博碩士論文 100284003 詳細資訊




以作者查詢圖書館館藏 以作者查詢臺灣博碩士 以作者查詢全國書目 勘誤回報 、線上人數:5 、訪客IP:34.207.82.217
姓名 楊景行(Jing-Xing Yang)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 環狀核苷酸磷酸二酯酶4B對內毒素誘導巨噬細胞 產生IL-1Ra和樹突細胞表現TLRs之影響 及其對乾癬症生成之潛在角色
(Effects of Phosphodiesterase 4B on Endotoxin-induced IL-1Ra Production in Macrophages and TLR Expression in Dendritic Cells and Its Potential Role in the Pathogenesis of Psoriasis)
檔案 [Endnote RIS 格式]    [Bibtex 格式]    [相關文章]   [文章引用]   [完整記錄]   [館藏目錄]   至系統瀏覽論文 ( 永不開放)
摘要(中) 巨噬細胞與樹突細胞(Dendritic cells)能辨識病原菌並引發免疫發炎反應,於先天免疫系統扮演重要的角色。Phosphodiesterases 4 (PDE4)為水解cAMP的專一酵素,抑制PDE4以增加兩種細胞內cAMP濃度可減緩多種發炎反應,其中部分反應已被證實主要是由PDE4四個亞型(PDE4A-4D)中的PDE4B參與調控。在本研究中,我們利用PDE4抑制劑與PDE4基因剔除鼠及其細胞進行實驗,發現PDE4B在這些細胞中可以調控更多不同的免疫發炎反應。
已知內毒素lipopolysaccharide (LPS)活化TLR4可誘導巨噬細胞產生促發炎及抗發炎細胞激素。PDE4抑制劑,例如rolipram,被認為是多種發炎反應的免疫抑制劑。在本論文的第一部分中,我們利用LPS刺激小鼠腹腔巨噬細胞,首先發現PDE4抑制劑rolipram會明顯提升LPS所誘導抗發炎細胞激素interleukin-1 receptor antagonist (IL-1Ra)的釋放,此作用是由於增加IL-1Ra的轉錄作用而不是影響其mRNA的穩定度。進一步利用PDE4-/-腹腔巨噬細胞進行實驗顯示,由LPS單獨處理所誘導的IL-1Ra釋放不是受PKA調控,然而與rolipram共同處理所增加的IL-1Ra則是經由抑制PDE4B所致,且需要活化PKA而非Epac訊息傳導路徑。此外,LPS與rolipram兩者作用都需要活化CREB以增加IL-1Ra表現。再者,我們發現在LPS刺激的PDE4B-/-巨噬細胞中,其STAT3 (Tyr705)磷酸化會增加,但此STAT3的活化不是造成該細胞增加IL-1Ra的主要原因。在LPS誘導小鼠敗血症的模型中,PDE4B-/-小鼠的血清中有較多IL-1Ra的累積,此與先前報導該小鼠增加存活率的結果一致。這些研究證實PDE4B在巨噬細胞中會負調控抗發炎細胞激素的產生。在本論文的第二部分中,我們發現處理rolipram或剔除PDE4B可顯著降低小鼠骨髓細胞分化為CD11c+未成熟樹突細胞數以及細胞表面CD11c的表現量,但剔除PDE4A與4D則無此抑制作用。此外,於LPS誘導樹突細胞成熟過程中,rolipram或剔除PDE4B會使CD11c+樹突細胞群更為下降。再者,我們使用定量PCR方法檢測小鼠樹突細胞內Toll-like receptor (TLR)的表現,結果顯示,以LPS處理細胞4小時,TLR1、2、3、6、7與9的mRNA表現量呈顯著上升,而24-36小時後其表現量均會回至基礎值。在這些LPS所誘導的TLRs中,TLR1, 6, 7, 與9的表現會被rolipram顯著抑制,而主要是經由抑制PDE4B所致,顯示PDE4B對於這些先天免疫受體的表現有不可或缺的重要性。在TLR7促效劑imiquimod誘導的乾癬模型中,我們發現PDE4抑制劑可有效減緩小鼠乾癬性皮膚炎的嚴重程度。這些結果證實PDE4,主要是PDE4B,在發炎狀況下會參與調控樹突細胞的分化與免疫功能。綜合上述結果,我們認為研發PDE4B選擇性抑制劑應能保留非選擇性PDE4抑制劑的療效,然而去除其負作用。
摘要(英) Macrophages and dendritic cells (DCs) are important in innate immune system, where they recognize pathogens and initiate inflammatory responses. Elevation of cAMP by inhibition of phosphodieasterases 4 (PDE4), enzymes that degrade cAMP with high affinity, in these cells is known to suppress various inflammatory responses. Among the four PDE4 isoforms (PDE4A-4D), PDE4B has been shown to play a major role in some of these responses. In this study, using PDE4 inhibitors and PDE4-deficient mice and cells, we demonstrate that PDE4B is involved in modulating additional immune responses in these cells under endotoxin lipopolysaccharide (LPS) stimulation.
Activation of TLR4 by LPS is known to induce both pro-inflammatory and anti-inflammatory cytokine production in macrophages. Here in the first part of the study, we show that PDE4 inhibitors, such as rolipram, enhance the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) secretion in LPS-stimulated mouse peritoneal macrophages, and this response was regulated at the transcriptional level rather than an increased IL-1Ra mRNA stability. Studies with PDE4-deficient macrophages revealed that the IL-1Ra upregulation elicited by LPS alone is PKA-independent, whereas the rolipram-enhanced response was mediated by inhibition of only PDE4B, one of the three PDE4 isoforms expressed in macrophages, and it requires PKA but not Epac activity. However, both pathways activate CREB to induce IL-1Ra expression. PDE4B ablation also promoted STAT3 phosphorylation (Tyr705) to LPS stimulation, but this STAT3 activation is not entirely responsible for the IL-1Ra upregulation in PDE4B-deficient macrophages. In a model of LPS-induced sepsis, only PDE4B-deficient mice displayed an increased circulating IL-1Ra, suggesting a protective role of PDE4B inactivation in vivo. These findings demonstrate that PDE4B negatively modulates anti-inflammatory cytokine expression in macrophages. In the second part of the study, we demonstrate that during in vitro differentiation of mouse bone marrow (BM) cells to immature DCs (imDCs), rolipram or ablation of PDE4B, but PDE4A or PDE4D, significantly reduced CD11c+ imDC population and the cell surface level of CD11c. The CD11c+ population was further decreased by rolipram and PDE4B ablation following LPS induction of DC maturation. Quantitative PCR analysis revealed that the mRNA expression of Toll-like receptor (TLR) 1, 2, 3, 6, 7, and 9 in BMDCs was markedly upregulated at 4 h of LPS stimulation and then declined to near or lower than basal levels at 24 or 36 h. Among these TLRs, the induction of TLR1, 6, 7, and 9 mRNA was greatly inhibited by rolipram and this inhibition was shown to be mediated mainly by inhibition of PDE4B, indicating an essential role of PDE4B in the expression of these innate immune receptors. In a murine model of TLR7 agonist-induced psoriasis, we further showed that PDE4 inhibitor significantly attenuated the severity of psoriatic symptoms in mice treated with imiquimod. These data demonstrate an important role of PDE4, particularly PDE4B, in regulation of DC development and functions under inflammatory conditions. Taken together, our findings provide further evidence that the development of PDE4B-selective inhibitor should retain the therapeutic benefits but devoid the side effects of non-selective PDE4 inhibitors.
關鍵字(中) ★ 環狀核苷酸磷酸二酯酶4
★ 白細胞介素-1受體拮抗劑
★ 巨噬細胞
★ 樹突細胞
★ 乾癬
