PDE4和cAMP訊號傳導於小鼠骨髓細胞分化為樹突細胞之角色

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梁梓祺(Tzu-chi Liang) 查詢紙本館藏

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PDE4和cAMP訊號傳導於小鼠骨髓細胞分化為樹突細胞之角色
(Role of PDE4 and cAMP signaling in differentiation of dendritic cells from mouse bone marrow cells)

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摘要(中)

樹突細胞(Dendritic cells, DCs)為抗原呈現細胞，於先天及後天免疫系統扮演重要的角色。樹突細胞於周邊組織中有吞入抗原、移動至局部淋巴組織的能力，且隨著細胞的成熟，可活化抗原專一的T細胞。已知在許多發炎細胞(包含樹突細胞)內，增加cAMP濃度能抑制多種發炎反應。然而cAMP訊號傳導如何調控樹突細胞分化、成熟及功能，至今仍不甚明瞭。Type 4 phosphodieasterases (PDE4s)為水解cAMP的酵素，表現於大部分發炎細胞中，可調控許多發炎反應。為此，本研究欲探討PDE4或cAMP信號傳導是否會調節樹突細胞的分化與成熟，我們首先利用GM-CSF刺激小鼠骨髓細胞分化為未成熟樹突細胞，並以流式細胞儀分析CD11c螢光抗體標染的樹突細胞。結果顯示，培養第八天後的細胞中有81.7 ± 1.1 %為未成熟樹突細胞，此分化程度可分別被PDE4抑制劑Rolipram、 PDE3抑制劑Cilostazol結合Rolipram、 cAMP類似物dibutyryl cAMP (dbcAMP)及非選擇性PDE抑制劑IBMX所抑制，抑制程度分別為12.26 ± 1.3 %、 35.5 ± 1.6 %、 18.3 ± 1.4 %及16.8 ± 2.4 %。同時，細胞表面CD11c的螢光強度，也被該等藥劑所抑制，抑制程度分別為21.8 ± 2 %、 35 ± 2.9 %、 58.8 ± 0.3 %及41.4 ± 2.21 %。Cilostazol 單獨處理細胞則無抑制作用。此外，利用PDE4基因剔除鼠之骨髓細胞進行實驗發現Rolipram抑制樹突細胞分化的影響，主要是經由抑制PDE4B、其次為PDE4A所致。在LPS誘導樹突細胞成熟期間，CD11c+細胞群及CD11c+的平均螢光強度均會顯著下降，而CD11c+CD86+ 細胞群(成熟樹突細胞)則增加約3.2倍，但細胞表面CD86的平均螢光強度與未經LPS處理之CD11c+CD86+細胞群相當。若以所有圈選的(gated)細胞分析成熟樹突細胞，我們發現，Rolipram會抑制LPS刺激所產生的CD11c+CD86+ 細胞群，抑制程度為21.4 ± 2.36 %；但若僅就CD11c+細胞群中之CD11c+CD86+細胞進行比較，Rolilpram卻無顯著抑制作用。利用PDE4基因剔除鼠樹突細胞進一步分析，發現Rolipram抑制樹突細胞成熟可能是經由抑制PDE4A和PDE4B所致。此外，如同LPS誘導樹突細胞成熟，dbcAMP或Rolipram單獨處理未成熟樹突細胞也有不同程度誘導細胞成熟的作用。至於研究樹突細胞功能，我們利用卵蛋白(OVA)致敏小鼠脾臟CD4+ T 細胞與樹突細胞共同培養，在OVA刺激下，T細胞會被活化而增生，然而PDE4B-/-樹突細胞對此增生反應有減弱的現象。綜合以上結果得知，PDE4，特別是PDE4B會調控樹突細胞的分化及功能。這些發現可作為未來研發PDE4抑制劑用以治療與樹突細胞有關之發炎疾病的理論基礎。

摘要(英)

