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系統識別號 U0026-2208201320502800
論文名稱(中文) 環狀腺核苷單磷酸在腸病毒71型感染模式中的表現
論文名稱(英文) Cyclic adenosine monophosphate expression in enterovirus 71 infection
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 101
學期 2
出版年 102
研究生(中文) 林明璋
研究生(英文) Ming-Zhang Lin
電子信箱 midnight6998@hotmail.com
學號 s46001105
學位類別 碩士
語文別 中文
論文頁數 86頁
口試委員 指導教授-劉清泉
口試委員-王貞仁
口試委員-林貴香
口試委員-王世敏
中文關鍵字 腸病毒71型  環狀腺核苷單磷酸  免疫球蛋白  milrinone  IFN-γ  MCP-1 
英文關鍵字 Enterovirus 71  cyclic adenosine 3′,5′-monophosphate  Human intravenous immunoglobulin  milrinone  IFN-γ  MCP-1 
學科別分類
中文摘要 腸病毒71型是繼小兒麻痺病毒即將被根除之際,目前最具威脅性的微小病毒科病毒,已在亞太各地造成許多大流行,台灣在1998年首次爆發大流行,之後每2-3年流行一次,近年分別在2008以及2012年造成大流行,腸病毒71型感染的症狀以手足口症以及疱疹性咽峽炎是兩種最常見的病症,部分患者會因為腸病毒71型高度的神經侵襲性,導致中樞神經感染引發腦幹腦炎,目前臨床上將腸病毒71型腦幹腦炎的病患分成三個階段: 單純腦幹腦炎、自主神經失調和肺水腫。臨床主要以藥物做為階段性的治療,包括靜脈注射免疫球蛋白對於腸病毒71型自主神經失調以及肺水腫患者,明顯改善自主神經失調以及細胞激素風暴,可避免自主神經失調患者惡化成肺水腫,明顯提升了患者的存活率。2000年後也引入milrinone做為肺水腫治療藥物,milrinone是一種第三型磷酸雙酯酶抑制劑,可增加細胞內環狀腺核苷單磷酸 (cyclic adenosine monophosphate, cAMP) 的濃度,可降低交感神經系統的活性和減少IL-13的產生,同樣也降低白血球以及血小板的數目,臨床試驗也證明milrinone能大幅提升肺水腫患者的存活率,因此我們想了解腸病毒71型感染後對於細胞環狀腺核苷單磷酸的變化以及milrinone是否是藉由提升感染細胞環狀腺核苷單磷酸濃度而改變肺水腫患者細胞激素和免疫細胞的變化。我們以腸病毒71型感染RD細胞,發現隨感染時間的增加,病毒效價會上升且細胞內以及細胞外環狀腺核苷單磷酸濃度會下降,其中以細胞外環狀腺核苷單磷酸濃度降低的幅度最大,此外SK-N-SH、THP-1、Jurkat、HL-60以及hPBMC等細胞株在感染腸病毒71型後也會造成細胞外環狀腺核苷單磷酸下降,若我們在RD細胞感染後先給予免疫球蛋白除了可降低病毒的感染率及病毒效價之外,也可減少病毒所造成細胞外環狀腺核苷單磷酸的下降,我們也嘗試在RD細胞感染後16小時給予milrinone,發現可明顯提升感染細胞外環狀腺核苷單磷酸濃度,卻無法降低病毒的感染率以及病毒效價上升。我們也在動物實驗看到小鼠感染MP4後會導致脾臟、腦幹、脊髓細胞內環狀腺核苷單磷酸濃度下降,且小鼠血清中TNF、IFN-γ以及MCP-1濃度有意義的上升,同時分析小鼠脾臟免疫細胞的分布情況,發現淋巴細胞在感染第六天後明顯的下降,而單核球細胞的則是在第六天時明顯的上升,在感染後第四天給予100 ng/g milrinone治療後有效提升小鼠的存活率,同時改善病毒感染造成的體重下降,對於臨床疾病嚴重度也有統計意義的降低,並提升因病毒感染導致脾臟、腦幹、脊髓細胞內環狀腺核苷單磷酸濃度下降的情況,並且降低IFN-γ以及MCP-1的濃度,milrinone治療後也影響了脾臟免疫細胞的分布,減少了病毒感染導致淋巴細胞的降低,以及降低病毒感染導致單核球上升的情況,綜合上述發現,我們認為在感染腸病毒71型後會造成SK-N-SH、THP-1、Jurkat、HL-60、hPBMC等細胞株以及小鼠脾臟、腦幹、脊髓細胞環狀腺核苷單磷酸的下降,給予milrinone提升細胞環狀腺核苷單磷酸的濃度可降低IFN-γ以及MCP-1的濃度,因此環狀腺核苷單磷酸在腸病毒 71 型感染導致肺水腫之免疫致病機轉上扮演重要的角色。
英文摘要 Enterovirus 71 (EV71) is a neurotropic virus which belongs to the family Picornaviridae. It is one of the notable pathogens in Taiwan since the outbreak in 1998. EV71 infection commonly results in hand-foot-and-mouth disease (HFMD) and herpangina , some cases may progress to severe neurological complications such as brain stem encephalitis (BE). EV71 BE has been categorized into three clinical stages including