關鍵字(英) ★ PDE4
★ IL-1Ra
★ Macrophage
★ Dendritic cell
★ Toll-like receptor
★ Psoriasis
論文目次 Declaration………………………………………………….……………...........…………………….i
中文摘要………………………………………………….………………………..........………..ii-iii
Abstract………………………………………………….………..……….....……...………...…iv-v
Acknowledgments…………………………....…………………..….........….…vi-vii
Table of Contents…………………………………………………..............viii-ix
List of Figures……………………………………………………….................x-xi
List of tables……………………………………………………..…………………...……….....xii
Abbreviations……………………………………….………….……………......……..xiii-xiv
Chapter 1: Phosphodiesterase 4B negatively regulates endotoxin-activated
interleukin-1 receptor antagonist responses in macrophages…....……......................................1
1-1 Introduction……………………………………………………...……….…...…………...2-5
1-2 Materials and Methods……………………………….………………...………….……….6
1-2-1 Reagents…………………………………………........…………...………….……..6
1-2-2 Cell line……………………………….........…………………...……………………6
1-2-3 Mice…………………………………………..........………………….....…………6-7
1-2-4 Primary macrophages………........………………......…………7-8
1-2-5 RNA isolation, cDNA synthesis, and
quantitative PCR…….……....................…..……8-9
1-2-6 RNA stability assay……………………........……...………………..9
1-2-7 Western blot analysis……………........………...……..…9-10
1-2-8 LPS-induced systemic inflammation.…...........…10
1-2-9 Cytokine measurement………………………...........………...…10
1-2-10 Cell viability assay…………………........……...…………10-11
1-2-11 Statistical analysis……………………...……………..…11
1-3 Results………………………………………………………………………….........…...…….12
1-3-1 Inhibition of PDE4 upregulates LPS-induced
IL-1Ra production in mouse macrophages….....12-13
1-3-2 PDE4 inhibitor does not alter intracellular
form IL-1Ra mRNA level or cell viability
in LPS-stimulated mouse peritoneal macrophages
......................................….....13-14
1-3-3 Inhibition of PDE4 does not increase IL-1Ra
mRNA stability……..........................………..14
1-3-4 Ablation of PDE4B increases LPS-induced
IL-1Ra production in macrophage……...….……....14-15
1-3-5 Cyclic AMP-PKA signaling mediates the
stimulating effects of PDE4B ablation and
rolipram inhibition on IL-1Ra productio....…15-16
1-3-6 LPS-induced IL-1Ra production in PDE4B null
macrophages requires both PKA-dependent and
PKA-independent CREB activation….........…….16-17
1-3-7 STAT3 activation elicited by PDE4B ablation
is not fully responsible for the observed
IL-1Ra upregulation……………......…………………......…17-19
1-3-8 Serum level of IL-1Ra is elevated in PDE4B-
deficient mice during LPS-induced sepsis....19-20
1-4 Discussion…………………….....…………………………………………………....….21-25
1-5 References…………………….....………………………………………………....…….26-30
Chapter 2: Phosphodiesterase 4B regulates cell differentiation and TLR expression in bone marrow-derived dendritic cells and its potential function…..….......….31
2-1 Introduction…………………………………………………….....………....…………32-39
2-2 Materials and Methods………………………………..…………………...………….…40
2-2-1 Reagents…………………………………............………………………………….40
2-2-2 Mice……………………………………...............……………………………………40
2-2-3 Generation of bone marrow-derived dendritic
cells (BMDCs)….….........................…..40-41
2-2-4 RNA isolation, cDNA synthesis, and
quantitative PCR………….....................………41-42
2-2-5 Fluorescence-activated cell sorting (FACS)
analysis by flow cytometry…....................42
2-2-6 Induction of psoriasis-like skin inflammation
by imiquimod (IMQ)….….......................…..42
2-2-7 Severity scoring of skin inflammation…………...42-43
2-2-8 Statistical analysis……………………..………………………………..…….43
2-3 Results………………………………………………............………….………………………44
2-3-1 Ablation of PDE4B suppresses bone marrow-derived
dendritic cell differentiation………….………......44-45
2-3-2 Inhibition of PDE4 reduces CD11c+ cell
population during LPS- or OVA-induced
dendritic cell maturation……………………......……………45-46
2-3-3 LPS induces PDE4B mRNA expression in bone
marrow-derived DCs…………………………………………………………....46-47
2-3-4 Inhibition of PDE4 downregulates pattern
recognition receptor expression in dendritic
cells during LPS-induced cell maturation……..47-49
2-3-5 Effects of PDE4 ablation on TLR mRNA
expression during LPS-induced DC maturation…49-51
2-3-6 Inhibition of PDE4 attenuates the severity
of imiquimod (IMQ)-induced psoriasis-like
inflammation……………………………................……..…51-52
2-4 Discussion………………………………………........……………………………….….53-57
2-5 References………………………………………........……………………………..……58-65
Figures and Figure Legends………..………………………………………………...66-99
Tables……………..………………..………………………………………...........……….….…100
Appendix…………………………………..……..……........………………………..……101-104
參考文獻 Aksentijevich, I., S.L. Masters, P.J. Ferguson, P. Dancey, J. Frenkel, A. van Royen-Kerkhoff, R. Laxer, U. Tedgard, E.W. Cowen, T.H. Pham, M. Booty, J.D. Estes, N.G. Sandler, N. Plass, D.L. Stone, M.L. Turner, S. Hill, J.A. Butman, R. Schneider, P. Babyn, H.I. El-Shanti, E. Pope, K. Barron, X. Bing, A. Laurence, C.C. Lee, D. Chapelle, G.I. Clarke, K. Ohson, M. Nicholson, M. Gadina, B. Yang, B.D. Korman, P.K. Gregersen, P.M. van Hagen, A.E. Hak, M. Huizing, P. Rahman, D.C. Douek, E.F. Remmers, D.L. Kastner, and R. Goldbach-Mansky. 2009. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 360:2426-2437.

