cannabinoid receptor results in inhibition of adenylyl cyclase. Mol. Pharmacol. 48 (2): 352-361.
Specter, S., Rivenbark, M., Newton, C., Kawakami, Y. and Lancz, G. (1980) Prevention and reversal of delta-9-tetrahydrocannabinol-induced depression of natural killer cell activity by interleukin-2. Int. J. Immunopharmacol. 11: 63-68.
Stefano, G.B., Liu, Y. and Goligorsky, M.S. (1996) Cannabinoid receptors coupled to nitric oxide release in invertebrate immunocytes, microglia, and human monocytes. J. Biol. Chem. 271: 19238-19242.
Stefano, GB., Salzet, M., Magazine HI. and Bilfinger, TV. (1998) Antagonism of LPS and IFN-gamma induction of iNOS in human saphenous vein endothelium by morphine and anandamide by nitric oxide inhibition of adenylate cyclase. J. Cardio. Pharmacol. 31: 813-820
Stella, N., Schweitzer, P. and Piomelli D. (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature. 388: 773-778.
Sugiura, T., Kondo, S., Sukagawa, A., Tonegawa, T. and Nakane, S. (1996) N-arachidonylethanolamide (anandamide), an endogenous cannabinoid receptor ligand, and related lipid molecules in the nervous tissues. J. Lipid Mediat. Cell. Signal 14: 51-56.
Tang, J.L., Lancz, G., Specter,S. and Bullock, H. (1992) Marijuana and immunity: tetrahydrocannabinol-mediated inhibition of growth and phagocytic activity of the murine macrophage cell line, P388D1. Int. J. Immunopharmacol. 14: 253-262.
Thanos, D., and Maniatis, T. (1995) NF-kB: a lesson in familiy values. Cell 80: 529-532.
Ueda, N., Yamamoto, K., Yamamoto, S., Tokunaga, T., Shirakawa, E., Shinkai, H., Ogawa, M., Sato, T., Kudo, I. Inoue, K., Takizawa, H., Nagano, T., Kirobe, M., Matsuki, N. and Saito, H. (1995) Lipoxygenase-catalyzed oxygenation of arachidonylethanolamide, a cannabinoid receptor agonist. Biochem. Biophys. Acta 1254: 127-134.
Varga, K., Wagner, JA., Bridgen, DT. and Kunos G. (1998) Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J. 12 (11):1035-1044.
Venance, L., Piomelli, D., Glowinski, J. and Giaume, C. (1995) Inhibition by anandamide of gap junctions and intercellular calcium signalling in striatal astrocytes. Nature 376: 590-594.
Wagner, J.A., Varga, K., Ellis, E.F., Rzigalinski, B.A., Martin, B.R. and Kunos, G. (1997) Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature 390: 518-520.
Wartmann, M., Campbell, D., Subramanian, A., Burstein, S.H. and Davis, R.J. (1995) The MAP kinase signal transduction pathway is activated by the endogenous cannabinoid anandamide. FEBS Lett. 359: 133-136.
Watzl, B., Scuderi, P. and Watson, R. R. (1991) Marijuana components stimulate human peripheral blood mononuclear cell secretion of interferon-gamma and suppress interleukin-1-alpha in vitro. Int. J. Immunopharmacol. 13: 1091-1097.
Williams, J.A. and Shacter, E. (1997) Regulation of macrophage cytokine production by prostaglandin E2. Distinct roles of cyclooxygenase-1 and -2. J. Biol. Chem. 272: 25693-98.
Wing, D. R., Leuschner, J. T. A., Brent, G. A., Harvey, D. J. and Paton, W. D. M. (1985) Quantification of in vivo membrane associated delta-9-tetrahydrocannabinol and its effects on membrane fluidity, in Proceedings of the 9th International Congress of Pharmacology 3rd Satellite Symposium on Cannabis (Harvey, D. J., ed.) IRL Press, Oxford, UK 411-418.
Wink, DA. and Mitchell JB.(1998) Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Rad Biol. Med. 25: 434-456.
Xie, Q-W., Whisnant, R., and Nathan, C. (1993) Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon g and bacterial lipopolysaccharide. J. Exp. Med. 177: 1779-1784.
Yu, M., Ives, D. and Ramesha, C.S. (1997) Synthesis of prostaglandin E2 ethanolamide from anadamide by cyclooxygenase-2. J. Biol. Chem. 272: 21181-21186.