uncomplicated BE, autonomic nervous system (ANS) dysregulation, and pulmonary edema (PE). Patients with PE tended to have higher total WBC counts, platelet counts and hight mortality than ANS dysreglution patients. IL-6, IL-8, IL10, IL-13 and IFN-γ were higher in patients with ANS dysreglution and PE. Patients with PE had lower CD4+, CD8+ T lymphocytes and natural killer cell (NK) than ANS dysregulation and BE patients. An inactivated vaccine against EV71 has been completed phase 3 clinical trial in China. Human intravenous immunoglobulin (IVIG) is clinically used in treating ANS dysregulation and PE patients. IVIG can modulate cytokine expression that decrease in the plasma concentration of IL-6, IL-8, IL-10, IL-13, and IFN-γ in patient with ANS dysregulation and PE. Milrinone, a phosphodiesterase (PDE)-3 inhibitor was introduced to patients with EV71 PE since 2000 in Taiwan. It increases cardiac output and reduces systemic vascular resistance, prevent intracellular cyclic adenosine 3′,5′-monophosphate (cAMP) degradation by PDEs and elevate cAMP concentration. Milrinone-treated group was associated with reduced mortality by reducing inflammatory cells and serum level of IL-13. In this study, we investigated the expression of cAMP in EV71 infection in in vitro and animal model. Intracellular and extracellular cAMP was lower than control after EV71 infection in RD cell. Levels of extracellular cAMP decreased more than intracellular. Levels of extracellular cAMP were also decreased in SK-N-SH, THP-1, HL-60, Jurkat cell lines and hPBMC after EV71 infection. Treating with milrinone was able to increase RD extracellular cAMP but not altered viral titer and infection rate. In addition, levels of cAMP in spleen, spinal cord and brain stem also decreased in MP4-infected ICR mice. The change of splenocyte distribution including the decreased lymphocytes and increased monocytes were noted in MP4-infected ICR mice. After treated with milrinone we found that increased body weight and survival rate but without altered viral titer. Milrinone was able to increase spleen, spinal cord and brain stem level of cAMP and also change splenocyte distributions that by decreasing monocyte and increasing lymphocyte after infection. Our findings showed that cAMP may play an important role in the immunopathogenesis of EV71-associated ANS dysregulation and PE.
