臺灣博碩士論文加值系統

登革病毒 (DV) 感染造成的臨床症狀包含輕微的登革熱以及嚴重的登革出血熱與登革休克症候群。臨床研究證實登革重症病患血清中所表現的抗發炎細胞激素介白素10 (IL-10) 較登革輕症病患高；然而，登革病毒調控介白素10表現之確切分子機制以及其在病理上的意義目前尚未明瞭。本研究論文證實登革病毒感染人類單核球細胞株THP-1可誘導介白素10以及其下游訊息分子細胞激素訊號抑制分子3 (SOCS3) 的表現。進一步發現登革病毒可藉由蛋白質激酶A (PKA) 活化磷脂酰肌醇3激酶 (PI3K)/蛋白質激酶B (PKB) 進而促使轉錄因子環磷酸腺苷反應元件結合蛋白 (CREB) 磷酸化並且入核轉錄誘導介白素10的產生。實驗室先前研究證實肝醣合成酶激酶3 (GSK-3) 可藉由抑制環磷酸腺苷反應元件结合蛋白活性，以降低介白素10生成。而登革病毒感染後確實可藉由蛋白質激酶A/磷脂酰肌醇3激酶訊息路徑抑制肝醣合成酶激酶3的活性；且利用肝醣合成酶激酶3抑制劑可增加登革病毒所誘導之環磷酸腺苷反應元件結合蛋白磷酸化以及介白素10表現量。然而不僅僅是TLR3非依賴性作用，抑制已知的登革病毒受器包括CD209 (DC-SIGN)、CD29 (integrin β1) 以及CD61 (integrin β3) 並不會影響介白素10生成。除此之外，登革病毒所誘導之介白素10亦可促成登革病毒之複製作用及破壞干擾素γ (IFN-γ) 的訊息傳遞。由上述結果指出，登革病毒感染單核球後可藉由調控蛋白質激酶A/磷脂酰肌醇3激酶/蛋白質激酶B/肝醣合成酶激酶3/環磷酸腺苷反應元件結合蛋白的活性誘導介白素10生成，並可能促成介白素10/細胞激素訊號抑制分子3所媒介之免疫逃脫現象。

Dengue virus (DV)-caused anti-inflammatory cytokine interleukin (IL)-10 production is much higher in patients with severe dengue hemorrhagic fever and dengue shock syndrome than those with mild dengue fever; however, the mechanism underlying IL-10 regulation and its pathological significance remain unclear. Here we show that DV infection significantly increases IL-10-mediated expression of suppressor of cytokine signaling 3 in human monocytic THP-1 cells. In DV-infected cells, activation of cyclic adenosine monophosphate (cAMP) response element-binding (CREB), largely through protein kinase A (PKA)- and phosphoinositide (PI) 3-kinase-regulated manners, determines IL-10 increase. Furthermore, sequential activation of PKA facilitates PI3K/PKB signaling. Notably, DV infection causes glycogen synthase kinase (GSK)-3 inactivation in a PKA/PI3K-regulated manner and inhibiting GSK-3 considerably increases DV-induced IL-10 following CREB activation. However, not only TLR3 independently, blocking the well-known DV receptors, including heparan sulfate, CD209 (DC-SIGN), CD29 (integrin β1), and CD61 (integrin β3), do not inhibit DV-induced IL-10. This study also explore the effects of IL-10 signaling on facilitation of viral replication. These results show a molecular basis of PKA/PI3K/PKB/GSK-3/CREB for DV infection-induced IL-10 production followed by IL-10/SOCS3-mediated advantages for viral replication in monocytes.

