現今對於日本腦炎發生淋巴細胞浸潤參與的相關細胞和作用機制仍不清楚。淋巴細胞浸潤到中央神經系統的過程中，腦部微血管內皮細胞層扮演重要的角色。我們發現日本腦炎病毒容易感染大腦微血管內皮細胞，但病毒卻極少在細胞內繁殖複製。所以日本腦炎病毒幾乎不影響內皮細胞存活和內皮細胞層完整性，卻發現有較多淋巴細胞的牽引和貼附到內皮細胞層。實驗結果指出日本腦炎病毒感染的內皮細胞會增加ICAM-1、CINC-1與RANTES的表現，導致淋巴細胞吸引和貼附到內皮細胞層的數目增加。我們進一步研究發現ERK、CPLA2、NF-κB和CREB的磷酸化與活化參與調控內皮細胞ICAM-1、CINC-1和RANTES的表現。由這些證據顯示，內皮細胞層經由日本腦炎病毒感染並不會破壞其完整性；而是誘發更多淋巴細胞的牽引和貼附到內皮細胞層。再加上其他未知的因素造成內皮細胞層完整性破壞，最後導致神經發炎和日本腦炎的現象。

Currently, the underlying mechanisms and the specific cell types associated with Japanese encephalitis-associated leukocyte trafficking are not understood. Brain microvascular endothelial cells represent a functional barrier and could play key roles in leukocyte central nervous system trafficking. We found that cultured brain microvascular endothelial cells were susceptible to Japanese encephalitis virus (JEV) infection with limited amplification. This type of JEV infection had negligible effects on cell viability and barrier integrity. Instead, JEV-infected endothelial cells attracted more leukocytes adhesion onto surfaces and the supernatants promoted chemotaxis of leukocytes. Infection with JEV was found to elicit the elevated production of intercellular adhesion molecule-1, cytokine-induced neutrophil chemoattractant-1, and regulated-upon-activation normal T-cell expressed and secreted, contributing to the aforementioned leukocyte adhesion and chemotaxis. We further demonstrated that extracellular signal-regulated kinase was a key upstream regulator which stimulated extensive endothelial gene induction by up-regulating cytosolic phospholipase A2, NF-κB, and cAMP response element binding protein via signals involving phosphorylation. These data suggest that JEV infection could activate brain microvascular endothelial cells and modify their characteristics without compromising the barrier integrity, making them favorable for the recruitment and adhesion of circulating leukocytes, thereby together with other unidentified barrier disrupting mechanisms contributing to Japanese encephalitis and associated neuroinflammation.

論文目次

中文摘要 I
英文摘要 II
論文目次 IV
圖表目次 IX
附表目次 XIII
縮寫表 XIV
第一章、 緒論 1
第一節、 日本腦炎病毒 1
第二節、 血腦屏障 2
第三節、 病毒與血腦屏障的關係 4
第四節、 研究動機 5
第二章、 材料與方法 7
第一節、 病毒製備與感染 7
一、 病毒增殖 7
二、 病毒溶斑試驗 7
三、 病毒感染 8
第二節、 初代細胞培養 8
一、 初代大腦微血管周細胞 8
二、 初代神經膠細胞 9
三、 初代大腦微血管內皮細胞 9
四、 細胞共培養模式 10
第三節、 實驗分析方法 10
一、 西方墨點法 10
二、 細胞存活度測試(MTS assay) 11
三、 RT-PCR 12
四、 Real time RT-PCR 13
五、 ELISA 13
六、 細胞免疫染色 14
七、 EMSA 14
八、 細胞趨化貼付能力分析 16
九、 細胞電阻阻抗性分析(TEER) 17
十、 共同免疫沉澱法 (Co-immunoprecipitation)17
十一、細胞通透性分析 18
十二、統計分析 18
第三章、 實驗結果 19
第一節、 日本腦炎病毒對體外模擬血腦屏障的影響19
一、初代細胞培養和鑑定 19
二、日本腦炎病毒感染細胞能力分析 19
三、日本腦炎病毒感染造成血腦屏障通透性上升 20四、日本腦炎病毒感染對細胞毒性的影響 20
五、日本腦炎病毒對由內皮細胞模擬之血腦屏障通透性影響 21
六、日本腦炎病毒感染會透過周細胞造成血腦屏障通透性上升 22
七、周細胞是利用分泌一些因子改變內皮細胞層通透性 22
八、日本腦炎病毒感染會透過神經膠細胞造成血腦屏障通透性上升 23
九、神經膠細胞是利用分泌一些因子去改變內皮細胞層的通透性 24
第二節、感染日本腦炎病毒之周細胞對內皮細胞影 25
一、日本腦炎病毒感染對周細胞影響 25
二、感染日本腦炎病毒之周細胞對內皮細胞影響 25
三、日本腦炎病毒感染誘發周細胞產生IL-6分子機
制 26
四、IL-6對內皮細胞影響 28
五、IL-6誘發內皮細胞緊密蛋白降解 29
六、IL-6透過Ubr-1造成ZO-1蛋白降解 31七、IL-6透過JaK-STAT路徑誘發Ubr-1的表現 32
八、IL-6透過JaK-STAT路徑間接調控內皮細胞層通透性 32
第三節、感染日本腦炎病毒之神經膠細胞對內皮細胞影響 33
一、日本腦炎病毒感染對神經膠細胞的影響 33
二、感染日本腦炎病毒之神經膠細胞對內皮細胞影