論文目次 中文摘要...................I
英文摘要...................III
誌謝......................V
目錄......................VI
圖目錄....................X
縮寫索引..................XII
壹、緒論..................1
腸病毒 71 型之介紹.........1
A.腸病毒的分類.............1
B.腸病毒 71 型的病毒學概論.....................1
C.腸病毒 71 型的感染與複製.....................2
D.腸病毒 71 型的行病學........................3
E.腸病毒 71 型的傳染以及臨床病症................4
F.腸病毒 71 型的致病機轉.......................5
G.腸病毒 71 型感染與免疫細胞的關係..............5
H.腸病毒 71 型感染與細胞激素之間的關係...........6
二、腸病毒71型的臨床治療.......................10
A.腸病毒重症目前臨床治療藥物簡介.................10
B.靜脈注射免疫球蛋白 (intravenous immunoglobulin, IVIG).....10
C.Milrinone (Phosphodiesterase III inhibitor)............11
三、環狀腺核苷單磷酸簡介.....................................12
A.細胞內環狀腺核苷單磷酸與免疫系統的關係........................13
B.細胞外環狀腺核苷單磷酸與免疫系統的關係........................13
C.病毒感染與環狀腺核苷單磷酸濃度的關係..........................14
D.腸病毒71型感染與環狀腺核苷單磷酸的關係........................15
貳、研究動機與目的...........................................16
參、實驗材料與方法...........................................17
一、實驗材料................................................17
A.病毒株...................................................17
B.細胞株...................................................17
C.實驗動物.................................................18
D.藥品與試劑...............................................18
E.實驗材料.................................................22
F.實驗耗材.................................................24
二、實驗方法................................................25
A.細胞培養.................................................25
B.病毒培養.................................................27
C.免疫細胞株活化實驗.........................................28
D.以流式細胞儀偵測病毒抗原表現................................29
E.細胞存活率之測定..........................................29
F.腸病毒71型感染ICR新生鼠....................................29
G.腸病毒71型感染ICR新生鼠臨床分數評分..........................30
H.細胞內環狀腺核苷單磷酸檢測..................................30
I.細胞外環狀腺核苷單磷酸檢測..................................30
J.老鼠腦部環狀腺核苷單磷酸檢測................................31
K.老鼠脾臟免疫細胞分析.......................................31
L.Cytometric Bead Array (CBA) 分析小鼠血清中細胞激素.........31
肆、結果...................................................33
一、腸病毒感染後細胞內以及細胞外環狀腺核苷單磷酸變化..............33
二、偵測多種細胞在感染腸病毒71型後細胞外環狀腺核苷單磷酸變化.......33
三、腸病毒71型感染率以及病毒效價與細胞外環狀腺核苷單磷酸的變化.....34
四、觀察細胞存活率對於細胞外環狀腺核苷單磷酸的影響................35
五、免疫球蛋白對感染後環狀腺核苷單磷酸濃度的影響.................35
六、Milrinone對感染後環狀腺核苷單磷酸濃度的影響.................36
七、Milrinone對感染後感染率以及病毒效價影響....................37
八、同時給予免疫球蛋白以及milrinone對感染後的影響...............37
A.細胞外環狀腺核苷單磷酸在同時給予兩種藥物的變化.................37
B.同時給予兩種藥物對感染率的影響...............................38
C.同時給予兩種藥物對病毒效價的影響.............................38
九、小鼠感染腸病毒71型小鼠適應株(MP4)後各器官環狀腺核苷單磷酸變化..39
十、小鼠感染腸病毒71型小鼠適應株 MP4)後以milrinone治療對病症影響..39
A.感染後給予milrinone對於存活率影響..........................39
B.感染後給予milrinone對於小鼠體重影響.........................40
C.感染後給予milrinone對於臨床分數影響.........................40
D.感染後給予milrinone對於小鼠器官環狀線核苷單磷酸影響............40
E.感染後給予milrinone對於小鼠器官病毒效價影響..................41
十一、小鼠感染MP4後對脾臟免疫細胞的影響以及milrinone治療後的改變..42
A.小鼠感染MP4會影響脾臟免疫細胞動態分布........................42
B.Milrinone可以影響感染MP4小鼠的脾臟免疫細胞分布...............42
十二、小鼠感染MP4並給予milrinone治療對於細胞激素分泌的影響.......43
伍、討論...................................................45
一、腸病毒71型感染後對於細胞內以及細胞外環狀腺核苷單磷酸影響.......45
A.腸病毒71型感染後影響細胞內外環狀腺核苷單磷酸合成以及分解.........45
B.腸病毒71型感染後可能影響環狀腺核苷單磷酸運輸...................45
二、腸病毒71型臨床藥物使用對於細胞外環狀腺核苷單磷酸影響...........46
A.免疫球蛋白抑制感染率並間接提升細胞外環狀腺核苷單磷酸濃度.........46
B.Milrinone直接提升細胞在感染後細胞外環狀腺核苷單磷酸濃度........46
C.環狀腺核苷單磷酸與腸病毒71型複製的關係........................47
三、MP4感染小鼠與環狀腺核苷單磷酸濃度關係.......................48
A.MP4感染後造成器官病毒效價的上升.............................48
B.MP4感染兒茶酚胺類的產生與環狀腺核苷單磷酸關係..................49
四、MP4感染小鼠造成器官環狀腺核苷單磷酸降低與免疫細胞分布改變的關係.50
五、使用milrinone提升小鼠脾臟環狀腺核苷單磷酸影響脾臟免疫細胞分布..51
六、使用milrinone提升感染MP4小鼠器官環狀腺核苷單磷酸濃度與細胞激素.51
陸、結論...................................................54
柒、參考文獻................................................55
圖........................................................65
附錄......................................................81
作者簡歷...................................................86
參考文獻 Abe, S., et al. (2004). Plasma concentrations of cytokines and neurohumoral factors in a case of fulminant myocarditis successfully treated with intravenous immunoglobulin and percutaneous cardiopulmonary support. Circ J 68(12): 1223-1226.