Andersson, J., L. Bjork, C.A. Dinarello, H. Towbin, and U. Andersson. 1992. Lipopolysaccharide induces human interleukin-1 receptor antagonist and interleukin-1 production in the same cell. Eur J Immunol 22:2617-2623.

Arend, W.P., M.F. Smith, Jr., R.W. Janson, and F.G. Joslin. 1991. IL-1 receptor antagonist and IL-1 beta production in human monocytes are regulated differently. J Immunol 147:1530-1536.

Aronoff, D.M., C. Canetti, C.H. Serezani, M. Luo, and M. Peters-Golden. 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 174:595-599.

Aronoff, D.M., J.K. Carstens, G.H. Chen, G.B. Toews, and M. Peters-Golden. 2006. Short communication: differences between macrophages and dendritic cells in the cyclic AMP-dependent regulation of lipopolysaccharide-induced cytokine and chemokine synthesis. J Interferon Cytokine Res 26:827-833.

Avni, D., O. Ernst, A. Philosoph, and T. Zor. 2010. Role of CREB in modulation of TNFalpha and IL-10 expression in LPS-stimulated RAW264.7 macrophages. Mol Immunol 47:1396-1403.

Carl, V.S., K. Brown-Steinke, M.J. Nicklin, and M.F. Smith, Jr. 2002. Toll-like receptor 2 and 4 (TLR2 and TLR4) agonists differentially regulate secretory interleukin-1 receptor antagonist gene expression in macrophages. J Biol Chem 277:17448-17456.

Carl, V.S., J.K. Gautam, L.D. Comeau, and M.F. Smith, Jr. 2004. Role of endogenous IL-10 in LPS-induced STAT3 activation and IL-1 receptor antagonist gene expression. J Leukoc Biol 76:735-742.

Darragh, J., O. Ananieva, A. Courtney, S. Elcombe, and J.S. Arthur. 2010. MSK1 regulates the transcription of IL-1ra in response to TLR activation in macrophages. Biochem J 425:595-602.

Deeks, E.D. 2015. Apremilast: A Review in Psoriasis and Psoriatic Arthritis. Drugs 75:1393-1403.

Dinarello, C.A. 2011. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117:3720-3732.

Dripps, D.J., B.J. Brandhuber, R.C. Thompson, and S.P. Eisenberg. 1991. Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266:10331-10336.

Edwards, J.P., and L.A. Emens. 2010. The multikinase inhibitor sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE(2) in murine macrophages. Int Immunopharmacol 10:1220-1228.