響 34
三、MMPs對內皮細胞層通透性的影響 34
四、MMPs誘發內皮細胞VEGF 釋放 35
五、VEGF 對內皮細胞的影響 36
第四節、日本腦炎病毒對內皮細胞的影響 36
一、日本腦炎病毒感染誘發內皮細胞發炎表現情形36
二、經感染日本腦炎病毒之內皮細胞對免疫細胞遷移和貼附能力的影響 37
三、誘發內皮細胞發炎表現之分子機制 37
第四章、 討論與結論 40
第五章、 參考文獻 48
第六章、 圖表 76
第七章、 附表 123

圖表目次

圖一、 初代細胞鑑定 82
圖二、 日本腦炎病毒感染能力分析 83
圖三、 日本腦炎病毒對由周細胞、 神經膠細胞、 內皮
細胞模擬之血腦屏障通透性分析 84
圖四、 日本腦炎病毒細胞毒性分析 85
圖五、 日本腦炎病毒對由內皮細胞模擬之血腦屏障通透
性影響分析 86
圖六、 日本腦炎病毒對由周細胞和內皮細胞模擬之血腦
屏障通透性分析分析 87
圖七、 日本腦炎病毒對由周細胞和內皮細胞模擬之血腦
屏障通透性影響分析 88
圖八、 經日本腦炎病毒感染的周細胞對由內皮細胞模擬
之血腦屏障通透性影響分析 89
圖九、 日本腦炎病毒對由神經膠細胞和內皮細胞模擬之
血腦屏障通透性影響分析 90
圖十、 日本腦炎病毒對由神經膠細胞和內皮細胞模擬
之血腦屏障通透性影響分析 91

圖十一、 經日本腦炎病毒感染的神經膠細胞對由內皮
細胞模擬之血腦屏障通透性影響分析 92
圖十二、 日本腦炎病毒誘發周細胞發炎介子蛋白表現
量分析 93
圖十三、 日本腦炎病毒誘發周細胞發炎介子mRNA表現
量分析 95
圖十四、 經感染日本腦炎病毒的周細胞對內皮細胞層
通透性和周邊血液單核球趨化能力分析 96
圖十五、 日本腦炎病毒活化TLR、MAPK路徑誘發周細
胞IL-6表現 98
圖十六、 日本腦炎病毒活化PTK、Ras、PI3K、PKC和cPLA
2路徑誘發周細胞IL-6表現 99
圖十七、 日本腦炎病毒感染活化周細胞MAPK路徑 100
圖十八、 日本腦炎病毒感染活化周細胞轉錄因子分析102
圖十九、 日本腦炎病毒感染周細胞對內皮細胞緊密蛋
白表現分析 103
圖二十、 日本腦炎病毒誘發周細胞產生之IL-6對內皮
細胞緊密蛋白的影響 104
圖二十一、 日本腦炎病毒誘發周細胞產生之IL-6對內

皮細胞緊密蛋白表現量的影響 105
圖二十二、 日本腦炎病毒誘發周細胞產生之IL-6對內
皮細胞緊密mRNA表現量的影響 106
圖二十三、 日本腦炎病毒誘發周細胞產生之IL-6經由
蛋白降解影響內皮細胞緊密蛋白表現量 107
圖二十四、 IL-6透過Ubr-1造成ZO-1蛋白質降解 109
圖二十五、 IL-6透過Ubr-1造成ZO-1蛋白質降解而影
響內皮細胞層通透性 110
圖二十六、 IL-6透過JaK-STAT路徑誘發Ubr-1的表
現 112
圖二十七、 IL-6透過JaK-STAT間接調控內皮細胞層通
透性 114
圖二十八、 日本腦炎病毒感染誘發神經膠細胞MMPs表
現情形 116
圖二十九、 日本腦炎病毒感染神經膠細胞對內皮細胞
之影響 117
圖三十、 日本腦炎病毒感染神經膠細胞對大腦皮質內
皮細胞通透性之影響 119
圖三十一、 內皮細胞處理日本腦炎病毒感染神經膠細

胞之上清液分析VEGF表現情形 120
圖三十二、 日本腦炎病毒感染神經膠細胞之上清液對
大腦皮質內皮細胞之影響 121
圖三十三、 內皮細胞經日本腦炎病毒感染誘發發炎反
應 122
圖三十四、 內皮細胞經日本腦炎病毒感染對免疫細胞
貼附和趨化的影響 123
圖三十五、 日本腦炎病毒感染誘發內皮細胞發炎反應
之路徑 124
圖三十六、 日本腦炎病毒感染誘發內皮細胞發炎反應
之訊息傳遞路徑 126
圖三十七、 日本腦炎病毒感染對細胞的影響 128


附表目次

附表一、 RT-PCR引子 129
附表二、 Real-time PCR引子 130

1.Abbott, N. J. 2002. Astrocyte-endothelial interactions and blood-brain barrier permeability. Journal of anatomy 200:629-638.
2.Ahmad, R., J. Ennaciri, P. Cordeiro, S. El Bassam, and J. Menezes. 2007. Herpes simplex virus-1 up-regulates IL-15 gene expression in monocytic cells through the activation of protein tyrosine kinase and PKC zeta/lambda signaling pathways. J Mol Biol 367:25-35.
3.Aleyas, A. G., J. A. George, Y. W. Han, M. M. Rahman, S. J. Kim, S. B. Han, B. S. Kim, K. Kim, and S. K. Eo. 2009. Functional modulation of dendritic cells and macrophages by Japanese encephalitis virus through MyD88 adaptor molecule-dependent and -independent pathways. Journal of immunology 183:2462-2474.
4.Ali, M. H., S. A. Schlidt, N. S. Chandel, K. L. Hynes, P. T. Schumacker, and B. L. Gewertz. 1999. Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction. Am J Physiol 277:L1057-1065.
5.Andrassy, M., A. Bierhaus, M. Hong, J. Sis, S. Schiekofer, P. M. Humper, J. Chen, M. Haap, W. Renn, E. Schleicher, H. U. Haring, K. Andrassy, and P. P. Nawroth. 2002. Erythropoietin-mediated decrease of the redox-sensitive transcription factor NF-kappaB is inversely correlated with the hemoglobin level. Clin Nephrol 58:179-189.
6.Assaf, A., H. Esteves, S. J. Curnow, and M. J. Browning. 2009. A threshold level of TLR9 mRNA predicts cellular responsiveness to CpG-ODN in haematological and non-haematological tumour cell lines. Cell Immunol 259:90-99.