中文摘要 I
Abstract II
誌謝 III
Abbreviations IV
Contents VII
I. Introduction 1
I-1. Characteristics of DV 1
I-2. Epidemiology of DV 4
I-3. Clinical 〈a class="ktg6us78hf8vdu7" href="#"〉symptoms〈/a〉 and laboratory findings of DV infection 5
I-4. Mechanisms of DHF/DSS pathogenesis 5
I-5. IL-10 7
I-6. The role of IL-10 in dengue disease 8
I-7. Interferon 10
I-8. Glycogen synthase kinase-3β 11
II. Study Objective and Specific Aims 13
II-1. Objective 13
II-2. Specific aims 13
1. To 〈a class="ktg6us78hf8vdu7" href="#"〉check〈/a〉 the expression and function of IL-10 in DV-infected monocytes. 13
2. To investigate the role of CREB in DV-induced IL-10 production. 13
3. To clarify the activity of GSK-3β in DV-induced IL-10 production. 13
4. To test the involvement of cell surface molecules in DV-induced IL-10 production. 13
5. To investigate the role of IL-10 during DV infection. 13
III. Materials and Methods 14
III-1. Cell lines, reagents, and antibodies 14
III-2. Virus culture 15
III-3. Plaque assay 15
III-4. DV infection 15
III-5. UV inactivation 16
III-6. Western blotting 16
III-7. ELISA 16
III-8. PKA activity assay 16
III-9. PIP3 generation assay 16
III-10. Immunostaining 17
III-11. RNA interference 17
III-12. Cytotoxicity assay 18
III-13. Statistical analysis 18
IV. Results 19
IV-1. Infection of DV causes IL-10 production and its downstream SOCS3 expression in human monocytic THP-1 cells 19
IV-2. DV infection induces PKA- and PI3K-regulated CREB activation followed by CREB-mediated IL-10 production 19
IV-3. DV infection induces PKA activation leading to PI3K/PKB activation 20
IV-4. PKA/PKB-regulated GSK-3 inactivation is also involved for DV-facilitated CREB-mediated IL-10 production 21
IV-5. Signaling of TLR3, DC-SIGN, β1- and β3-integrins, and heparan sulfate is not involved for DV-induced IL-10 production 22
IV-6. DV-induced IL-10 production mediates IFN-γ/STAT1 signaling inhibition 23
V. Discussion 24
VI. Conclusion and Implication 28
References 29
Figures and Figure Legends 39
Figure 1. DV infection induces IL-10 production and activation in human monocytic THP-1 cells. 39
Figure 2. DV infection induces CREB-mediated IL-10 production through PKA- and PI3K-regulated pathways. 40
Figure 3. DV infection activates PKA followed by PKA-regulated PI3K/PKB. 42
Figure 4. DV infection induces PKA/PI3K-regulated GSK-3β inactivation, which facilitates CREB-mediated IL-10 production. 43
Figure 5. DV infection induces IL-10 production independent of heparan sulfate, DC-SIGN, β1- and β3-integrins, and TLR3 signaling. 45
Figure 6. DV-induced IL-10 facilitates virus escape from IFN-γ/STAT1-mediated antiviral immunosurveillance. 47
Figure 7. A model of IL-10 induction in DV-infected monocytes. 48
Appendix 49
A. Materials 49
A-1 Chemicals 49
A-2 Antibodies 50
A-3 Kits 51
A-4 Consumables 52
A-5 Apparatus 52
B. Methods 53
B-1 Cell culture 53
B-2 Western blot 55
B-3 Lentiviral-based shRNA knockdown 57
Curriculum Vitae 60

Avirutnan, P., et al. Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. J. Infect. Dis. 2006. 193: 1078-1088.
Avirutnan, P., et al. Binding of flavivirus nonstructural protein NS1 to C4b binding protein modulates complement activation. J. Immunol. 2011. 187: 424-433.
Benarroch, D., et al. The RNA helicase, nucleotide 5'-triphosphatase, and RNA 5'-triphosphatase activities of dengue virus protein NS3 are Mg2+-dependent and require a functional Walker B motif in the helicase catalytic core Virology. 2004. 328: 208–218.
Benarroch, D., et al. A structural basis for the inhibition of the NS5 dengue virus mRNA 2'-O-methyltransferase domain by ribavirin 5'-triphosphate. J Biol Chem. 2004. 279: 35638-35643.
Beurel, E. and Jope, R. S. The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog. Neuralbiol. 2006. 79: 173-189.
Beurel, E., et al. Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends. Immunol. 2009. 31: 24-31.
Bedadala, G. R., et al. Lytic HSV-1 infection induces the multifunctional transcription factor early growth response-1 (EGR-1) in rabbit corneal cells. Virol. J. 2011. 8: 262.
Bekker, L. G., et al. Selective increase in plasma tumor necrosis factor-α and concomitant clinical deterioration after initiating therapy in patients with severe tuberculosis. J. Infect. Dis. 1998. 178: 580–584.
Chareonsirisuthigul, T., et al. Dengue virus (DENV) antibody-dependent enhancement of infection upregulates the production of anti-inflammatory cytokines, but suppresses anti-DENV (a class=ktg6us78hf8vdu7 href=#)free(/a) radical and pro-inflammatory cytokine production, in THP-1 cells. J. Gen. Virol. 2007. 88: 365-375.