Feng, W., Y. Wang, J. Zhang, X. Wang, C. Li, and Z. Chang. 2000. Effects of CTx and 8-bromo-cAMP on LPS-induced gene expression of cytokines in murine peritoneal macrophages. Biochem Biophys Res Commun 269:570-573.

Garnock-Jones, K.P. 2015. Roflumilast: A Review in COPD. Drugs 75:1645-1656.

Gerlo, S., P. Verdood, and R. Kooijman. 2010. Modulation of cytokine production by cyclic adenosine monophosphate analogs in human leukocytes. J Interferon Cytokine Res 30:883-891.

Hertz, A.L., A.T. Bender, K.C. Smith, M. Gilchrist, P.S. Amieux, A. Aderem, and J.A. Beavo. 2009. Elevated cyclic AMP and PDE4 inhibition induce chemokine expression in human monocyte-derived macrophages. Proc Natl Acad Sci U S A 106:21978-21983.

Hirsch, E., V.M. Irikura, S.M. Paul, and D. Hirsh. 1996. Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc Natl Acad Sci U S A 93:11008-11013.

Houslay, M.D., M. Sullivan, and G.B. Bolger. 1998. The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions. Adv Pharmacol 44:225-342.

Ji, Q., Y. Di, X. He, Q. Liu, J. Liu, W. Li, and L. Zhang. 2016. Intrathecal injection of phosphodiesterase 4B-specific siRNA attenuates neuropathic pain in rats with L5 spinal nerve ligation. Mol Med Rep 13:1914-1922.

Jin, S.L., and M. Conti. 2002. Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses. Proc Natl Acad Sci U S A 99:7628-7633.

Jin, S.L., S.L. Ding, and S.C. Lin. 2012. Phosphodiesterase 4 and its inhibitors in inflammatory diseases. Chang Gung Med J 35:197-210.

Jin, S.L., S. Goya, S. Nakae, D. Wang, M. Bruss, C. Hou, D. Umetsu, and M. Conti. 2010. Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol 126:1252-1259 e1212.

Jin, S.L., L. Lan, M. Zoudilova, and M. Conti. 2005. Specific role of phosphodiesterase 4B in lipopolysaccharide-induced signaling in mouse macrophages. J Immunol 175:1523-1531.

Johnson, C.R., D. Kitz, and J.R. Little. 1983. A method for the derivation and continuous propagation of cloned murine bone marrow macrophages. J Immunol Methods 65:319-332.

Kasai, T., K. Inada, T. Takakuwa, Y. Yamada, Y. Inoue, T. Shimamura, S. Taniguchi, S. Sato, G. Wakabayashi, and S. Endo. 1997. Anti-inflammatory cytokine levels in patients with septic shock. Res Commun Mol Pathol Pharmacol 98:34-42.

Kawai, T., and S. Akira. 2010. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373-384.

Kay, J., and L. Calabrese. 2004. The role of interleukin-1 in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 43 Suppl 3:iii2-iii9.

Kuhn, R., F. Schwenk, M. Aguet, and K. Rajewsky. 1995. Inducible gene targeting in mice. Science 269:1427-1429.

Lai, C. R., Lo, H. C., Chen Y. L., Yang J. X., Ding S. L., Hsu H. H., Conti M., Wu C. P., and Jin, S. L. C. 2015. Phosphodiesterase 4B is essential for lipopolysaccharide-induced CC chemokine ligand 3 production in mouse macrophages. J. Med. Sci. 35, 111–121.

Liew, F.Y., D. Xu, E.K. Brint, and L.A. O′Neill. 2005. Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5:446-458.

Ma, D., P. Wu, R.W. Egan, M.M. Billah, and P. Wang. 1999. Phosphodiesterase 4B gene transcription is activated by lipopolysaccharide and inhibited by interleukin-10 in human monocytes. Mol Pharmacol 55:50-57.

Ma, H., J. Shi, C. Wang, L. Guo, Y. Gong, J. Li, Y. Gong, F. Yun, H. Zhao, and E. Li. 2014. Blockade of PDE4B limits lung vascular permeability and lung inflammation in LPS-induced acute lung injury. Biochem Biophys Res Commun 450:1560-1567.

Marsh, C.B., S.A. Moore, H.A. Pope, and M.D. Wewers. 1994. IL-1ra suppresses endotoxin-induced IL-1 beta and TNF-alpha release from mononuclear phagocytes. Am J Physiol 267:L39-45.

Molnarfi, N., L. Gruaz, J.M. Dayer, and D. Burger. 2007. Opposite regulation of IL-1beta and secreted IL-1 receptor antagonist production by phosphatidylinositide-3 kinases in human monocytes activated by lipopolysaccharides or contact with T cells. J Immunol 178:446-454.

Palmer, G., D. Talabot-Ayer, G. Kaya, and C. Gabay. 2007. Type I IL-1 receptor mediates IL-1 and intracellular IL-1 receptor antagonist effects in skin inflammation. J Invest Dermatol 127:1938-1946.

Palomo, J., D. Dietrich, P. Martin, G. Palmer, and C. Gabay. 2015. The interleukin (IL)-1 cytokine family--Balance between agonists and antagonists in inflammatory diseases. Cytokine 76:25-37.

Pearse, D.D., and Z.A. Hughes. 2016. PDE4B as a microglia target to reduce neuroinflammation. Glia 64:1698-1709.