7.Atreya, R., and M. F. Neurath. 2008. Signaling molecules: the pathogenic role of the IL-6/STAT-3 trans signaling pathway in intestinal inflammation and in colonic cancer. Curr Drug Targets 9:369-374.
8.Balogh, S. A., C. S. McDowell, and V. H. Denenberg. 2002. Behavioral characterization of mice lacking the ubiquitin ligase UBR1 of the N-end rule pathway. Genes Brain Behav 1:223-229.
9.Barut, S., Y. A. Unlu, A. Karaoglan, M. Tuncdemir, F. K. Dagistanli, M. Ozturk, and A. Colak. 2005. The neuroprotective effects of z-DEVD.fmk, a caspase-3 inhibitor, on traumatic spinal cord injury in rats. Surg Neurol 64:213-220; discussion 220.
10.Batra, A., L. L. Latour, C. A. Ruetzler, J. M. Hallenbeck, M. Spatz, S. Warach, and E. C. Henning. 2010. Increased plasma and tissue MMP levels are associated with BCSFB and BBB disruption evident on post-contrast FLAIR after experimental stroke. J Cereb Blood Flow Metab 30:1188-1199.
11.Biswas, S. M., S. Kar, R. Singh, D. Chakraborty, V. Vipat, C. G. Raut, A. C. Mishra, M. M. Gore, and D. Ghosh. 2010. Immunomodulatory cytokines determine the outcome of Japanese encephalitis virus infection in mice. J Med Virol 82:304-310.
12.Brodie, C., N. Weizman, A. Katzoff, S. Lustig, and D. Kobiler. 1997. Astrocyte activation by Sindbis virus: expression of GFAP, cytokines, and adhesion molecules. Glia 19:275-285.
13.Burke, D. S., and A. Nisalak. 1982. Detection of Japanese encephalitis virus immunoglobulin M antibodies in serum by antibody capture radioimmunoassay. J Clin Microbiol 15:353-361.
14.Burke, D. S., A. Nisalak, and M. A. Ussery. 1982. Antibody capture immunoassay detection of japanese encephalitis virus immunoglobulin m and g antibodies in cerebrospinal fluid. J Clin Microbiol 16:1034-1042.
15.Cao, S., Y. Li, J. Ye, X. Yang, L. Chen, X. Liu, and H. Chen. 2011. Japanese encephalitis Virus wild strain infection suppresses dendritic cells maturation and function, and causes the expansion of regulatory T cells. Virol J 8:39.
16.Chen, B. C., and W. W. Lin. 2000. Pyrimidinoceptor potentiation of macrophage PGE(2) release involved in the induction of nitric oxide synthase. Br J Pharmacol 130:777-786.
17.Chen, C. J., Y. C. Ou, C. Y. Chang, H. C. Pan, S. L. Liao, S. Y. Chen, S. L. Raung, and C. Y. Lai. 2012. Glutamate released by Japanese encephalitis virus-infected microglia involves TNF-alpha signaling and contributes to neuronal death. Glia 60:487-501.
18.Chen, C. J., Y. C. Ou, C. Y. Chang, H. C. Pan, S. L. Liao, S. L. Raung, and S. Y. Chen. 2011. TNF-alpha and IL-1beta mediate Japanese encephalitis virus-induced RANTES gene expression in astrocytes. Neurochem Int 58:234-242.
19.Chen, C. J., Y. C. Ou, C. Y. Chang, H. C. Pan, S. Y. Lin, S. L. Liao, S. L. Raung, S. Y. Chen, and C. J. Chang. 2011. Src signaling involvement in Japanese encephalitis virus-induced cytokine production in microglia. Neurochemistry international 58:924-933.
20.Chen, C. J., S. L. Raung, M. D. Kuo, and Y. M. Wang. 2002. Suppression of Japanese encephalitis virus infection by non-steroidal anti-inflammatory drugs. J Gen Virol 83:1897-1905.
21.Chiang, E. T., D. A. Persaud-Sawin, S. Kulkarni, J. G. Garcia, and F. Imani. 2006. Bluetongue virus and double-stranded RNA increase human vascular permeability: role of p38 MAPK. J Clin Immunol 26:406-416.
22.Correale, J., and A. Villa. 2009. Cellular elements of the blood-brain barrier. Neurochemical research 34:2067-2077.
23.D''Addario, M., A. Ahmad, A. Morgan, and J. Menezes. 2000. Binding of the Epstein-Barr virus major envelope glycoprotein gp350 results in the upregulation of the TNF-alpha gene expression in monocytic cells via NF-kappaB involving PKC, PI3-K and tyrosine kinases. J Mol Biol 298:765-778.
24.Das, S., M. K. Mishra, J. Ghosh, and A. Basu. 2008. Japanese Encephalitis Virus infection induces IL-18 and IL-1beta in microglia and astrocytes: correlation with in vitro cytokine responsiveness of glial cells and subsequent neuronal death. Journal of neuroimmunology 195:60-72.
25.Didier, N., I. A. Romero, C. Creminon, A. Wijkhuisen, J. Grassi, and A. Mabondzo. 2003. Secretion of interleukin-1beta by astrocytes mediates endothelin-1 and tumour necrosis factor-alpha effects on human brain microvascular endothelial cell permeability. J Neurochem 86:246-254.
26.Diglio, C. A., P. Grammas, F. Giacomelli, and J. Wiener. 1982. Primary culture of rat cerebral microvascular endothelial cells. Isolation, growth, and characterization. Laboratory investigation; a journal of technical methods and pathology 46:554-563.
27.Doherty, M. J., and A. E. Canfield. 1999. Gene expression during vascular pericyte differentiation. Critical reviews in eukaryotic gene expression 9:1-17.
28.Dutta, K., M. K. Mishra, A. Nazmi, K. L. Kumawat, and A. Basu. 2010. Minocycline differentially modulates macrophage mediated peripheral immune response following Japanese encephalitis virus infection. Immunobiology 215:884-893.