Alam, R., et al. (1992). Interleukin-8 and RANTES inhibit basophil histamine release induced with monocyte chemotactic and activating factor/monocyte chemoattractant peptide-1 and histamine releasing factor. Am J Respir Cell Mol Biol 7(4): 427-433.
Aronoff, D. M., et al. (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(2): 595-599.
Aronoff, D. M., et al. (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(11): 827-833.
Babcock, A. A., et al. (2003). Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J Neurosci 23(21): 7922-7930.
Beckner, S. K. (1984). Decreased adenylate cyclase responsiveness of transformed cells correlates with the presence of a viral transforming protein. FEBS Lett 166(1): 170-174.
Boehm, U., et al. (1997). Cellular responses to interferon-gamma. Annu Rev Immunol 15: 749-795.
Bonagura, V. R., et al. (2008). Biologic IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol 122(1): 210-212.
Bopp, T., et al. (2007). Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 204(6): 1303-1310.
Borsody, M. K. and J. M. Weiss (2002). Alteration of locus coeruleus neuronal activity by interleukin-1 and the involvement of endogenous corticotropin-releasing hormone. Neuroimmunomodulation 10(2): 101-121.
Cao, R., et al. (2010). Presence of high-titer neutralizing antibodies against enterovirus 71 in intravenous immunoglobulin manufactured from Chinese donors. Clin Infect Dis 50(1): 125-126.
Cardosa, M. J., et al. (1999). Isolation of subgenus B adenovirus during a fatal outbreak of enterovirus 71-associated hand, foot, and mouth disease in Sibu, Sarawak. Lancet 354(9183): 987-991.
Carrillo-de Sauvage, M. A., et al. (2012). CCL2-expressing astrocytes mediate the extravasation of T lymphocytes in the brain. Evidence from patients with glioma and experimental models in vivo. PLoS One 7(2): e30762.
Chang, Y. C., et al. (2006). Lipoteichoic acid-induced nitric oxide synthase expression in RAW 264.7 macrophages is mediated by cyclooxygenase-2, prostaglandin E2, protein kinase A, p38 MAPK, and nuclear factor-kappaB pathways. Cell Signal 18(8): 1235-1243.
Chen, C. S., et al. (2004). 腸病毒71型感染小鼠引發中樞神經系統病變及肺部功能異常之探討 成功大學學位論文全文系統 etd-0820105-124947
Chen, C. S., et al. (2007). Retrograde axonal transport: a major transmission route of enterovirus 71 in mice. J Virol 81(17): 8996-9003.
Chen, Y. C., et al. (2004). A murine oral enterovirus 71 infection model with central nervous system involvement. J Gen Virol 85(Pt 1): 69-77.
Chi, C. Y., et al. (2013). Milrinone Therapy for Enterovirus 71-Induced Pulmonary Edema and/or Neurogenic Shock in Children: A Randomized Controlled Trial. Crit Care Med 41(7): 1754-1760.
Chumakov, M., et al. (1979). Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria. Arch Virol 60(3-4): 329-340.
Delghandi, M. P., et al. (2005). The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells. Cell Signal 17(11): 1343-1351.
Deng, Y. Y., et al. (2009). Monocyte chemoattractant protein-1 (MCP-1) produced via NF-kappaB signaling pathway mediates migration of amoeboid microglia in the periventricular white matter in hypoxic neonatal rats. Glia 57(6): 604-621.
Di Paola, R., et al. (2011). Olprinone, a PDE3 inhibitor, modulates the inflammation associated with myocardial ischemia-reperfusion injury in rats. Eur J Pharmacol 650(2-3): 612-620.
Dinarello, C. A. (1997). Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest 112(6 Suppl): 321S-329S.