Chaturvedi, U. C., et al. Sequential production of cytokines by dengue virus-infected human peripheral blood leukocyte cultures. J. Med. Virol. 1999. 59: 335-340.
Chaturvedi, U. C., et al. Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis. FEMS Immunol. Med. Microbiol. 2000. 28: 183-188.
Ciullo, I., et al. cAMP signaling selectively influences Ras effectors pathways. Oncogene. 2001. 20: 1186-1192.
Cross, D. A. E., et al. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995. 378: 785-789.
Chen, Y., et al. Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nat. Med. 1997. 3: 866-871.
Chen, S. T., et al. CLEC5A is critical for dengue-virus-induced lethal disease. Nature. 2008. 453: 672-676.
Chen, M. C., et al. Deletion of the C-terminal region of dengue virus nonstructural protein 1 (NS1) abolishes anti-NS1-mediated platelet dysfunction and bleeding tendency. J. Immunol. 2009. 183: 1797-1803.
Chang, Y. P., et al. Autophagy facilitates IFN-gamma-induced Jak2-STAT1 activation and cellular inflammation. J. Biol. Chem. 2010. 285: 28715-28722.
Chang, C. J., et al. The heterogeneous nuclear ribonucleoprotein K (hnRNP K) interacts with dengue virus core protein. DNA. Cell. Biol. 2001. 20: 569-577.
Chang, J., et al. Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells. Proc. Natl. Acad. Sci. U. S. A. 2009. 106: 18327-32.
Chuang, Y. C., et al. Macrophage migration inhibitory factor induced by dengue virus infection increases vascular permeability. Cytokine. 2011. 54: 222–231.
Chuang, Y. C., et al. Dengue virus-induced autoantibodies bind to plasminogen and enhance its activation. J. Immunol. 2011. 187: 6483-6490.
Clyde, K., et al. Recent advances in deciphering viral and host determinants of dengue virus replication and pathogenesis. J. Virol. 2006. 80: 11418-11431.
Cologna, R. and Rico-Hesse, R. American genotype structures decrease dengue virus output from human monocytes and dendritic cells. J. Virol. 2003. 77: 3929-3938.
Couper, K. N., et al. IL-10 - the master regulator of immunity to infection. J. Immunol. 2008. 180: 5771-5777.
Dagvadorj, J., et al. Interleukin-10 inhibits tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW 264.7 cells through reduced MyD88 expression. Innate. Immun. 2008. 14: 109-15.
Ejrnaes, M., et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J. Exp. Med. 2006. 203: 2461-2472.
Embi, N., et al. Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur. J. Biochem. 1980. 107: 519-527.
Fiol, C. J., et al. A secondary phosphorylation of CREB at Ser129 is required for the cAMP-mediated control of gene expression. J. Biol. Chem. 1994. 269: 32187-32193.
Fang, X., et al. Phosphorylation and inactivation of glycogen synthase kinase 3 by the protein kinase A. Proc. Natl. Acad. Sci. 2000. 97: 11960-11965.
Falgout, B., et al. Proper processing of dengue virus nonstructural glycoprotein NS1 requires the N-terminal hydrophobic signal sequence and the downstream nonstructural protein NS2a. J. Virol. 1989. 63: 1852-1860.
Falkler, W. A., et al. Human antibody to dengue soluble complement-fixing (SCF) antigens. J. Immunol. 1973. 111: 1804-1809.
Falconar, A. K. Antibody responses are generated to immunodominant ELK/KLE-type motifs on the nonstructural-1 glycoprotein during live dengue virus infections in mice and humans: implications for diagnosis, pathogenesis, and vaccine design. Clin. Vaccine Immunol. 2007. 14: 493-504.
Fickenscher, H., et al. The interleukin-10 family of cytokines. Trends. Immunol. 2002. 23: 89-96.
Finbloom, D. S. and Winestock, K. D. IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes. J. Immunol. 1995. 155: 1079-1090.
Fiorentino, D. F., et al. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J. Exp. Med. 1989. 170: 2081-2095.
Garcia-Garcia, E., et al. Signal transduction during Fc receptor-mediated phagocytosis. J. Leukoc. Biol. 2002. 72: 1092-1108.
Gonzalez, G. A. and Montminy, M. R. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 1989. 59: 675-680.
Green, S., et al. Elevated plasma interleukin-10 levels in acute dengue correlate with disease severity. J. Med. Virol. 1999. 59: 329-334.