29.Ennaciri, J., R. Ahmad, and J. Menezes. 2007. Interaction of monocytic cells with respiratory syncytial virus results in activation of NF-kappaB and PKC-alpha/beta leading to up-regulation of IL-15 gene expression. J Leukoc Biol 81:625-631.
30.Fitzgerald, J., T. J. Dietz, and M. Hughes-Fulford. 2000. Prostaglandin E2-induced up-regulation of c-fos messenger ribonucleic acid is primarily mediated by 3'',5''-cyclic adenosine monophosphate in MC3T3-E1 osteoblasts. Endocrinology 141:291-298.
31.Fujii, Y., K. Kitaura, K. Nakamichi, T. Takasaki, R. Suzuki, and I. Kurane. 2008. Accumulation of T-cells with selected T-cell receptors in the brains of Japanese encephalitis virus-infected mice. Jpn J Infect Dis 61:40-48.
32.Fujita, H., A. Asahina, M. Komine, and K. Tamaki. 2007. ERK inhibitor PD98059 promotes the phenotypic and functional maturation of murine resident Langerhans cells. J Dermatol 34:403-406.
33.Furst, R., M. F. Bubik, P. Bihari, B. A. Mayer, A. G. Khandoga, F. Hoffmann, M. Rehberg, F. Krombach, S. Zahler, and A. M. Vollmar. 2008. Atrial natriuretic peptide protects against histamine-induced endothelial barrier dysfunction in vivo. Mol Pharmacol 74:1-8.
34.Garcel, A., W. Fauquette, M. P. Dehouck, J. M. Crance, and A. L. Favier. 2012. Vaccinia virus-induced smallpox postvaccinal encephalitis in case of blood-brain barrier damage. Vaccine 30:1397-1405.
35.Gherardi, R. K., L. Belec, G. Fromont, M. Divine, D. Malapert, P. Gaulard, and J. D. Degos. 1994. Elevated levels of interleukin-1 beta (IL-1 beta) and IL-6 in serum and increased production of IL-1 beta mRNA in lymph nodes of patients with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome. Blood 83:2587-2593.
36.Gorina, R., C. Sanfeliu, A. Galito, A. Messeguer, and A. M. Planas. 2007. Exposure of glia to pro-oxidant agents revealed selective Stat1 activation by H2O2 and Jak2-independent antioxidant features of the Jak2 inhibitor AG490. Glia 55:1313-1324.
37.Goyal, A., M. Konar, A. Setia, A. Narang, and S. Ghosh. 2010. Galactose specific adhesin of enteroaggregative E. coli induces IL-8 secretion via activation of MAPK and STAT-3 in INT-407 cells. Biochim Biophys Acta 1800:574-579.
38.Granja, A. G., E. G. Sanchez, P. Sabina, M. Fresno, and Y. Revilla. 2009. African swine fever virus blocks the host cell antiviral inflammatory response through a direct inhibition of PKC-theta-mediated p300 transactivation. J Virol 83:969-980.
39.Gupta, N., V. Lomash, and P. V. Rao. 2010. Expression profile of Japanese encephalitis virus induced neuroinflammation and its implication in disease severity. J Clin Virol 49:4-10.
40.Gupta, N., S. R. Santhosh, J. P. Babu, M. M. Parida, and P. V. Rao. 2010. Chemokine profiling of Japanese encephalitis virus-infected mouse neuroblastoma cells by microarray and real-time RT-PCR: implication in neuropathogenesis. Virus Res 147:107-112.
41.Gupta, V. K. 2009. CSD, BBB and MMP-9 elevations: animal experiments versus clinical phenomena in migraine. Expert Rev Neurother 9:1595-1614.
42.Hadad, N., L. Tuval, V. Elgazar-Carmom, and R. Levy. 2011. Endothelial ICAM-1 protein induction is regulated by cytosolic phospholipase A2alpha via both NF-kappaB and CREB transcription factors. J Immunol 186:1816-1827.
43.Han, Y. H., H. J. Moon, B. R. You, and W. H. Park. 2009. The effect of MG132, a proteasome inhibitor on HeLa cells in relation to cell growth, reactive oxygen species and GSH. Oncol Rep 22:215-221.
44.Haraguchi, S., E. N. Brigino-Buenaventura, R. Hitchcock, M. James-Yarish, R. A. Good, and N. K. Day. 2001. Involvement of a herbimycin A-sensitive protein tyrosine kinase in extracellular action of HIV-1 Nef. Immunol Lett 75:97-101.
45.Harman, A. N., J. Lai, S. Turville, S. Samarajiwa, L. Gray, V. Marsden, S. K. Mercier, K. Jones, N. Nasr, A. Rustagi, H. Cumming, H. Donaghy, J. Mak, M. Gale, Jr., M. Churchill, P. Hertzog, and A. L. Cunningham. 2011. HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production. Blood 118:298-308.
46.Hellstrom, M., H. Gerhardt, M. Kalen, X. Li, U. Eriksson, H. Wolburg, and C. Betsholtz. 2001. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153:543-553.
47.Hoke, C. H., Jr., D. W. Vaughn, A. Nisalak, P. Intralawan, S. Poolsuppasit, V. Jongsawas, U. Titsyakorn, and R. T. Johnson. 1992. Effect of high-dose dexamethasone on the outcome of acute encephalitis due to Japanese encephalitis virus. J Infect Dis 165:631-637.
48.Hori, S., S. Ohtsuki, K. Hosoya, E. Nakashima, and T. Terasaki. 2004. A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J Neurochem 89:503-513.
49.Huang, H. N., V. Rajanbabu, C. Y. Pan, Y. L. Chan, C. F. Hui, J. Y. Chen, and C. J. Wu. 2011. Modulation of the immune-related gene responses to protect mice against Japanese encephalitis virus using the antimicrobial peptide, tilapia hepcidin 1-5. Biomaterials 32:6804-6814.