Dendritic cells (DCs) are antigen presenting cells important in both innate and adaptive immune systems. DCs in peripheral tissues are capable of capturing antigens and migrating to local lymphoid tissues where the DCs become mature and enable to activate antigen-specific T cells. Elevation of intracellular cAMP concentration suppresses various inflammatory responses in almost all inflammatory cell types, including DCs. However, the information on how cAMP signaling regulates the differentiation, maturation and function of DCs is limited. Type 4 phosphodieasterases (PDE4s), enzymes that degrade cAMP with high affinity, are the predominant PDE isozymes expressed in most inflammatory cells, and are critical in regulation of various inflammatory responses. To determine whether PDE4, thereby the cAMP signaling, regulates DC differentiation and maturation, in this study we stimulated mouse bone marrow cells with GM-CSF in the presence of cAMP-elevating agents to assess their effects on DC differentiation. Flow cytometry analyses revealed that 81.7 ± 1.1 % cells harvested on day 8 of culture developed into immature DCs (imDCs), demonstrated by the expression of CD11c on these cells. This process was inhibited by the PDE4 inhibitor Rolipram, the combination of Rolipram and the PDE3 inhibitor cilostazol, dibutyryl cAMP (dbcAMP), and the non-selective PDE inhibitor IBMX at both the CD11+ population (12.26 ± 1.3 %, 35.5 ± 1.6 %, 18.3 ± 1.4 %, and 16.8 ± 2.4 %, respectirely) and the level of CD11c expression (i.e. CD11c mean fluorescence intensity; 21.8 ± 2 %, 35 ± 2.9 %, 58.8 ± 0.3 % and 41.4 ± 2.21 %, respectirely). However, Cilostazol alone lacked these effects. The experiments using PDE4 null bone marrow cells further demonstrated that PDE4B and possibly PDE4A, but not PDE4D, mediated the Rolipram effect on the differentiation of imDC population. During LPS induced DC maturation, the CD11c+ population and the mean fluorescence intensity (MFI) of CD11c+ were significantly decreased (p<0.05), whereas the CD11c+CD86+ population (mature DCs) was increased by approximately 3.2 folds. This increase however was not accompanied by an increase in MFI of CD86. Rolipram also showed an inhibition (21.4 ± 2.36 %) in the LPS-induced CD11c+CD86+ population when the total gated cells were analyzed, but this decrease was not obtained when the CD11c+ population was analyzed. Further study on PDE4 null DCs suggested that the Rolipram effect on the CD11+CD86+ population was probably mediated by inhibiton of both PDE4A and PDE4B. Similar to LPS, our results showed that dbcAMP or Rolipram alone also induced DC maturation albeit at less extent. In a functional study using ovalbumin (OVA) – primed spleen CD4+ T cells, we found that DC-induced T cell proliferation in response to OVA was attenuated in PDE4B-deficient DCs compared to PDE4B wild - type DCs. Taken together, these findings indicate an involvement of PDE4, particularly PDE4B, in the development and function of DCs. They also form the basis for the development of PDE4 inhibitors for the treatment of inflammatory diseases that are mediated by DCs.

關鍵字(中)

★ 樹突細胞
★ 磷酸雙酯酶
★ 抗原呈現細胞

關鍵字(英)