Guzman, M. G., et al. Dengue: a continuing global threat. Nat. Rev. Microbiol. 2010. 12: S7-16.
Guzman, A. and Isturiz, R. E. Update on the global spread of dengue. Int. J. Antimicrob. Agents. 2010. 36: S40-S42.
Halstead, S. B. and O’Rourke, E. J. Dengue viruses and mononuclear phagocytes I. infection enhancement by non-neutralizing antibody. J. Exp. Med. 1977. 146: 201-217.
Halstead, S. B., et al. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet. Infect. Dis. 2010. 10: 712–22.
Hofmann, C., et al. Glycogen synthase kinase-3β: a master regulator of toll-like receptor-mediated chronic intestinal inflammation. Inflamm. Bowel. Dis. 2010. 16: 1850-1858.
Huang, W. C., et al. Glycogen synthase kinase-3 negatively regulates anti-inflammatory interleukin-10 for lipopolysaccharide iNOS/NO biosynthesis and RANTES production in microglial cells. Immunology. 2009. 128: e275-e286.
Huang, J. H., et al. Laboratory-based dengue surveillance in Taiwan, 2005: a molecular epidemiologic study. Am. J. Trop. Med. Hyg. 2007. 77: 903–909.
Hung, N. T., et al. Dengue hemorrhagic fever in infants: a study of clinical and cytokine profiles. J. Infect. Dis. 2004. 189: 221-232.
Hu, X., et al. IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity. 2006. 24: 563-574.
Ito, S., et al. Interleukin-10 inhibits expression of both interferon α-and interferon γ-induced genes by suppressing tyrosine phosphorylation of STAT1. Blood. 1999. 93: 1456-1463.
Jennifer, L., et al. Global spread and persistence of dengue. Annu. Rev. Microbiol. 2008. 62: 71-92.
Jones, M., et al. Dengue virus inhibits alpha interferon signaling by reducing STAT2 expression. J. Virol. 2005. 79: 5414-5420.
Jope, R. S. and Johnson, G. V. The glamour and gloom of glycogen synthase kinase-3. Trends. Biochem. Sci. 2004. 29: 95-102.
Jung, M., et al. Expression profiling of IL-10-regulated genes in human monocytes and peripheral blood mononuclear cells from psoriatic patients during IL-10 therapy. Eur. J. Immunol. 2004. 34: 481–493.
Kanlaya, R., et al. Vimentin interacts with heterogeneous nuclear ribonucleoproteins and dengue nonstructural protein 1 and is important for viral replication and release. Mol. Biosyst. 2010. 6: 795–806.
Kaufmann, B. and Rossmann, M. G. Molecular mechanisms involved in the early steps of flavivirus cell entry. Microbes. Infect. 2011. 13: 1-9.
Kawai, T. and Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 2010. 11: 373-384.
Kotenko, S. V. The family of IL-10-related cytokines and their receptors: related, but to what extent? Cytokine. Growth. Factor. Rev. 2002. 13: 223-240.
Kyle, J. L. and Harris, E. Global spread and persistence of dengue. Annu. Rev. Microbiol. 2008. 62: 71–92.
Li, L., et al. The flavivirus precursor membrane-envelope protein complex: structure and maturation. Science. 2008. 319: 1830-1834.
Lin, C. F., et al. Generation of IgM anti-platelet autoantibody in dengue patients. J. Med. Virol. 2001. 63: 143-149.
Lin, C. F., et al. Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide. J. Immunol. 2002. 169: 657-664.
Lin, C. F., et al. Antibodies from dengue patient sera cross-react with endothelial cells and induce damage. J. Med. Virol. 2003. 69: 82-90.
Lin, C. F., et al. IFN-gamma synergizes with LPS to induce nitric oxide biosynthesis through glycogen synthase kinase-3-inhibited IL-10. J. Cell. Biochem. 2008. 105: 746-755.
Lin, C. C., et al. Characteristic of dengue disease in Taiwan: 2002-2007. Am. J. Trop. Med. Hyg. 2010. 82: 731–739.
Lindenbach, B. D., et al. Genetic interaction of flavivirus nonstructural proteins NS1 and NS4A as a determinant of replicase function. J. Virol. 1999. 73: 4611-4621.
Liu, L., et al. Influenza A virus induces interleukin-27 through cyclooxygenase-2 and protein kinase A signaling. J. Biol. Chem. 2012. 287: 11899-11910.