50.Huet, E., B. Vallee, J. Delbe, S. Mourah, V. Pruliere-Escabasse, M. Tremouilleres, K. Kadomatsu, S. Doan, C. Baudouin, S. Menashi, and E. E. Gabison. 2011. EMMPRIN modulates epithelial barrier function through a MMP-mediated occludin cleavage: implications in dry eye disease. Am J Pathol 179:1278-1286.
51.Ikezoe, T., C. Nishioka, K. Bandobashi, Y. Yang, Y. Kuwayama, Y. Adachi, T. Takeuchi, H. P. Koeffler, and H. Taguchi. 2007. Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells. Leuk Res 31:673-682.
52.Jan, R. H., Y. L. Lin, C. J. Chen, T. Y. Lin, Y. C. Hsu, L. K. Chen, and B. L. Chiang. 2012. Hepatitis B virus surface antigen can activate human monocyte-derived dendritic cells by NF-kB and p38 mitogen-activated protein kinase mediated signaling. Microbiol Immunol 56:719-727.
53.Johnson, R. T., D. S. Burke, M. Elwell, C. J. Leake, A. Nisalak, C. H. Hoke, and W. Lorsomrudee. 1985. Japanese encephalitis: immunocytochemical studies of viral antigen and inflammatory cells in fatal cases. Ann Neurol 18:567-573.
54.Kanda, N., and S. Watanabe. 2003. 17beta-estradiol inhibits the production of RANTES in human keratinocytes. J Invest Dermatol 120:420-427.
55.Katyshev, V., and P. Dore-Duffy. 2012. Pericyte coculture models to study astrocyte, pericyte, and endothelial cell interactions. Methods Mol Biol 814:467-481.
56.Khatri, M., and J. M. Sharma. 2006. Infectious bursal disease virus infection induces macrophage activation via p38 MAPK and NF-kappaB pathways. Virus Res 118:70-77.
57.Kimura, A., T. Naka, T. Muta, O. Takeuchi, S. Akira, I. Kawase, and T. Kishimoto. 2005. Suppressor of cytokine signaling-1 selectively inhibits LPS-induced IL-6 production by regulating JAK-STAT. Proc Natl Acad Sci U S A 102:17089-17094.
58.Komatsu, K., Y. Nakanishi, N. Nemoto, T. Hori, T. Sawada, and M. Kobayashi. 2004. Expression and quantitative analysis of matrix metalloproteinase-2 and -9 in human gliomas. Brain Tumor Pathol 21:105-112.
59.Kose, N., T. Asashima, M. Muta, H. Iizasa, Y. Sai, T. Terasaki, and E. Nakashima. 2007. Altered expression of basement membrane-related molecules in rat brain pericyte, endothelial, and astrocyte cell lines after transforming growth factor-beta1 treatment. Drug Metab Pharmacokinet 22:255-266.
60.Kulshreshtha, R., A. Mathur, and U. C. Chaturvedi. 1988. Immunological memory in latent Japanese encephalitis virus infection. Br J Exp Pathol 69:465-471.
61.Kumar, S., J. Kalita, V. Saxena, M. Y. Khan, V. K. Khanna, S. Sharma, T. N. Dhole, and U. K. Misra. 2009. Some observations on the tropism of Japanese encephalitis virus in rat brain. Brain Res 1268:135-141.
62.Kwon, Y. T., Z. Xia, I. V. Davydov, S. H. Lecker, and A. Varshavsky. 2001. Construction and analysis of mouse strains lacking the ubiquitin ligase UBR1 (E3alpha) of the N-end rule pathway. Mol Cell Biol 21:8007-8021.
63.Le Goffic, R., V. Balloy, M. Lagranderie, L. Alexopoulou, N. Escriou, R. Flavell, M. Chignard, and M. Si-Tahar. 2006. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog 2:e53.
64.Lee, S. K., and P. H. Stern. 2000. Divergent effects of protein kinase C (PKC) inhibitors staurosporine and bisindolylmaleimide I (GF109203X) on bone resorption. Biochem Pharmacol 60:923-926.
65.Li, W., L. J. Henderson, E. O. Major, and L. Al-Harthi. 2011. IFN-gamma mediates enhancement of HIV replication in astrocytes by inducing an antagonist of the beta-catenin pathway (DKK1) in a STAT 3-dependent manner. J Immunol 186:6771-6778.
66.Li, Y., J. Ye, X. Yang, M. Xu, L. Chen, L. Mei, J. Zhu, X. Liu, H. Chen, and S. Cao. 2011. Infection of mouse bone marrow-derived dendritic cells by live attenuated Japanese encephalitis virus induces cells maturation and triggers T cells activation. Vaccine 29:855-862.
67.Lin, C. F., S. C. Chiu, Y. L. Hsiao, S. W. Wan, H. Y. Lei, A. L. Shiau, H. S. Liu, T. M. Yeh, S. H. Chen, C. C. Liu, and Y. S. Lin. 2005. Expression of cytokine, chemokine, and adhesion molecules during endothelial cell activation induced by antibodies against dengue virus nonstructural protein 1. J Immunol 174:395-403.
68.Lin, K. L., D. Y. Yang, I. M. Chu, F. C. Cheng, C. J. Chen, S. P. Ho, and H. C. Pan. 2010. DuraSeal as a ligature in the anastomosis of rat sciatic nerve gap injury. The Journal of surgical research 161:101-110.
69.Liou, M. L., and C. Y. Hsu. 1998. Japanese encephalitis virus is transported across the cerebral blood vessels by endocytosis in mouse brain. Cell Tissue Res 293:389-394.
70.Liu, G. H., J. Qu, and X. Shen. 2008. NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. Biochim Biophys Acta 1783:713-727.
71.Lleo, A., E. Galea, and M. Sastre. 2007. Molecular targets of non-steroidal anti-inflammatory drugs in neurodegenerative diseases. Cellular and molecular life sciences : CMLS 64:1403-1418.