Eigler, A., et al. (1998). Anti-inflammatory activities of cAMP-elevating agents: enhancement of IL-10 synthesis and concurrent suppression of TNF production. J Leukoc Biol 63(1): 101-107.
Eppinger, M. J., et al. (1996). Regulatory effects of interleukin-10 on lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg 112(5): 1301-1305; discussion 1305-1306.
Fimia, G. M. and P. Sassone-Corsi (2001). Cyclic AMP signalling. J Cell Sci 114(Pt 11): 1971-1972.
Friedman, R. M. and I. Pastan (1969). Interferon and cyclic-3'5'-adenosine monophosphate: potentiation of antiviral activity. Biochem Biophys Res Commun 36(5): 735-740.
Fu, Y. C., et al. (2006). Comparison of heart failure in children with enterovirus 71 rhombencephalitis and cats with norepinephrine cardiotoxicity. Pediatr Cardiol 27(5): 577-584.
Gloerich, M. and J. L. Bos (2010). Epac: defining a new mechanism for cAMP action. Annu Rev Pharmacol Toxicol 50: 355-375.
Grandoch, M., et al. (2010). The role of Epac proteins, novel cAMP mediators, in the regulation of immune, lung and neuronal function. Br J Pharmacol 159(2): 265-284.
Gunn, M. D., et al. (1997). Monocyte chemoattractant protein-1 is sufficient for the chemotaxis of monocytes and lymphocytes in transgenic mice but requires an additional stimulus for inflammatory activation. J Immunol 158(1): 376-383.
Hagiwara, A., et al. (1978). Epidemic of hand, foot and mouth disease associated with enterovirus 71 infection. Intervirology 9(1): 60-63.
Hansen, R. J. and J. P. Balthasar (2004). Mechanisms of IVIG action in immune thrombocytopenic purpura. Clin Lab 50(3-4): 133-140.
Harashima, T. and J. Heitman (2005). Galpha subunit Gpa2 recruits kelch repeat subunits that inhibit receptor-G protein coupling during cAMP-induced dimorphic transitions in Saccharomyces cerevisiae. Mol Biol Cell 16(10): 4557-4571.
Hilleman, D. E. and W. P. Forbes (1989). Role of milrinone in the management of congestive heart failure. DICP 23(5): 357-362.
Hinoshita, E., et al. (2001). Decreased expression of an ATP-binding cassette transporter, MRP2, in human livers with hepatitis C virus infection. J Hepatol 35(6): 765-773.
Ho, M., et al. (1999). An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med 341(13): 929-935.
Hochrein, H., et al. (2000). Interleukin (IL)-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J Exp Med 192(6): 823-833.
Hofer, A. M. and K. Lefkimmiatis (2007). Extracellular calcium and cAMP: second messengers as "third messengers"? Physiology (Bethesda) 22: 320-327.
Huang, M. L., et al. (2013). Cross-reactive neutralizing antibody responses to enterovirus 71 infections in young children: implications for vaccine development. PLoS Negl Trop Dis 7(2): e2067.
Huang, S. W., et al. (2011). Exogenous interleukin-6, interleukin-13, and interferon-gamma provoke pulmonary abnormality with mild edema in enterovirus 71-infected mice. Respir Res 12: 147.
Hughes, R. A., et al. (2003). Practice parameter: immunotherapy for Guillain-Barre syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 61(6): 736-740.
Ishimaru, Y., et al. (1980). Outbreaks of hand, foot, and mouth disease by enterovirus 71. High incidence of complication disorders of central nervous system. Arch Dis Child 55(8): 583-588.
Ivashkiv, L. B., et al. (1994). Inhibition of IFN-gamma induction of class II MHC genes by cAMP and prostaglandins. Immunopharmacology 27(1): 67-77.
Jackson, E. K. and D. K. Raghvendra (2004). The extracellular cyclic AMP-adenosine pathway in renal physiology. Annu Rev Physiol 66: 571-599.
Jiang, Y., et al. (1992). Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J Immunol 148(8): 2423-2428.
Johnson, K. W., et al. (1988). cAMP antagonizes interleukin 2-promoted T-cell cycle progression at a discrete point in early G1. Proc Natl Acad Sci U S A 85(16): 6072-6076.