Ma, L., et al. Solution structure of dengue virus capsid protein reveals another fold. Proc. Natl. Acad. Sci. U. S. A. 2004. 101: 3414-3419.
Mayer, S. I., et al. Elk-1, CREB, and MKP-1 regulate Egr-1 expression in gonadotropin-releasing hormone stimulated gonadotrophs. J. Cell. Biochem. 2008. 105: 1267-1278.
Meyer, C. J., et al. Mechanical control of cyclic AMP signaling and gene transcription through integrins. Nat. Cell. Biol. 2000. 2: 666-668.
Munoz-Jordan, J. L., et al. Inhibition of interferon signaling by dengue virus. Proc. Natl. Acad. Sci. U. S. A. 2003. 100: 14333-14338.
Munoz-Jordan, J. L., et al. Inhibition of alpha/beta interferon signaling by the NS4B protein of flaviviruses. J. Virol. 2005. 79: 8004-8013.
Mazzon, M., et al. Dengue virus NS5 inhibits interferon-α signaling by blocking signal transducer and activator of transcription 2 phosphorylation. J. Infect. Dis. 2009. 200: 1261-1270.
Martina, B. E., et al. Dengue virus pathogenesis: an integrated view. Clin. Microbiol. Rev. 2009. 22: 564-581.
Martin, M., et al. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat. Immuol. 2005. 6: 777-784.
Maurer, U., et al. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol. Cell. 2006. 21: 749-760.
Mayr, B. and Montminy, M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell. Biol. 2001. 2: 599-609.
Nakayama et al. Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. J. Biol. Chem. 2009. 284: 1612-1619.
Netsawang, J., et al. Nuclear localization of dengue virus capsid protein is required for DAXX interaction and apoptosis. Virus. Res. 2010. 147: 275-283.
Noisakran, S., et al. Characterization of dengue virus NS1 stably expressed in 293T cell lines. J. Virol. Methods. 2007. 142: 67-80.
Noh, K. T., et al. Protein kinase C δ (PKCδ)-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascade regulates glycogen synthase kinase-3 (GSK-3) inhibition-mediated interleukin-10 (IL-10) expression in lipopolysaccharide (LPS)-induced endotoxemia. J. Biol. Chem. 2012. 287: 14226-14233.
Park, C. Y., et al. Nonstructural 5A protein activates beta-catenin signaling cascades: implication of hepatitis C virus-induced liver pathogenesis. J. Hepatol. 2009. 51: 853-864.
Perera, R. and Kuhn, R. Structural proteomics of dengue virus. Curr. Opin. Microbiol. 2008. 11: 369-377.
Perez, A. B., et al. IL-10 levels in Dengue patients: some findings from the exceptional epidemiological conditions in Cuba. J. Med. Virol. 2004. 73: 230-234.
Pearl, L. H. and Barford, D. Regulation of protein kinases in insulin, growth factor and Wnt signalling. Curr. Opin. Struct. Biol. 2002. 12: 761-767.
Platanias, L. C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat .Rev. Immunol. 2005. 5: 375-386.
Pryor, M. J., et al. Nuclear localization of dengue virus nonstructural protein 5 through its importin alpha/beta-recognized nuclear localization sequences is integral to viral infection. Traffic. 2007. 8: 795-807.
Reyes-Del, V. J. et al. Heat shock protein 90 and heat shock protein 70 are components of dengue virus receptor complex in human cells. J. Virol. 2005. 79: 4557-4567.
Reddi, H., et al. A carboxy-terminal region of the hepatitis B virus X protein promotes DNA interaction of CREB and mimics the native protein for transactivation function. Virus. Genes. 2003. 26: 227-238.
Rothman, A. L., et al. Immunopathogenesis of dengue hemorrhagic fever. Virology. 1999. 257: 1-6.
Rothman, A. L. Dengue: defining protective versus pathologic immunity. J. Clin. Invest. 2004. 113: 946-951.
Rodenhuis-Zybert, I. A., et al. Dengue virus life cycle: viral and host factors modulating infectivity. Cell. Mol. Life Sci. 2010. 67: 2773–2786.
Rosen, L. The Emperor's New Clothes revisited, or reflections on the pathogenesis of dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 1977. 26: 337-343.
Ruhul Amin, M., et al. Prediction of the post-translational modification sites on dengue virus E protein and deciphering their role in pathogenesis. Int. J. Bioinform. Res. Appl. 2010. 6: 508-521.