★ Dendritic cell
★ Cyclic nucleotide phosphodiesterase
★ Antigen presenting cell

論文目次

中文摘要 i
英文摘要 iii
誌謝 v
目錄 vi
圖目錄 viii
縮寫檢索表 ix
一緒論 1
1-1 樹突細胞與免疫反應 1
1-2 Adenosine 3’,5’-cyclic monophosphate (cAMP)之訊息傳導 2
1-3 cAMP與免疫發炎反應之調控 4
1-4 環狀核苷酸磷酸二酯酶(Cyclic nucleotide phosphodiesterases; PDE) 5
1-4-1 PDE的分類、結構及功能 5
1-4-2 PDE4結構特性及其活性調控 7
1-5 PDE4與樹突細胞 8
二研究動機與目的 10
三材料與方法 11
3-1 材料 11
3-1-1 實驗小鼠 11
3-1-2 實驗藥品 11
3-2 實驗方法 12
3-2-1 小鼠骨髓細胞分離 12
3-2-2 小鼠骨髓細胞培養分化為未成熟樹突細胞(immature dendritic cell; imDC) 12
3-2-3 培養未成熟樹突細胞(imDC)分化成為成熟樹突細胞(mDC) 13
3-2-4 流式細胞儀技術分析(Fluorescence-Activated Cell Sorting; FACS) 14
3-2-5 卵蛋白抗原致敏作用(Ovalbumin-priming) 14
3-2-6 小鼠脾臟細胞分離及CD4+ T細胞純化 14
3-2-7 絲裂霉素(Mitomycin C)處理抗原呈現細胞 15
3-2-8 淋巴細胞混合反應(Mix lymphocyte reaction; MLR) 16
四實驗結果 17
4-1 cAMP訊息傳導對小鼠骨髓細胞分化為未成熟樹突細胞之影響 17
4-1-1 PDE抑制劑與cAMP類似物dibutylyl-cAMP (dbcAMP)對小鼠骨髓細胞分化成未成熟樹突細胞之影響 17
4-1-2 剔除PDE4基因對小鼠骨髓細胞分化為未成熟樹突細胞之影響 18
4-2 cAMP訊息傳導對小鼠骨髓細胞分化為成熟樹突細胞之影響 19
4-2-1 LPS對小鼠骨髓細胞分化為成熟樹突細胞之影響 19
4-2-2 cAMP與PDE抑制劑對LPS刺激樹突細胞成熟分化之影響 20
4-2-3 剔除PDE4基因對LPS刺激樹突細胞成熟分化之影響 21
4-2-4 PDE4抑制劑與cAMP對樹突細胞成熟分化之影響 22
4-3 PDE4B-/-小鼠樹突細胞對於卵蛋白致敏(ovalbumin-priming)小鼠脾臟CD4+ T 細胞增生之影響 23
五討論 25
5-1 cAMP及PDE4訊息傳導對小鼠骨髓細胞分化成未成熟樹突細胞之影響 25
5-2 LPS對小鼠骨髓細胞分化為成熟樹突細胞之影響 27
5-3 PDE4抑制劑與cAMP對樹突細胞成熟分化之影響 28
5-4 PDE4B-/-小鼠樹突細胞對卵蛋白致敏(ovalbumin-priming)小鼠脾臟CD4+ T 細胞細胞增生之影響 29
六圖與圖解 30
參考文獻 42
附圖 53