Yukawa, K., Tanaka, T., Tsuji, S. and Akira S. (1998) Expressions of CCAAT/Enhancer-binding proteins beta and delta and their activities are intensified by cAMP signaling as well as Ca2+/calmodulin kinases activation in hippocampal neurons. J. Biol Chem. 273: 31345-31351
Zheng, ZM. and Specter, SC. (1992) Delta-9-tetrahydrocannabinol suppresses tumor necrosis factor alpha maturation and secretion but not its transcription in mouse macrophages. Int.J. Immunopharmacol. 18: 53-68
Zhang, Y. and Rom, WN. (1993) Regulation of the interleukin-1 beta (IL-1 beta) gene by mycobacterial components and lipopolysaccharide is mediated by two nuclear factor-IL6 motifs. Mol.Cell. Biol.13: 3831-3837
Zias, J., Stark, H., Sellgman, J., Levy, R. Werker, E., Breuer, A. and Mechoulam, R. (1993) Early medical use of cannabis. Nature. 363 (6426):215-217
參考文獻-Part-II
Armitage, R. (1994) Tumor necrosis factor receptor superfamily members and their ligands. Curr. Opin. Immunol. 6: 407-413.
Baker, S.J. and Reedy, E.P. (1996) Transducers of life and death: TNF receptor superfamily and associated proteins. Oncogene 12: 1-9.
Beutler, B. and Huffel, C. V. (1994) Unraveling function in the TNF ligand and receptor families. Science 264: 667-668.
Gruss, H.-J. and Dower, S. K. (1995) Tumor necrosis factor ligand superfamily: involvement in the pathology of malignant lymphomas. Blood 85: 3378-3383.
Harrop, J.A., McDonnell, P.C. and Brigham-Burke, M. (1998) Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth. J. Biol. Chem. 273: 27548-27556.
Harrop, J.A., Reddy, M. and Dede, K. (1998) Antibodies to TR2 (Herpesvirus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines. J. Immunol. 161: 1786-1794.
Hsu, H., Solovyev, I., Colombero, A., Elliott, R., Kelley, M. and Boyle, W.J. (1997) ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5. J. Biol. Chem. 272: 13471-13474.
Kitson. J., Raven, T., Jiang, Y.-P., Goeddel, D. V., Giles, K. M., Pun , K.-T., Grinhma, C. J., Brown, R. and Farrow, S. N. (1996) A death-domain-containing receptor that mediates apoptosis. Nature 384: 372-374.
Kuby, J. (1996) Immunology. W. H. Freeman and company, New York. pp. 245-270.
Kunkel, S.L., Strieter, R.M., Lindley, I.J.D. and Westwick, J. (1995) Chemokines: new ligands, receptors and activities. Immunol. Today 16: 550-561.
Kwon, B.S., Tan, K.B., Ni, J., Lee, K.O., Kim, K.K., Kim, Y.J., Wang, S., Gentz, R., Yu, G.L. and Harrop, J. (1997) A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J. Biol. Chem. 272: 14272-14276.
Marsters, S. A., Sheridan, J. P., Donahue, C. J., Pitti, R. M., Gray, C. L., Goddard, A. D., Bauer, K. D. and Ashkenazi, A. (1996) APO-3, a new member of the TNF receptor family, contains a death domain and activates apoptosis and NF-kB. Curr. Biol. 6: 1669-1674.
Mauri, D.N., Ebner, R., Kochel, K.D., Montgomery, R., Cheung, T.C., Yu, G.L., Ruben, S., Murphy, M., Eisenberg, R.J. and Cohen, G.H. (1998) LIGHT, a new member of the TNF superfamily, and lymphotoxin a are ligands for herpesvirus entry mediator. Immunity 8: 21-30.
Montgomery, R.I., Warner, M.S., Lum, B.J. and Spear, P.G. (1996) Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 87: 427-436.
Spear, P. G. (1993) Entry of alphaherpesviruses into cells. Semin. Virol. 4: 167-180.
Tan KB. Harrop J. Reddy M. Young P. Terrett J. Emery J. Moore G. and Truneh A. (1997) Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene. 204 (1-2):35-46.
Vandenabeele, P., Declercq, W., Beyaert, R. and Fiers, W. (1995) Two tumor necrosis factor receptors: structure and function. Trends Cell. Biol. 5: 392-399.
Whitbeck JC. Peng C. Lou H. Xu R. Willis SH. Ponce de Leon M. Peng T. Nicola AV. Montgomery RI. Warner MS. Soulika AM. Spruce LA. Moore WT. Lambris JD. Spear PG. Cohen GH. Eisenberg RJ. (1997) Glycoprotein D of herpes simplex virus (HSV) binds directly to HVEM, a member of the tumor necrosis factor receptor superfamily and a mediator of HSV entry. J.Virology. 71(8): 6083-6093.
Zhai, Y., Guo, R., Hsu, T.L., Yu, G.L., Ni, J. and Kwon, B.S. (1998) LIGHT, a novel ligand for lymphotoxin b receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer. J. Clin. Invest. 102: 1142-1151.