Sabat, R., et al. Biology of interleukin-10. Cytokine. Growth. Factor. Rev. 2010. 21: 331-344.
Saraiva, M. and O'Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 2010. 10: 170-181.
Schroder, K., et al. Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol, 2004. 75: 163-189.
Selin, L. K., et al. Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations. J. Exp. Med. 1998. 188: 1705-1715.
Simmons, C. P., et al. Dengue. N. Engl. J. Med. 2012. 366: 1423-1432.
Shresta, S., et al. Interferon-dependent immunity is essential for resistance to primary dengue virus infection in mice, whereas T- and B-cell-dependent immunity are less critical. J. Virol. 2004. 78: 2701-2710.
Shuai, K. and Liu, B. Regulation of JAK-STAT signalling in the immune system. Nat. Rev. Immunol. 2003. 3: 900-911.
Song, M. M. and Shuai, K. The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. J. Biol. Chem. 1998. 273: 35056-35062.
Srikiatkhachorn, A. and Green, S. Markers of dengue disease severity. Curr. Top. Microbiol. Immunol. 2010. 338: 67-82.
Sutherland, C., et al. Inactivation of glycogen synthase kinase-3β by phosphorylation: new kinase connections in insulin and growth-factor signaling. Biochem. J. 1993. 296: 15-19.
Suvas, S., et al. CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. J. Immunol. 2004. 172: 4123–4132.
Sugimoto, Y. and Narumiya, S. Prostaglandin E receptors. J. Biol. Chem. 2007. 282: 11613-11617.
Tsai, Y. T., et al. Human TLR3 recognizes dengue virus and modulates viral replication in vitro. Cell. Microbiol. 2009. 11: 604-615.
Tsai, C. C., et al. Glycogen synthase kinase-3beta facilitates IFN-gamma-induced STAT1 activation by regulating Src homology-2 domain-containing phosphatase 2. J. Immunol. 183: 856-864.
Tassaneetrithep, B., et al. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J. Exp. Med. 2003. 197: 823-829.
Tan, B. H., et al. Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity. Virology. 1996. 216: 317-325.
Thiel, G. and Cibelli, G. Regulation of life and death by the zinc finger transcription factor Egr-1. J. Cell. Physiol. 2002. 193: 287-292.
Ubol, S., et al. Mechanisms of immune evasion induced by a complex of dengue virus and preexisting enhancing antibodies. J. Infect. Dis. 2010. 201: 923-935.
Wang, M. J., et al. Glycogen synthase kinase-3β inactivation inhibits tumor necrosis factor-α production in microglia by modulating nuclear factor κB and MLK3/JNK signaling cascades. J. Neuroinflammation. 2010. 7: 99.
Weber-Nordt, R. M., et al. Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain. J. Biol. Chem. 1996. 271: 27954-27961.
Wen, A. Y., et al. The role of the transcription factor CREB in immune function. J. Immunol. 2010. 185: 6413-6419.
World Health Organization. Dengue: Guidelines for diagnosis, treatment, prevention and control. 2009. Geneva, TDR: World Health Organization.
Wu, W. L., et al. Triggering of DC migration by dengue virus stimulation of COX-2-dependent signaling cascades in vitro highlights the significance of these cascades beyond inflammation. Eur. J. Immunol. 2009. 39: 3413-3422.
Yang, K. D., et al. Antibody-dependent enhancement of heterotypic dengue infections involved in suppression of IFNgamma production. J. Med. Virol. 63: 150-157.
Yoon, S. I., et al. Conformational changes mediate interleukin-10 receptor 2 (IL-10R2) binding to IL-10 and assembly of the signaling complex. J. Biol. Chem. 2006. 281: 35088-35096.
Yost, C., et al. The axis-inducing activity, stability, and subcellular distribution of β-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes. Dev. 1996. 10: 1443-1454.
Yoshimura, A., et al. SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol. 2007. 7: 454-465.
Yu, I. M., et al. Structure of the immature dengue virus at low pH primes proteolytic maturation. Science. 2008. 319: 1834-1837.
You, M., et al. Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Mol. Cell. Biol. 1999. 19: 2416-2424.
Zhang, Y., et al. Conformational changes of the flavivirus E glycoprotein. Structure. 2004. 12: 1607–1618.
Zhang, J. L., et al. Up-regulated expression of β3 integrin induced by dengue virus serotype 2 infection associated with virus entry into human dermal microvascular endothelial cells. Biochem. Biophys. Res. Commun. 2007. 356: 763-768.