參考文獻

1. Aronoff, D. M., Canetti, C., Serezani, C. H., Luo, M. & Peters-Golden, M. (2005). Cutting edge: macrophage inhibition by cyclic AMP (cAMP): differential roles of protein kinase A and exchange protein directly activated by cAMP-1. J Immunol 174, 595-9.
2. Baillie, G. S., MacKenzie, S. J., McPhee, I. & Houslay, M. D. (2000). Sub-family selective actions in the ability of Erk2 MAP kinase to phosphorylate and regulate the activity of PDE4 cyclic AMP-specific phosphodiesterases. Br J Pharmacol 131, 811-9.
3. Banchereau, J., Briere, F., Caux, C., Davoust, J., Lebecque, S., Liu, Y. J., Pulendran, B. & Palucka, K. (2000). Immunobiology of dendritic cells. Annu Rev Immunol 18, 767-811.
4. Banchereau, J. & Steinman, R. M. (1998). Dendritic cells and the control of immunity. Nature 392, 245-52.
5. Banner, K. H., Moriggi, E., Da Ros, B., Schioppacassi, G., Semeraro, C. & Page, C. P. (1996). The effect of selective phosphodiesterase 3 and 4 isoenzyme inhibitors and established anti-asthma drugs on inflammatory cell activation. Br J Pharmacol 119, 1255-61.
6. Barnette, M. S., Christensen, S. B., Essayan, D. M., Grous, M., Prabhakar, U., Rush, J. A., Kagey-Sobotka, A. & Torphy, T. J. (1998). SB 207499 (Ariflo), a potent and selective second-generation phosphodiesterase 4 inhibitor: in vitro anti-inflammatory actions. J Pharmacol Exp Ther 284, 420-6.
7. Beard, M. B., Olsen, A. E., Jones, R. E., Erdogan, S., Houslay, M. D. & Bolger, G. B. (2000). UCR1 and UCR2 domains unique to the cAMP-specific phosphodiesterase family form a discrete module via electrostatic interactions. J Biol Chem 275, 10349-58.
8. Beavo JA, Houslay MD, Francis SH. (2007). Cyclic nucleotide phosphodiesterase superfamily. In: Beavo JA, Francis SH, Houslay MD, eds. Cyclic Nucleotide Phosphodiesterases in Health and Disease. Boca Raton, FL: CRC Press, 3-17.
9. Bolger GB. (2007). Phosphodiesterase isoforms - An annotated list. In: Beavo JA, Francis SH, Houslay MD, eds. Cyclic Nucleotide Phosphodiesterases in Health and Disease.Boca Raton, FL: CRC Press, 19-31.
10. Bos, J. L. (2003). Epac: a new cAMP target and new avenues in cAMP research. Nat Rev Mol Cell Biol 4, 733-8.
11. Bos, J. L. (2005). Linking Rap to cell adhesion. Curr Opin Cell Biol 17, 123-8.
12. Butcher, R. W. & Sutherland, E. W. (1962). Adenosine 3’,5’-phosphate in biological materials. I. Purification and properties of cyclic 3’,5’-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3’,5’-phosphate in human urine. J Biol Chem 237, 1244-50.
13. Chang, H. S., Jeon, K. W., Kim, Y. H., Chung, I. Y. & Park, C. S. (2000). Role of cAMP-dependent pathway in eosinophil apoptosis and survival. Cell Immunol 203, 29-38.
14. Chen, C. N., Denome, S. & Davis, R. L. (1986). Molecular analysis of cDNA clones and the corresponding genomic coding sequences of the Drosophila dunce+ gene, the structural gene for cAMP phosphodiesterase. Proc Natl Acad Sci U S A 83, 9313-7.
15. Conti, M. & Beavo, J. (2007). Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76, 481-511.
16. Conti, M. & Jin, S. L. (1999). The molecular biology of cyclic nucleotide phosphodiesterases. Prog Nucleic Acid Res Mol Biol 63, 1-38.
17. Conti, M., Richter, W., Mehats, C., Livera, G., Park, J. Y. & Jin, C. (2003). Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem 278, 5493-6.
18. Davis, R. L. & Dauwalder, B. (1991). The Drosophila dunce locus: learning and memory genes in the fly. Trends Genet 7, 224-9.
19. de Rooij, J., Zwartkruis, F. J., Verheijen, M. H., Cool, R. H., Nijman, S. M., Wittinghofer, A. & Bos, J. L. (1998). Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396, 474-7.
20. Diamant, Z. & Spina, D. (2011). PDE4-inhibitors: a novel, targeted therapy for obstructive airways disease. Pulm Pharmacol Ther 24, 353-60.
21. Dieu, M. C., Vanbervliet, B., Vicari, A., Bridon, J. M., Oldham, E., Ait-Yahia, S., Briere, F., Zlotnik, A., Lebecque, S. & Caux, C. (1998). Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med 188, 373-86.
22. Fan Chung, K. (2006). Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol 533, 110-7.
23. Feng, W., Wang, Y., Zhang, J., Wang, X., Li, C. & Chang, Z. (2000). Effects of CTx and 8-bromo-cAMP on LPS-induced gene expression of cytokines in murine peritoneal macrophages. Biochem Biophys Res Commun 269, 570-3.