72.Loiarro, M., C. Sette, G. Gallo, A. Ciacci, N. Fanto, D. Mastroianni, P. Carminati, and V. Ruggiero. 2005. Peptide-mediated interference of TIR domain dimerization in MyD88 inhibits interleukin-1-dependent activation of NF-{kappa}B. J Biol Chem 280:15809-15814.
73.Lu, X., A. Masic, Q. Liu, and Y. Zhou. 2011. Regulation of influenza A virus induced CXCL-10 gene expression requires PI3K/Akt pathway and IRF3 transcription factor. Mol Immunol 48:1417-1423.
74.Marampon, F., G. Bossi, C. Ciccarelli, A. Di Rocco, A. Sacchi, R. G. Pestell, and B. M. Zani. 2009. MEK/ERK inhibitor U0126 affects in vitro and in vivo growth of embryonal rhabdomyosarcoma. Mol Cancer Ther 8:543-551.
75.Maruo, N., I. Morita, M. Shirao, and S. Murota. 1992. IL-6 increases endothelial permeability in vitro. Endocrinology 131:710-714.
76.Mathur, A., M. Bharadwaj, R. Kulshreshtha, S. Rawat, A. Jain, and U. C. Chaturvedi. 1988. Immunopathological study of spleen during Japanese encephalitis virus infection in mice. Br J Exp Pathol 69:423-432.
77.Merlo, S., and M. A. Sortino. 2012. Estrogen activates matrix metalloproteinases-2 and -9 to increase beta amyloid degradation. Molecular and cellular neurosciences 49:423-429.
78.Mi, H., H. Haeberle, and B. A. Barres. 2001. Induction of astrocyte differentiation by endothelial cells. J Neurosci 21:1538-1547.
79.Mishra, M. K., K. Dutta, S. K. Saheb, and A. Basu. 2009. Understanding the molecular mechanism of blood-brain barrier damage in an experimental model of Japanese encephalitis: correlation with minocycline administration as a therapeutic agent. Neurochem Int 55:717-723.
80.Mishra, M. K., D. Ghosh, R. Duseja, and A. Basu. 2009. Antioxidant potential of Minocycline in Japanese Encephalitis Virus infection in murine neuroblastoma cells: correlation with membrane fluidity and cell death. Neurochem Int 54:464-470.
81.Nagel, S., Y. Su, S. Horstmann, S. Heiland, H. Gardner, J. Koziol, F. J. Martinez-Torres, and S. Wagner. 2008. Minocycline and hypothermia for reperfusion injury after focal cerebral ischemia in the rat: effects on BBB breakdown and MMP expression in the acute and subacute phase. Brain Res 1188:198-206.
82.Nooteboom, A., C. J. Van Der Linden, and T. Hendriks. 2002. Tumor necrosis factor-alpha and interleukin-1beta mediate endothelial permeability induced by lipopolysaccharide-stimulated whole blood. Crit Care Med 30:2063-2068.
83.Novotny, N. M., T. A. Markel, P. R. Crisostomo, and D. R. Meldrum. 2008. Differential IL-6 and VEGF secretion in adult and neonatal mesenchymal stem cells: role of NFkB. Cytokine 43:215-219.
84.Oku, N., E. Sasabe, E. Ueta, T. Yamamoto, and T. Osaki. 2006. Tight junction protein claudin-1 enhances the invasive activity of oral squamous cell carcinoma cells by promoting cleavage of laminin-5 gamma2 chain via matrix metalloproteinase (MMP)-2 and membrane-type MMP-1. Cancer Res 66:5251-5257.
85.Palma-Nicolas, J. P., E. Lopez, and A. M. Lopez-Colome. 2010. Thrombin stimulates RPE cell motility by PKC-zeta- and NF-kappaB-dependent gene expression of MCP-1 and CINC-1/GRO chemokines. J Cell Biochem 110:948-967.
86.Papageorgiou, A., C. P. Dinney, and D. J. McConkey. 2007. Interferon-alpha induces TRAIL expression and cell death via an IRF-1-dependent mechanism in human bladder cancer cells. Cancer Biol Ther 6:872-879.
87.Park, J. E., G. A. Keller, and N. Ferrara. 1993. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell 4:1317-1326.
88.Patel, C. B., D. M. Cohen, P. Ahobila-Vajjula, L. M. Sundberg, T. Chacko, and P. A. Narayana. 2009. Effect of VEGF treatment on the blood-spinal cord barrier permeability in experimental spinal cord injury: dynamic contrast-enhanced magnetic resonance imaging. J Neurotrauma 26:1005-1016.
89.Perez-Alvarez, S., M. E. Solesio, J. Manzanares, J. Jordan, and M. F. Galindo. 2009. Lactacystin requires reactive oxygen species and Bax redistribution to induce mitochondria-mediated cell death. Br J Pharmacol 158:1121-1130.
90.Perriere, N., P. Demeuse, E. Garcia, A. Regina, M. Debray, J. P. Andreux, P. Couvreur, J. M. Scherrmann, J. Temsamani, P. O. Couraud, M. A. Deli, and F. Roux. 2005. Puromycin-based purification of rat brain capillary endothelial cell cultures. Effect on the expression of blood-brain barrier-specific properties. J Neurochem 93:279-289.
91.Pu, H., J. Tian, I. E. Andras, K. Hayashi, G. Flora, B. Hennig, and M. Toborek. 2005. HIV-1 Tat protein-induced alterations of ZO-1 expression are mediated by redox-regulated ERK 1/2 activation. J Cereb Blood Flow Metab 25:1325-1335.
92.Raung, S. L., S. Y. Chen, S. L. Liao, J. H. Chen, and C. J. Chen. 2007. Japanese encephalitis virus infection stimulates Src tyrosine kinase in neuron/glia. Neurosci Lett 419:263-268.
93.Rojas, A. 2011. Comment on "Endothelial ICAM-1 protein induction is regulated by cytosolic phospholipase A2alpha via both NF-kappaB and CREB transcription factors". J Immunol 187:2041; author reply 2041.