Raz, R., C.K. Lee, L.A. Cannizzaro, P. d′Eustachio, and D.E. Levy. 1999. Essential role of STAT3 for embryonic stem cell pluripotency. Proc Natl Acad Sci U S A 96:2846-2851.
Reddy, S., S. Jia, R. Geoffrey, R. Lorier, M. Suchi, U. Broeckel, M.J. Hessner, and J. Verbsky. 2009. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med 360:2438-2444.

Rehani, K., H. Wang, C.A. Garcia, D.F. Kinane, and M. Martin. 2009. Toll-like receptor-mediated production of IL-1Ra is negatively regulated by GSK3 via the MAPK ERK1/2. J Immunol 182:547-553.

Saito, T., N. Sugimoto, K. Ohta, T. Shimizu, K. Ohtani, Y. Nakayama, T. Nakamura, Y. Hitomi, H. Nakamura, S. Koizumi, and A. Yachie. 2012. Phosphodiesterase inhibitors suppress Lactobacillus casei cell-wall-induced NF-kappaB and MAPK activations and cell proliferation through protein kinase A--or exchange protein activated by cAMP-dependent signal pathway. ScientificWorldJournal 2012:748572.

Schulte, W., J. Bernhagen, and R. Bucala. 2013. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets--an updated view. Mediators Inflamm 2013:165974.

Serezani, C.H., M.N. Ballinger, D.M. Aronoff, and M. Peters-Golden. 2008. Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol 39:127-132.

Tamassia, N., M. Castellucci, M. Rossato, S. Gasperini, D. Bosisio, M. Giacomelli, R. Badolato, M.A. Cassatella, and F. Bazzoni. 2010. Uncovering an IL-10-dependent NF-kappaB recruitment to the IL-1ra promoter that is impaired in STAT3 functionally defective patients. FASEB J 24:1365-1375.

Torphy, T.J. 1998. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 157:351-370.

Waage, A., P. Brandtzaeg, A. Halstensen, P. Kierulf, and T. Espevik. 1989. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med 169:333-338.

Xu, X.J., J.S. Reichner, B. Mastrofrancesco, W.L. Henry, Jr., and J.E. Albina. 2008. Prostaglandin E2 suppresses lipopolysaccharide-stimulated IFN-beta production. J Immunol 180:2125-2131.

Zhou, F., X. He, Y. Iwakura, R. Horai, and J.M. Stuart. 2005. Arthritis in mice that are deficient in interleukin-1 receptor antagonist is dependent on genetic background. Arthritis Rheum 52:3731-3738.

Abdollahi-Roodsaz, S., L.A. Joosten, M.F. Roelofs, T.R. Radstake, G. Matera, C. Popa, J.W. van der Meer, M.G. Netea, and W.B. van den Berg. 2007. Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum 56:2957-2967.

Baker, B.S., J.M. Ovigne, A.V. Powles, S. Corcoran, and L. Fry. 2003. Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis. Br J Dermatol 148:670-679.

Banchereau, J., and R.M. Steinman. 1998. Dendritic cells and the control of immunity. Nature 392:245-252.

Begon, E., L. Michel, B. Flageul, I. Beaudoin, F. Jean-Louis, H. Bachelez, L. Dubertret, and P. Musette. 2007. Expression, subcellular localization and cytokinic modulation of Toll-like receptors (TLRs) in normal human keratinocytes: TLR2 up-regulation in psoriatic skin. Eur J Dermatol 17:497-506.

Bros, M., E. Montermann, A. Cholaszczynska, and A.B. Reske-Kunz. 2016. The phosphodiesterase 4 inhibitor roflumilast augments the Th17-promoting capability of dendritic cells by enhancing IL-23 production, and impairs their T cell stimulatory activity due to elevated IL-10. Int Immunopharmacol 35:174-184.

Broz, P., and D.M. Monack. 2013. Newly described pattern recognition receptors team up against intracellular pathogens. Nat Rev Immunol 13:551-565.

Caruso, R., N. Warner, N. Inohara, and G. Nunez. 2014. NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 41:898-908.

Challier, J., D. Bruniquel, A.K. Sewell, and B. Laugel. 2013. Adenosine and cAMP signalling skew human dendritic cell differentiation towards a tolerogenic phenotype with defective CD8(+) T-cell priming capacity. Immunology 138:402-410.

Choe, J.Y., B. Crain, S.R. Wu, and M. Corr. 2003. Interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by toll-like receptor 4 signaling. J Exp Med 197:537-542.
Degraaf, A.J., Z. Zaslona, E. Bourdonnay, and M. Peters-Golden. 2014. Prostaglandin E2 reduces Toll-like receptor 4 expression in alveolar macrophages by inhibition of translation. Am J Respir Cell Mol Biol 51:242-250.

Delneste, Y., N. Herbault, B. Galea, G. Magistrelli, I. Bazin, J.Y. Bonnefoy, and P. Jeannin. 1999. Vasoactive intestinal peptide synergizes with TNF-alpha in inducing human dendritic cell maturation. J Immunol 163:3071-3075.

Drexler, S.K., and B.M. Foxwell. 2010. The role of toll-like receptors in chronic inflammation. Int J Biochem Cell Biol 42:506-518.

Frank, S., E. Copanaki, G.J. Burbach, U.C. Muller, and T. Deller. 2009. Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice. Neurosci Lett 453:41-44.

Galgani, M., V. De Rosa, S. De Simone, A. Leonardi, U. D′Oro, G. Napolitani, A.M. Masci, S. Zappacosta, and L. Racioppi. 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 279:32507-32514.

