TNF-α and IL-1β mediate Japanese encephalitis virus-induced RANTES gene expression in astrocytes
TNF-α and IL-1β mediate Japanese encephalitis virus-induced RANTES gene expression in astrocytes
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DOI：
10.1016/j.neuint.2010.12.009
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发表时间：
2011-02-01
影响因子：
4.2
通讯作者：
Chen, Shih-Yun
中科院分区：
文献类型：
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作者：
Chen, Chun-Jung;Ou, Yen-Chuan;Chen, Shih-Yun
日本脑炎病毒 (JEV) 感染会引起神经感染和神经炎症，其特征是严重的神经元破坏/功能障碍、伴随的小胶质细胞增生/星形胶质细胞增生，以及产生各种分子，启动免疫细胞向感染部位的募集。此前，我们报道了神经胶质细胞表达RANTES（激活后调节，正常T细胞表达和分泌），并具有响应乙脑病毒感染的趋化活性。在这项研究中，我们进一步证明了感染 JEV 的小胶质细胞在调节 RANTES 产生方面具有额外的活性。星形胶质细胞和小胶质细胞都通过可能与病毒复制相关的过程释放 RANTES 来应对 JEV 感染。独立于传染性病毒，JEV感染的小胶质细胞的上清液，而不是JEV感染的星形胶质细胞，导致星形胶质细胞产生额外的RANTES。抗体中和研究表明肿瘤坏死因子-α (TNF-α) 和白介素-1 β (IL-1 β) 可能参与介导额外的 RANTES 产生。用 TNF-α 和 IL-1β 处理星形胶质细胞培养物会激活对 RANTES 基因表达至关重要的几种信号分子和转录因子，包括活性氧、细胞外信号调节激酶、NF-κ B 和 NF-1L6，增加 RANTES 基因启动子活性，并引发 RANTES 产生。与 RANTES 一样，在 JEV 感染过程中，生物活性 TNF-α 和 IL-1β 的中和导致含有星形胶质细胞和小胶质细胞的混合胶质细胞上清液的趋化活性减弱。总之，JEV感染的小胶质细胞产生的TNF-α和IL-1β可能触发另一种机制，通过激活星形胶质细胞诱导RANTES基因表达的二次波。神经胶质细胞释放的 RANTES 可能在 JEV 感染期间招募免疫细胞中发挥作用。 (C) 2010 Elsevier Ltd. 保留所有权利。
Infection with Japanese encephalitis virus (JEV) causes neuroinfection and neuroinflammation characterized by profound neuronal destruction/dysfunction, concomitant microgliosis/astrogliosis, and production of various molecules that initiate the recruitment of immune cells to the sites of infection. Previously, we reported that glial cells expressed RANTES (regulated upon activation, normal T cell expressed and secreted) with chemotactic activity in response to JEV infection. In this study, we further demonstrated that JEV-infected microglia had an additional activity in regulating RANTES production. Both astrocytes and microglia responded to JEV infection by releasing RANTES through a process likely related to viral replication. Independent of infectious virus, supernatants of JEV-infected microglia, but not JEV-infected astrocytes, caused additional RANTES production from astrocytes. Antibody neutralization studies suggested the potential involvement of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in mediating additional RANTES production. Treatment of astrocyte cultures with TNF-alpha and IL-1 beta caused activation of several signaling molecules and transcription factors crucial to RANTES gene expression, including reactive oxygen species, extracellular signal-regulated kinase, NF-kappa B, and NF-1L6, increased RANTES gene promoter activity, and provoked RANTES production. As with RANTES, neutralization of bioactive TNF-alpha and IL-1 beta caused an attenuation of chemotactic activity from supernatants of mixed glia containing astrocytes and microglia during the course of JEV infection. In conclusion, TNF-alpha and IL-1 beta produced by JEV-infected microglia might trigger another mechanism which induces a secondary wave of RANTES gene expression by activating astrocytes. The released RANTES from glial cells might play a role in the recruitment of immune cells during JEV infection. (C) 2010 Elsevier Ltd. All rights reserved.