94.Rucker, H. K., H. J. Wynder, and W. E. Thomas. 2000. Cellular mechanisms of CNS pericytes. Brain Res Bull 51:363-369.
95.Sanceau, J., J. Hiscott, O. Delattre, and J. Wietzerbin. 2000. IFN-beta induces serine phosphorylation of Stat-1 in Ewing''s sarcoma cells and mediates apoptosis via induction of IRF-1 and activation of caspase-7. Oncogene 19:3372-3383.
96.Sattar, A. A., and R. Haque. 2007. Cytosolic PLA2 in zymogen granule fusion and amylase release: inhibition of GTP-induced fusion by arachidonyl trifluoromethyl ketone points to cPLA2 in G-protein-mediated secretory vesicle fusion. J Biochem 141:77-84.
97.Scheglovitova, O. N., Y. A. Romanov, E. V. Maksianina, N. V. Kabaeva, and A. G. Pronin. 2001. Herpes Simplex Type I Virus Infection of Cultured Human Vascular Endothelial Cells: Expression of Cell Adhesion Molecules and Induction of Interferon and Cytokine Production by Blood Mononuclear Cells. Russ J Immunol 6:367-376.
98.Schubert-Unkmeir, A., C. Konrad, H. Slanina, F. Czapek, S. Hebling, and M. Frosch. 2010. Neisseria meningitidis induces brain microvascular endothelial cell detachment from the matrix and cleavage of occludin: a role for MMP-8. PLoS Pathog 6:e1000874.
99.Seynhaeve, A. L., C. E. Vermeulen, A. M. Eggermont, and T. L. ten Hagen. 2006. Cytokines and vascular permeability: an in vitro study on human endothelial cells in relation to tumor necrosis factor-alpha-primed peripheral blood mononuclear cells. Cell Biochem Biophys 44:157-169.
100.Sgadari, C., G. Barillari, C. Palladino, S. Bellino, B. Taddeo, E. Toschi, and B. Ensoli. 2011. Fibroblast Growth Factor-2 and the HIV-1 Tat Protein Synergize in Promoting Bcl-2 Expression and Preventing Endothelial Cell Apoptosis: Implications for the Pathogenesis of AIDS-Associated Kaposi''s Sarcoma. International journal of vascular medicine 2011:452729.
101.Singh, A., R. Kulshreshtha, and A. Mathur. 2000. An enzyme immunoassay for detection of Japanese encephalitis virus-induced chemotactic cytokine. J Biosci 25:47-55.
102.So, E. Y., M. H. Kang, and B. S. Kim. 2006. Induction of chemokine and cytokine genes in astrocytes following infection with Theiler''s murine encephalomyelitis virus is mediated by the Toll-like receptor 3. Glia 53:858-867.
103.Sobue, K., N. Yamamoto, K. Yoneda, M. E. Hodgson, K. Yamashiro, N. Tsuruoka, T. Tsuda, H. Katsuya, Y. Miura, K. Asai, and T. Kato. 1999. Induction of blood-brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci Res 35:155-164.
104.Srivastava, S., N. Khanna, S. K. Saxena, A. Singh, A. Mathur, and T. N. Dhole. 1999. Degradation of Japanese encephalitis virus by neutrophils. Int J Exp Pathol 80:17-24.
105.Stipursky, J., L. Romao, V. Tortelli, V. M. Neto, and F. C. Gomes. 2011. Neuron-glia signaling: Implications for astrocyte differentiation and synapse formation. Life sciences 89:524-531.
106.Stirling, D. P., J. Liu, W. Plunet, J. D. Steeves, and W. Tetzlaff. 2008. SB203580, a p38 mitogen-activated protein kinase inhibitor, fails to improve functional outcome following a moderate spinal cord injury in rat. Neuroscience 155:128-137.
107.Stowell, N. C., J. Seideman, H. A. Raymond, K. A. Smalley, R. J. Lamb, D. D. Egenolf, P. J. Bugelski, L. A. Murray, P. A. Marsters, R. A. Bunting, R. A. Flavell, L. Alexopoulou, L. R. San Mateo, D. E. Griswold, R. T. Sarisky, M. L. Mbow, and A. M. Das. 2009. Long-term activation of TLR3 by poly(I:C) induces inflammation and impairs lung function in mice. Respir Res 10:43.
108.Su, H. L., C. L. Liao, and Y. L. Lin. 2002. Japanese encephalitis virus infection initiates endoplasmic reticulum stress and an unfolded protein response. Journal of virology 76:4162-4171.
109.Suri, N. K., and K. Banerjee. 1995. Growth and cytopathic effect of Japanese encephalitis virus in astrocyte-enriched cell cultures from neonatal mouse brains. Acta Virol 39:143-148.
110.Teruya, H., M. Tomita, M. Senba, C. Ishikawa, M. Tamayose, A. Miyazato, S. Yara, Y. Tanaka, Y. Iwakura, J. Fujita, and N. Mori. 2008. Human T-cell leukemia virus type I infects human lung epithelial cells and induces gene expression of cytokines, chemokines and cell adhesion molecules. Retrovirology 5:86.
111.Traweger, A., D. Fang, Y. C. Liu, W. Stelzhammer, I. A. Krizbai, F. Fresser, H. C. Bauer, and H. Bauer. 2002. The tight junction-specific protein occludin is a functional target of the E3 ubiquitin-protein ligase itch. J Biol Chem 277:10201-10208.
112.Tung, W. H., H. W. Tsai, I. T. Lee, H. L. Hsieh, W. J. Chen, Y. L. Chen, and C. M. Yang. 2010. Japanese encephalitis virus induces matrix metalloproteinase-9 in rat brain astrocytes via NF-kappaB signalling dependent on MAPKs and reactive oxygen species. Br J Pharmacol 161:1566-1583.