Gambuzza, M., N. Licata, E. Palella, D. Celi, V. Foti Cuzzola, D. Italiano, S. Marino, and P. Bramanti. 2011. Targeting Toll-like receptors: emerging therapeutics for multiple sclerosis management. J Neuroimmunol 239:1-12.

Ganguly, D., S. Haak, V. Sisirak, and B. Reizis. 2013. The role of dendritic cells in autoimmunity. Nat Rev Immunol 13:566-577.

Gantner, F., R. Kupferschmidt, C. Schudt, A. Wendel, and A. Hatzelmann. 1997. In vitro differentiation of human monocytes to macrophages: change of PDE profile and its relationship to suppression of tumour necrosis factor-alpha release by PDE inhibitors. Br J Pharmacol 121:221-231.

Garay, J., J.A. D′Angelo, Y. Park, C.M. Summa, M.L. Aiken, E. Morales, K. Badizadegan, E. Fiebiger, and B.L. Dickinson. 2010. Crosstalk between PKA and Epac regulates the phenotypic maturation and function of human dendritic cells. J Immunol 185:3227-3238.
Gaspari, A.A. 2006. Innate and adaptive immunity and the pathophysiology of psoriasis. J Am Acad Dermatol 54:S67-80.

Gay, N.J., M.F. Symmons, M. Gangloff, and C.E. Bryant. 2014. Assembly and localization of Toll-like receptor signalling complexes. Nat Rev Immunol 14:546-558.

Giordano, D., D.M. Magaletti, E.A. Clark, and J.A. Beavo. 2003. Cyclic nucleotides promote monocyte differentiation toward a DC-SIGN+ (CD209) intermediate cell and impair differentiation into dendritic cells. J Immunol 171:6421-6430.

Guggino, G., A.R. Giardina, F. Ciccia, G. Triolo, F. Dieli, and G. Sireci. 2012. Are Toll-like receptors and decoy receptors involved in the immunopathogenesis of systemic lupus erythematosus and lupus-like syndromes? Clin Dev Immunol 2012:135932.

Gutierrez-Canas, I., Y. Juarranz, B. Santiago, A. Arranz, C. Martinez, M. Galindo, M. Paya, R.P. Gomariz, and J.L. Pablos. 2006. VIP down-regulates TLR4 expression and TLR4-mediated chemokine production in human rheumatoid synovial fibroblasts. Rheumatology (Oxford) 45:527-532.

Hari, A., T.L. Flach, Y. Shi, and P.R. Mydlarski. 2010. Toll-like receptors: role in dermatological disease. Mediators Inflamm 2010:437246.

Heystek, H.C., A.C. Thierry, P. Soulard, and C. Moulon. 2003. Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1-polarizing capacity. Int Immunol 15:827-835.

Huang, Q.Q., and R.M. Pope. 2009. The role of toll-like receptors in rheumatoid arthritis. Curr Rheumatol Rep 11:357-364.

Husebye, H., O. Halaas, H. Stenmark, G. Tunheim, O. Sandanger, B. Bogen, A. Brech, E. Latz, and T. Espevik. 2006. Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity. EMBO J 25:683-692.

Jiang, X., S.A. McClellan, R.P. Barrett, Y. Zhang, and L.D. Hazlett. 2012. Vasoactive intestinal peptide downregulates proinflammatory TLRs while upregulating anti-inflammatory TLRs in the infected cornea. J Immunol 189:269-278.

Jin, S.L., S.L. Ding, and S.C. Lin. 2012. Phosphodiesterase 4 and its inhibitors in inflammatory diseases. Chang Gung Med J 35:197-210.

Jin, S.L., S. Goya, S. Nakae, D. Wang, M. Bruss, C. Hou, D. Umetsu, and M. Conti. 2010. Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol 126:1252-1259 e1212.
Jin, S.L., L. Lan, M. Zoudilova, and M. Conti. 2005. Specific role of phosphodiesterase 4B in lipopolysaccharide-induced signaling in mouse macrophages. J Immunol 175:1523-1531.

Kalinski, P., C.M. Hilkens, A. Snijders, F.G. Snijdewint, and M.L. Kapsenberg. 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.

Kambayashi, T., R.P. Wallin, and H.G. Ljunggren. 2001. cAMP-elevating agents suppress dendritic cell function. J Leukoc Biol 70:903-910.

Kawai, T., and S. Akira. 2010. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373-384.

Kjaer, T.N., K. Thorsen, N. Jessen, K. Stenderup, and S.B. Pedersen. 2015. Resveratrol ameliorates imiquimod-induced psoriasis-like skin inflammation in mice. PLoS One 10:e0126599.

Koblansky, A.A., D. Jankovic, H. Oh, S. Hieny, W. Sungnak, R. Mathur, M.S. Hayden, S. Akira, A. Sher, and S. Ghosh. 2013. Recognition of profilin by Toll-like receptor 12 is critical for host resistance to Toxoplasma gondii. Immunity 38:119-130.

Kocieda, V.P., S. Adhikary, F. Emig, J.H. Yen, M.G. Toscano, and D. Ganea. 2012. Prostaglandin E2-induced IL-23p19 subunit is regulated by cAMP-responsive element-binding protein and C/AATT enhancer-binding protein beta in bone marrow-derived dendritic cells. J Biol Chem 287:36922-36935.