24. Francis, S. H., Turko, I. V., Grimes, K. A. & Corbin, J. D. (2000). Histidine-607 and histidine-643 provide important interactions for metal support of catalysis in phosphodiesterase-5. Biochemistry 39, 9591-6.
25. Gagliardi, M. C., Sallusto, F., Marinaro, M., Langenkamp, A., Lanzavecchia, A. & De Magistris, M. T. (2000). Cholera toxin induces maturation of human dendritic cells and licences them for Th2 priming. Eur J Immunol 30, 2394-403.
26. Galgani, M., De Rosa, V., De Simone, S., Leonardi, A., D’Oro, U., Napolitani, G., Masci, A. M., Zappacosta, S. & Racioppi, L. (2004). Cyclic AMP modulates the functional plasticity of immature dendritic cells by inhibiting Src-like kinases through protein kinase A-mediated signaling. J Biol Chem 279, 32507-14.
27. Gantner, F., Schudt, C., Wendel, A. & Hatzelmann, A. (1999). Characterization of the phosphodiesterase (PDE) pattern of in vitro-generated human dendritic cells (DC) and the influence of PDE inhibitors on DC function. Pulm Pharmacol Ther 12, 377-86.
28. Garay, J., D’Angelo, J. A., Park, Y., Summa, C. M., Aiken, M. L., Morales, E., Badizadegan, K., Fiebiger, E. & Dickinson, B. L. (2010). Crosstalk between PKA and Epac regulates the phenotypic maturation and function of human dendritic cells. J Immunol 185, 3227-38.
29. Giembycz, M. A., Corrigan, C. J., Seybold, J., Newton, R. & Barnes, P. J. (1996). Identification of cyclic AMP phosphodiesterases 3, 4 and 7 in human CD4+ and CD8+ T-lymphocytes: role in regulating proliferation and the biosynthesis of interleukin-2. Br J Pharmacol 118, 1945-58.
30. Giordano, D., Magaletti, D. M., Clark, E. A. & Beavo, J. A. (2003). Cyclic nucleotides promote monocyte differentiation toward a DC-SIGN+ (CD209) intermediate cell and impair differentiation into dendritic cells. J Immunol 171, 6421-30.
31. Gloerich, M. & Bos, J. L. (2010). Epac: defining a new mechanism for cAMP action. Annu Rev Pharmacol Toxicol 50, 355-75.
32. Hatzelmann, A. & Schudt, C. (2001). Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 297, 267-79.
33. Heystek, H. C., Thierry, A. C., Soulard, P. & Moulon, C. (2003). Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1-polarizing capacity. Int Immunol 15, 827-35.
34. Hoffmann, R., Baillie, G. S., MacKenzie, S. J., Yarwood, S. J. & Houslay, M. D. (1999). The MAP kinase ERK2 inhibits the cyclic AMP-specific phosphodiesterase HSPDE4D3 by phosphorylating it at Ser579. EMBO J 18, 893-903.
35. Houslay, M. D. (2005). The long and short of vascular smooth muscle phosphodiesterase-4 as a putative therapeutic target. Mol Pharmacol 68, 563-7.
36. Houslay, M. D., Baillie, G. S. & Maurice, D. H. (2007). cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res 100, 950-66.
37. Houslay, M. D., Schafer, P. & Zhang, K. Y. (2005). Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 10, 1503-19.
38. Jacobitz, S., McLaughlin, M. M., Livi, G. P., Burman, M. & Torphy, T. J. (1996). Mapping the functional domains of human recombinant phosphodiesterase 4A: structural requirements for catalytic activity and rolipram binding. Mol Pharmacol 50, 891-9.
39. Jin, S. L., Ding, S. L. & Lin, S. C. (2012). Phosphodiesterase 4 and its inhibitors in inflammatory diseases. Chang Gung Med J 35, 197-210.
40. Jin, S. L., Goya, S., Nakae, S., Wang, D., Bruss, M., Hou, C., Umetsu, D. & Conti, M. (2010). Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol 126, 1252-9
41. Jin, S. L., Lan, L., Zoudilova, M. & Conti, M. (2005). Specific role of phosphodiesterase 4B in lipopolysaccharide-induced signaling in mouse macrophages. J Immunol 175, 1523-31.
42. Jin, S. L., Richter, W., & Conti, M. (2007). Insights into the physiological functions of PDE4s from knockout mice. In: Beavo JA, Francis SH, Houslay MD, eds. Cyclic Nucleotide Phosphodiesterases in Health and Disease. Boca Raton, FL: CRC Press, 323-346
43. Jing, H., Yen, J. H. & Ganea, D. (2004). A novel signaling pathway mediates the inhibition of CCL3/4 expression by prostaglandin E2. J Biol Chem 279, 55176-86.
44. Jozefowski, S., Bobek, M. & Marcinkiewicz, J. (2003). Exogenous but not endogenous prostanoids regulate cytokine secretion from murine bone marrow dendritic cells: EP2, DP, and IP but not EP1, EP3, and FP prostanoid receptors are involved. Int Immunopharmacol 3, 865-78.