113.Vanden Bush, T. J., and G. A. Bishop. 2008. TLR7 and CD40 cooperate in IL-6 production via enhanced JNK and AP-1 activation. Eur J Immunol 38:400-409.
114.Vicente-Suarez, I., J. Brayer, A. Villagra, F. Cheng, and E. M. Sotomayor. 2009. TLR5 ligation by flagellin converts tolerogenic dendritic cells into activating antigen-presenting cells that preferentially induce T-helper 1 responses. Immunol Lett 125:114-118.
115.Wang, H., J. Sun, and H. Goldstein. 2008. Human immunodeficiency virus type 1 infection increases the in vivo capacity of peripheral monocytes to cross the blood-brain barrier into the brain and the in vivo sensitivity of the blood-brain barrier to disruption by lipopolysaccharide. Journal of virology 82:7591-7600.
116.Wang, J. J., C. L. Liao, Y. W. Chiou, C. T. Chiou, Y. L. Huang, and L. K. Chen. 1997. Ultrastructure and localization of E proteins in cultured neuron cells infected with Japanese encephalitis virus. Virology 238:30-39.
117.Wang, M., C. Atayar, S. Rosati, A. Bosga-Bouwer, P. Kluin, and L. Visser. 2009. JNK is constitutively active in mantle cell lymphoma: cell cycle deregulation and polyploidy by JNK inhibitor SP600125. J Pathol 218:95-103.
118.Wang, X. H., G. T. Yan, L. H. Wang, X. H. Hao, K. Zhang, and H. Xue. 2004. The mediating role of cPLA2 in IL-1 beta and IL-6 release in LPS-induced HeLa cells. Cell Biochem Funct 22:41-44.
119.Washburn, B., and V. Schirrmacher. 2002. Human tumor cell infection by Newcastle Disease Virus leads to upregulation of HLA and cell adhesion molecules and to induction of interferons, chemokines and finally apoptosis. Int J Oncol 21:85-93.
120.Wilhelm, I., C. Fazakas, and I. A. Krizbai. 2011. In vitro models of the blood-brain barrier. Acta neurobiologiae experimentalis 71:113-128.
121.Yamamoto, M., S. H. Ramirez, S. Sato, T. Kiyota, R. L. Cerny, K. Kaibuchi, Y. Persidsky, and T. Ikezu. 2008. Phosphorylation of claudin-5 and occludin by rho kinase in brain endothelial cells. Am J Pathol 172:521-533.
122.Yamazaki, Y., Y. Nakano, T. Imamura, and T. Morita. 2007. Augmentation of vascular permeability of VEGF is enhanced by KDR-binding proteins. Biochem Biophys Res Commun 355:693-699.
123.Yang, D. K., B. H. Kim, C. H. Kweon, J. H. Kwon, S. I. Lim, and H. R. Han. 2004. Biophysical characterization of Japanese encephalitis virus (KV1899) isolated from pigs in Korea. J Vet Sci 5:125-130.
124.Yang, D. K., B. H. Kim, C. H. Kweon, J. H. Kwon, S. I. Lim, and H. R. Han. 2004. Molecular characterization of full-length genome of Japanese encephalitis virus (KV1899) isolated from pigs in Korea. J Vet Sci 5:197-205.
125.Yang, H. W., X. D. Hu, H. M. Zhang, W. J. Xin, M. T. Li, T. Zhang, L. J. Zhou, and X. G. Liu. 2004. Roles of CaMKII, PKA, and PKC in the induction and maintenance of LTP of C-fiber-evoked field potentials in rat spinal dorsal horn. J Neurophysiol 91:1122-1133.
126.Yang, K. D., W. T. Yeh, R. F. Chen, H. L. Chuon, H. P. Tsai, C. W. Yao, and M. F. Shaio. 2004. A model to study neurotropism and persistency of Japanese encephalitis virus infection in human neuroblastoma cells and leukocytes. J Gen Virol 85:635-642.
127.Yang, Y., J. Ye, X. Yang, R. Jiang, H. Chen, and S. Cao. 2011. Japanese encephalitis virus infection induces changes of mRNA profile of mouse spleen and brain. Virol J 8:80.
128.Zhang, Q., R. Gong, J. Qu, Y. Zhou, W. Liu, M. Chen, Y. Liu, Y. Zhu, and J. Wu. 2012. Activation of the Ras/Raf/MEK pathway facilitates hepatitis C virus replication via attenuation of the interferon-JAK-STAT pathway. J Virol 86:1544-1554.
129.Zhang, Y., Q. Zhai, Y. Luo, and M. E. Dorf. 2002. RANTES-mediated chemokine transcription in astrocytes involves activation and translocation of p90 ribosomal S6 protein kinase (RSK). J Biol Chem 277:19042-19048.
130.Zhao, L. J., X. L. Zhang, P. Zhao, J. Cao, M. M. Cao, S. Y. Zhu, H. Q. Liu, and Z. T. Qi. 2006. Up-regulation of ERK and p38 MAPK signaling pathways by hepatitis C virus E2 envelope protein in human T lymphoma cell line. J Leukoc Biol 80:424-432.
131.Zhou, C., J. Li, H. Wang, and C. Tang. 2009. Decreased somatostatin is related to the hypersensitivity of intestinal epithelia to LPS via upregulated TLR4-TBK1 pathway in rats chronically exposed to ethanol. Alcohol 43:293-303.
132.Zibell, G., B. Unkruer, A. Pekcec, A. M. Hartz, B. Bauer, D. S. Miller, and H. Potschka. 2009. Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition. Neuropharmacology 56:849-855.
133.Zipris, D., E. Lien, J. X. Xie, D. L. Greiner, J. P. Mordes, and A. A. Rossini. 2005. TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats. J Immunol 174:131-142.
134.Zlokovic, B. V. 2008. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178-201.
135.Zozulya, A., C. Weidenfeller, and H. J. Galla. 2008. Pericyte-endothelial cell interaction increases MMP-9 secretion at the blood-brain barrier in vitro. Brain Res 1189:1-11.