Kambayashi, T., et al. (2001). cAMP-elevating agents suppress dendritic cell function. J Leukoc Biol 70(6): 903-910.
Kammer, G. M. (1988). The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response. Immunol Today 9(7-8): 222-229.
Khong, W. X., et al. (2011). Sustained high levels of interleukin-6 contribute to the pathogenesis of enterovirus 71 in a neonate mouse model. J Virol 85(7): 3067-3076.
Kishimoto, C., et al. (2000). Immunoglobulin treatment ameliorates murine myocarditis associated with reduction of neurohumoral activity and improvement of extracellular matrix change. J Am Coll Cardiol 36(6): 1979-1984.
Komastu, T., et al. (1998). IL-12 and viral infections. Cytokine Growth Factor Rev 9(3-4): 277-285.
Leung, D. Y. (1989). The immunologic effects of IVIG in Kawasaki disease. Int Rev Immunol 5(2): 197-202.
Liang, Z. L., et al. (2013). Progress on the research and development of inactivated EV71 whole-virus vaccines. Hum Vaccin Immunother 9(8).
Lin, Y. W., et al. (2009). Lymphocyte and antibody responses reduce enterovirus 71 lethality in mice by decreasing tissue viral loads. J Virol 83(13): 6477-6483.
Lin, P., et al. (2005). Lysophosphatidylcholine modulates neutrophil oxidant production through elevation of cyclic AMP. J Immunol 174(5): 2981-2989.
Lin, Y. W., et al. (2009). Enterovirus 71 infection of human dendritic cells. Exp Biol Med (Maywood) 234(10): 1166-1173.
Nagy, G., et al. (1982). Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS diseases in Hungary in 1978. Arch Virol 71(3): 217-227.
M L Steer et al ., (1976) Cyclic AMP Ann Surg 184(1): 107–115.
Martin, S., et al. (1988). IL-1 and IFN-gamma increase vascular permeability. Immunology 64(2): 301-305.
McMinn, P. C. (2002). An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev 26(1): 91-107.
Melchers, W. J., et al. (1997). Kissing of the two predominant hairpin loops in the coxsackie B virus 3' untranslated region is the essential structural feature of the origin of replication required for negative-strand RNA synthesis. J Virol 71(1): 686-696.
Molica, S., et al. (1996). Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. Haematologica 81(2): 121-126.
Moore, K. W., et al. (2001). Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19: 683-765.
Moreno-Fernandez, M. E., et al. (2012). cAMP during HIV infection: friend or foe? AIDS Res Hum Retroviruses 28(1): 49-53.
Mosenden, R. and K. Tasken (2011). Cyclic AMP-mediated immune regulation--overview of mechanisms of action in T cells. Cell Signal 23(6): 1009-1016.
Muir, P., et al. (1998). Molecular typing of enteroviruses: current status and future requirements. The European Union Concerted Action on Virus Meningitis and Encephalitis. Clin Microbiol Rev 11(1): 202-227.
Murray, A. J. and D. A. Shewan (2008). Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration. Mol Cell Neurosci 38(4): 578-588.
Nishimura, Y., et al. (2009). Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med 15(7): 794-797.
Ousman, S. S. and S. David (2001). MIP-1alpha, MCP-1, GM-CSF, and TNF-alpha control the immune cell response that mediates rapid phagocytosis of myelin from the adult mouse spinal cord. J Neurosci 21(13): 4649-4656.
Ooi, M. H., et al. (2010). Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol 9(11): 1097-1105.
Ostrom, R. S. and P. A. Insel (2004). The evolving role of lipid rafts and caveolae in G protein-coupled receptor signaling: implications for molecular pharmacology. Br J Pharmacol 143(2): 235-245.
Ozaki, K. and W. J. Leonard (2002). Cytokine and cytokine receptor pleiotropy and redundancy. J Biol Chem 277(33): 29355-29358.
Proost, P., et al. (1996). Human monocyte chemotactic proteins-2 and -3: structural and functional comparison with MCP-1. J Leukoc Biol 59(1): 67-74.
Puneet, P., et al. (2005). Chemokines in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 288(1): L3-15.
Quan, N. and M. Herkenham (2002). Connecting cytokines and brain: a review of current issues. Histol Histopathol 17(1): 273-288.
Rossi, A. G., et al. (1998). Regulation of macrophage phagocytosis of apoptotic cells by cAMP. J Immunol 160(7): 3562-3568.