45. Kalinski, P., Hilkens, C. M., Snijders, A., Snijdewint, F. G. & Kapsenberg, M. L. (1997). IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol 159, 28-35.
46. Kambayashi, T., Jacob, C. O., Zhou, D., Mazurek, N., Fong, M. & Strassmann, G. (1995). Cyclic nucleotide phosphodiesterase type IV participates in the regulation of IL-10 and in the subsequent inhibition of TNF-alpha and IL-6 release by endotoxin-stimulated macrophages. J Immunol 155, 4909-16.
47. Kambayashi, T., Wallin, R. P. & Ljunggren, H. G. (2001). cAMP-elevating agents suppress dendritic cell function. J Leukoc Biol 70, 903-10.
48. Kamenetsky, M., Middelhaufe, S., Bank, E. M., Levin, L. R., Buck, J. & Steegborn, C. (2006). Molecular details of cAMP generation in mammalian cells: a tale of two systems. J Mol Biol 362, 623-39.
49. Kaupp, U. B. & Seifert, R. (2002). Cyclic nucleotide-gated ion channels. Physiol Rev 82, 769-824.
50. Kawasaki, H., Springett, G. M., Mochizuki, N., Toki, S., Nakaya, M., Matsuda, M., Housman, D. E. & Graybiel, A. M. (1998). A family of cAMP-binding proteins that directly activate Rap1. Science 282, 2275-9.
51. Keravis, T. & Lugnier, C. (2012). Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments. Br J Pharmacol 165, 1288-305.
52. Kita, H., Abu-Ghazaleh, R. I., Gleich, G. J. & Abraham, R. T. (1991). Regulation of Ig-induced eosinophil degranulation by adenosine 3’,5’-cyclic monophosphate. J Immunol 146, 2712-8.
53. Kovala, T., Sanwal, B. D. & Ball, E. H. (1997). Recombinant expression of a type IV, cAMP-specific phosphodiesterase: characterization and structure-function studies of deletion mutants. Biochemistry 36, 2968-76.
54. Kunkel, S. L., Wiggins, R. C., Chensue, S. W. & Larrick, J. (1986). Regulation of macrophage tumor necrosis factor production by prostaglandin E2. Biochem Biophys Res Commun 137, 404-10.
55. Lewis, K. L., Caton, M. L., Bogunovic, M., Greter, M., Grajkowska, L. T., Ng, D., Klinakis, A., Charo, I. F., Jung, S., Gommerman, J. L., Ivanov, II, Liu, K., Merad, M. & Reizis, B. (2011). Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35, 780-91.
56. Li, H. S., Yang, C. Y., Nallaparaju, K. C., Zhang, H., Liu, Y. J., Goldrath, A. W. & Watowich, S. S. (2012). The signal transducers STAT5 and STAT3 control expression of Id2 and E2-2 during dendritic cell development. Blood 120, 4363-73.
57. Liu, Y. J. (2001). Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106, 259-62.
58. Lugnier, C. (2006). Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 109, 366-98.
59. Lutz, M. B., Kukutsch, N., Ogilvie, A. L., Rossner, S., Koch, F., Romani, N. & Schuler, G. (1999). An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 223, 77-92.
60. MacKenzie, S. J. & Houslay, M. D. (2000). Action of rolipram on specific PDE4 cAMP phosphodiesterase isoforms and on the phosphorylation of cAMP-response-element-binding protein (CREB) and p38 mitogen-activated protein (MAP) kinase in U937 monocytic cells. Biochem J 347, 571-8.
61. Makranz, C., Cohen, G., Reichert, F., Kodama, T. & Rotshenker, S. (2006). cAMP cascade (PKA, Epac, adenylyl cyclase, Gi, and phosphodiesterases) regulates myelin phagocytosis mediated by complement receptor-3 and scavenger receptor-AI/II in microglia and macrophages. Glia 53, 441-8.
62. Manganiello, V. (2002). Short-term regulation of PDE4 activity. Br J Pharmacol 136, 339-40.
63. Mary, D., Aussel, C., Ferrua, B. & Fehlmann, M. (1987). Regulation of interleukin 2 synthesis by cAMP in human T cells. J Immunol 139, 1179-84.
64. Mehats, C., Andersen, C. B., Filopanti, M., Jin, S. L. & Conti, M. (2002). Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling. Trends Endocrinol Metab 13, 29-35.
65. McCahill, A., McSorley, T., Huston, E., Hill, E. V., Lynch, M. J., Gall, I., Keryer, G., Lygren, B., Tasken, K., van Heeke, G. & Houslay, M. D. (2005). In resting COS1 cells a dominant negative approach shows that specific, anchored PDE4 cAMP phosphodiesterase isoforms gate the activation, by basal cyclic AMP production, of AKAP-tethered protein kinase A type II located in the centrosomal region. Cell Signal 17, 1158-73.
66. McKenna, K., Beignon, A. S. & Bhardwaj, N. (2005). Plasmacytoid dendritic cells: linking innate and adaptive immunity. J Virol 79, 17-27.