Lee, C.C., A.M. Avalos, and H.L. Ploegh. 2012. Accessory molecules for Toll-like receptors and their function. Nat Rev Immunol 12:168-179.

Li, K., K.J. Anderson, Q. Peng, A. Noble, B. Lu, A.P. Kelly, N. Wang, S.H. Sacks, and W. Zhou. 2008. Cyclic AMP plays a critical role in C3a-receptor-mediated regulation of dendritic cells in antigen uptake and T-cell stimulation. Blood 112:5084-5094.

Liu, Z.Q., G.M. Deng, S. Foster, and A. Tarkowski. 2001. Staphylococcal peptidoglycans induce arthritis. Arthritis Res 3:375-380.

Luft, T., M. Jefford, P. Luetjens, T. Toy, H. Hochrein, K.A. Masterman, C. Maliszewski, K. Shortman, J. Cebon, and E. Maraskovsky. 2002. Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E(2) regulates the migratory capacity of specific DC subsets. Blood 100:1362-1372.

Lutz, M.B., N. Kukutsch, A.L. Ogilvie, S. Rossner, F. Koch, N. Romani, and G. Schuler. 1999. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 223:77-92.

Maldonado-Arocho, F.J., and K.A. Bradley. 2009. Anthrax edema toxin induces maturation of dendritic cells and enhances chemotaxis towards macrophage inflammatory protein 3beta. Infect Immun 77:2036-2042.

Mellman, I., and R.M. Steinman. 2001. Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255-258.

Merad, M., P. Sathe, J. Helft, J. Miller, and A. Mortha. 2013. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 31:563-604.

Michelsen, K.S., M.H. Wong, P.K. Shah, W. Zhang, J. Yano, T.M. Doherty, S. Akira, T.B. Rajavashisth, and M. Arditi. 2004. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci U S A 101:10679-10684.

Moreira, L.O., and D.S. Zamboni. 2012. NOD1 and NOD2 Signaling in Infection and Inflammation. Front Immunol 3:328.

Motoyoshi, S., Y. Yamamoto, S. Munesue, H. Igawa, A. Harashima, H. Saito, D. Han, T. Watanabe, H. Sato, and H. Yamamoto. 2014. cAMP ameliorates inflammation by modulation of macrophage receptor for advanced glycation end-products. Biochem J 463:75-82.

Mullick, A.E., P.S. Tobias, and L.K. Curtiss. 2005. Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest 115:3149-3156.

Muzio, M., D. Bosisio, N. Polentarutti, G. D′Amico, A. Stoppacciaro, R. Mancinelli, C. van′t Veer, G. Penton-Rol, L.P. Ruco, P. Allavena, and A. Mantovani. 2000. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 164:5998-6004.

Nhu, Q.M., N. Cuesta, and S.N. Vogel. 2006. Transcriptional regulation of lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) expression in murine macrophages: role of interferon regulatory factors 1 (IRF-1) and 2 (IRF-2). J Endotoxin Res 12:285-295.

Nomura, F., S. Akashi, Y. Sakao, S. Sato, T. Kawai, M. Matsumoto, K. Nakanishi, M. Kimoto, K. Miyake, K. Takeda, and S. Akira. 2000. Cutting edge: endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression. J Immunol 164:3476-3479.

O′Neill, L.A., and A.G. Bowie. 2007. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353-364.

Oehrl, S., H. Prakash, A. Ebling, N. Trenkler, P. Wolbing, A. Kunze, T. Dobel, M. Schmitz, A. Enk, and K. Schakel. 2017. The phosphodiesterase 4 inhibitor apremilast inhibits Th1 but promotes Th17 responses induced by 6-sulfo LacNAc (slan) dendritic cells. J Dermatol Sci 87:110-115.

Oldenburg, M., A. Kruger, R. Ferstl, A. Kaufmann, G. Nees, A. Sigmund, B. Bathke, H. Lauterbach, M. Suter, S. Dreher, U. Koedel, S. Akira, T. Kawai, J. Buer, H. Wagner, S. Bauer, H. Hochrein, and C.J. Kirschning. 2012. TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification. Science 337:1111-1115.

Onodera, K., T. Fujiwara, Y. Onishi, A. Itoh-Nakadai, Y. Okitsu, N. Fukuhara, K. Ishizawa, R. Shimizu, M. Yamamoto, and H. Harigae. 2016. GATA2 regulates dendritic cell differentiation. Blood 128:508-518.

Ouaaz, F., J. Arron, Y. Zheng, Y. Choi, and A.A. Beg. 2002. Dendritic cell development and survival require distinct NF-kappaB subunits. Immunity 16:257-270.

Park, S.Y., S.W. Lee, S.H. Baek, C.W. Lee, W.S. Lee, B.Y. Rhim, K.W. Hong, and C.D. Kim. 2013. Suppression of PU.1-linked TLR4 expression by cilostazol with decrease of cytokine production in macrophages from patients with rheumatoid arthritis. Br J Pharmacol 168:1401-1411.

Raetz, M., A. Kibardin, C.R. Sturge, R. Pifer, H. Li, E. Burstein, K. Ozato, S. Larin, and F. Yarovinsky. 2013. Cooperation of TLR12 and TLR11 in the IRF8-dependent IL-12 response to Toxoplasma gondii profilin. J Immunol 191:4818-4827.