Sassone-Corsi, P. (2012). The cyclic AMP pathway. Cold Spring Harb Perspect Biol 4(12).
Schmidt, N. J., et al. (1974). An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis 129(3): 304-309.
Schoffelmeer, A. N., et al. (1986). Role of adenylate cyclase in presynaptic alpha 2-adrenoceptor- and mu-opioid receptor-mediated inhibition of [3H]noradrenaline release from rat brain cortex slices. J Neurochem 46(6): 1711-1717.
Sekido, N., et al. (1993). Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8. Nature 365(6447): 654-657.
Serezani, C. H., et al. (2008). Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol 39(2): 127-132.
Shipley, J. B., et al. (1996). Milrinone: basic and clinical pharmacology and acute and chronic management. Am J Med Sci 311(6): 286-291.
Soboslay, P. T., et al. (1999). Regulatory effects of Th1-type (IFN-gamma, IL-12) and Th2-type cytokines (IL-10, IL-13) on parasite-specific cellular responsiveness in Onchocerca volvulus-infected humans and exposed endemic controls. Immunology 97(2): 219-225.
Sodhi, A., et al. (2004). Viral hijacking of G-protein-coupled-receptor signalling networks. Nat Rev Mol Cell Biol 5(12): 998-1012.
Solomon, T., et al. (2010). Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis 10(11): 778-790.
Stanwick, T. L. and A. J. Nahmias (1982). Effect of cyclic AMP and cyclic GMP on the activity of interferon against herpes simplex virus types 1 and 2, and vesicular stomatitis virus. Arch Virol 72(4): 247-256.
Vendetti, S., et al. (2006). Human CD4+ T lymphocytes with increased intracellular cAMP levels exert regulatory functions by releasing extracellular cAMP. J Leukoc Biol 80(4): 880-888.
Wang, S. M., et al. (2003). Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema. J Infect Dis 188(4): 564-570.
Wang, S. M., et al. (2005). Therapeutic efficacy of milrinone in the management of enterovirus 71-induced pulmonary edema. Pediatr Pulmonol 39(3): 219-223.
Wang, S. M., et al. (2006). Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis. J Clin Virol 37(1): 47-52.
Wang, S. M., et al. (2007). Cerebrospinal fluid cytokines in enterovirus 71 brain stem encephalitis and echovirus meningitis infections of varying severity. Clin Microbiol Infect 13(7): 677-682.
Wang, S. M., et al. (2008). Acute chemokine response in the blood and cerebrospinal fluid of children with enterovirus 71-associated brainstem encephalitis. J Infect Dis 198(7): 1002-1006.
Wang, S. M., et al. (2012). Cytokine immunopathogenesis of enterovirus 71 brain stem encephalitis. Clin Dev Immunol 2012: 876241.
Wang, Y. F., et al. (2004). A mouse-adapted enterovirus 71 strain causes neurological disease in mice after oral infection. J Virol 78(15): 7916-7924.
Weber, J. M. and R. B. Stewart (1975). Cyclic AMP potentiation of interferon antiviral activity and effect of interferon on cellular cyclic AMP levels. J Gen Virol 28(3): 363-372.
Wong, S. S., et al. (2010). Human enterovirus 71 and hand, foot and mouth disease. Epidemiol Infect 138(8): 1071-1089.
Wuyts, W. A., et al. (2003). Modulation by cAMP of IL-1beta-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells. Eur Respir J 22(2): 220-226.
Yamayoshi, S., et al. (2009). Scavenger receptor B2 is a cellular receptor for enterovirus 71." Nat Med 15(7): 798-801.
Yang, B., et al. (2009). Sialylated glycans as receptor and inhibitor of enterovirus 71 infection to DLD-1 intestinal cells. Virol J 6: 141.
Yang, S. L., et al. (2011). Annexin II binds to capsid protein VP1 of enterovirus 71 and enhances viral infectivity. J Virol 85(22): 11809-11820.
Yokoyama, U., et al. (2008). Epac1 is upregulated during neointima formation and promotes vascular smooth muscle cell migration. Am J Physiol Heart Circ Physiol 295(4): H1547-1555.
Zhu, F. C., et al. (2013). Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 381(9882): 2024-2032.
Zhu, Z., et al. (1999). Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 103(6): 779-788.
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