67. Millar, J. K., Pickard, B. S., Mackie, S., James, R., Christie, S., Buchanan, S. R., Malloy, M. P., Chubb, J. E., Huston, E., Baillie, G. S., Thomson, P. A., Hill, E. V., Brandon, N. J., Rain, J. C., Camargo, L. M., Whiting, P. J., Houslay, M. D., Blackwood, D. H., Muir, W. J. & Porteous, D. J. (2005). DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310, 1187-91.
68. Osugi, Y., Vuckovic, S. & Hart, D. N. (2002). Myeloid blood CD11c(+) dendritic cells and monocyte-derived dendritic cells differ in their ability to stimulate T lymphocytes. Blood 100, 2858-66.
69. Pidoux, G. & Tasken, K. (2010). Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins. J Mol Endocrinol 44, 271-84.
70. Price, L. S., Hajdo-Milasinovic, A., Zhao, J., Zwartkruis, F. J., Collard, J. G. & Bos, J. L. (2004). Rap1 regulates E-cadherin-mediated cell-cell adhesion. J Biol Chem 279, 35127-32.
71. Qiu, Y. H., Chen, C. N., Malone, T., Richter, L., Beckendorf, S. K. & Davis, R. L. (1991). Characterization of the memory gene dunce of Drosophila melanogaster. J Mol Biol 222, 553-65.
72. Raabe, T., Bukrinsky, M. & Currie, R. A. (1998). Relative contribution of transcription and translation to the induction of tumor necrosis factor-alpha by lipopolysaccharide. J Biol Chem 273, 974-80.
73. Reneland, R. H., Mah, S., Kammerer, S., Hoyal, C. R., Marnellos, G., Wilson, S. G., Sambrook, P. N., Spector, T. D., Nelson, M. R. & Braun, A. (2005). Association between a variation in the phosphodiesterase 4D gene and bone mineral density. BMC Med Genet 6, 9.
74. Richter, W. & Conti, M. (2002). Dimerization of the type 4 cAMP-specific phosphodiesterases is mediated by the upstream conserved regions (UCRs). J Biol Chem 277, 40212-21.
75. Rissoan, M. (1999). Reciprocal Control of T Helper Cell and Dendritic Cell Differentiation. Science 283, 1183-1186.
76. Robichaud, A., Stamatiou, P. B., Jin, S. L., Lachance, N., MacDonald, D., Laliberte, F., Liu, S., Huang, Z., Conti, M. & Chan, C. C. (2002). Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest 110, 1045-52.
77. Sallusto, F., Cella, M., Danieli, C. & Lanzavecchia, A. (1995). Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J Exp Med 182, 389-400.
78. Schwartz, J. H. (2001). The many dimensions of cAMP signaling. Proc Natl Acad Sci U S A 98, 13482-4.
79. Serezani, C. H., Ballinger, M. N., Aronoff, D. M. & Peters-Golden, M. (2008). Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol 39, 127-32.
80. Shabb, J. B. (2001). Physiological substrates of cAMP-dependent protein kinase. Chem Rev 101, 2381-411.
81. Singh-Jasuja, H., Thiolat, A., Ribon, M., Boissier, M. C., Bessis, N., Rammensee, H. G. & Decker, P. (2013). The mouse dendritic cell marker CD11c is down-regulated upon cell activation through Toll-like receptor triggering. Immunobiology 218, 28-39.
82. Souness, J. E., Aldous, D. & Sargent, C. (2000). Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors. Immunopharmacology 47, 127-62.
83. Steinman, R. M. (1991). The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9, 271-96.
84. Sutherland, E. W. & Rall, T. W. (1958). Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles. J Biol Chem 232, 1077-91.
85. Swinnen, J. V., Joseph, D. R. & Conti, M. (1989). Molecular cloning of rat homologues of the Drosophila melanogaster dunce cAMP phosphodiesterase: evidence for a family of genes. Proc Natl Acad Sci U S A 86, 5325-9.
86. Tasken, K. & Aandahl, E. M. (2004). Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol Rev 84, 137-67.
87. Torphy, T. J. (1998). Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 157, 351-70.
88. Turner, C. R., Cohan, V. L., Cheng, J. B., Showell, H. J., Pazoles, C. J. & Watson, J. W. (1996). The in vivo pharmacology of CP-80, 633, a selective inhibitor of phosphodiesterase 4. J Pharmacol Exp Ther 278, 1349-55.
89. van de Laar, L., Coffer, P. J. & Woltman, A. M. (2012). Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy. Blood 119, 3383-93.
90. van Rijt, L. S., Jung, S., Kleinjan, A., Vos, N., Willart, M., Duez, C., Hoogsteden, H. C. & Lambrecht, B. N. (2005). In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J Exp Med 201, 981-91.

指導教授

金秀蓮(Shiow-lian Jin)

審核日期

2013-7-17

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