Saito, T., N. Sugimoto, K. Ohta, T. Shimizu, K. Ohtani, Y. Nakayama, T. Nakamura, Y. Hitomi, H. Nakamura, S. Koizumi, and A. Yachie. 2012. Phosphodiesterase inhibitors suppress Lactobacillus casei cell-wall-induced NF-kappaB and MAPK activations and cell proliferation through protein kinase A--or exchange protein activated by cAMP-dependent signal pathway. ScientificWorldJournal 2012:748572.

Sasai, M., and M. Yamamoto. 2013. Pathogen recognition receptors: ligands and signaling pathways by Toll-like receptors. Int Rev Immunol 32:116-133.

Schiavoni, G., F. Mattei, P. Sestili, P. Borghi, M. Venditti, H.C. Morse, 3rd, F. Belardelli, and L. Gabriele. 2002. ICSBP is essential for the development of mouse type I interferon-producing cells and for the generation and activation of CD8alpha(+) dendritic cells. J Exp Med 196:1415-1425.

Schotte, R., M. Nagasawa, K. Weijer, H. Spits, and B. Blom. 2004. The ETS transcription factor Spi-B is required for human plasmacytoid dendritic cell development. J Exp Med 200:1503-1509.

Sheibanie, A.F., J.H. Yen, T. Khayrullina, F. Emig, M. Zhang, R. Tuma, and D. Ganea. 2007. The proinflammatory effect of prostaglandin E2 in experimental inflammatory bowel disease is mediated through the IL-23-->IL-17 axis. J Immunol 178:8138-8147.

Shi, Q., Z. Yin, B. Zhao, F. Sun, H. Yu, X. Yin, L. Zhang, and S. Wang. 2015. PGE2 Elevates IL-23 Production in Human Dendritic Cells via a cAMP Dependent Pathway. Mediators Inflamm 2015:984690.

Shi, Z., Z. Cai, S. Wen, C. Chen, C. Gendron, A. Sanchez, K. Patterson, S. Fu, J. Yang, D. Wildman, R.H. Finnell, and D. Zhang. 2009. Transcriptional regulation of the novel Toll-like receptor Tlr13. J Biol Chem 284:20540-20547.

Singh-Jasuja, H., A. Thiolat, M. Ribon, M.C. Boissier, N. Bessis, H.G. Rammensee, and P. Decker. 2013. The mouse dendritic cell marker CD11c is down-regulated upon cell activation through Toll-like receptor triggering. Immunobiology 218:28-39.

Takeuchi, O., and S. Akira. 2010. Pattern recognition receptors and inflammation. Cell 140:805-820.

van de Laar, L., M. Buitenhuis, F.M. Wensveen, H.L. Janssen, P.J. Coffer, and A.M. Woltman. 2010. Human CD34-derived myeloid dendritic cell development requires intact phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin signaling. J Immunol 184:6600-6611.

van de Laar, L., P.J. Coffer, and A.M. Woltman. 2012. Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy. Blood 119:3383-3393.

van de Laar, L., A. van den Bosch, A.T. Wierenga, H.L. Janssen, P.J. Coffer, and A.M. Woltman. 2011. Tight control of STAT5 activity determines human CD34-derived interstitial dendritic cell and langerhans cell development. J Immunol 186:7016-7024.

van der Fits, L., S. Mourits, J.S. Voerman, M. Kant, L. Boon, J.D. Laman, F. Cornelissen, A.M. Mus, E. Florencia, E.P. Prens, and E. Lubberts. 2009. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 182:5836-5845.

Veglia, F., E. Sciaraffia, A. Riccomi, D. Pinto, D.R. Negri, M.T. De Magistris, and S. Vendetti. 2011. Cholera toxin impairs the differentiation of monocytes into dendritic cells, inducing professional antigen-presenting myeloid cells. Infect Immun 79:1300-1310.

Visintin, A., A. Mazzoni, J.H. Spitzer, D.H. Wyllie, S.K. Dower, and D.M. Segal. 2001. Regulation of Toll-like receptors in human monocytes and dendritic cells. J Immunol 166:249-255.

Xie, J., J. Qian, J. Yang, S. Wang, M.E. Freeman, 3rd, and Q. Yi. 2005. Critical roles of Raf/MEK/ERK and PI3K/AKT signaling and inactivation of p38 MAP kinase in the differentiation and survival of monocyte-derived immature dendritic cells. Exp Hematol 33:564-572.

Yang, J.X., K.C. Hsieh, Y.L. Chen, C.K. Lee, M. Conti, T.H. Chuang, C.P. Wu, and S.C. Jin. 2017. Phosphodiesterase 4B negatively regulates endotoxin-activated interleukin-1 receptor antagonist responses in macrophages. Sci Rep 7:46165.

Yarovinsky, F., D. Zhang, J.F. Andersen, G.L. Bannenberg, C.N. Serhan, M.S. Hayden, S. Hieny, F.S. Sutterwala, R.A. Flavell, S. Ghosh, and A. Sher. 2005. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308:1626-1629.
指導教授 金秀蓮 莊宗顯(Shiow-Lian Catherine Jin Tsung-Hsien Chuang) 審核日期 2019-1-22
推文 facebook   plurk   twitter   funp   google   live   udn   HD   myshare   reddit   netvibes   friend   youpush   delicious   baidu   
網路書籤 Google bookmarks   del.icio.us   hemidemi   myshare   

若有論文相關問題,請聯絡國立中央大學圖書館推廣服務組 TEL:(03)422-7151轉57407,或E-mail聯絡  - 隱私權政策聲明