title: TNF-α and IL-1β mediate Japanese encephalitis virus-induced RANTES gene expression in astrocytes.
abstract: 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-α) and interleukin-1 beta (IL-1β) in mediating additional RANTES production. Treatment of astrocyte cultures with TNF-α and IL-1β caused activation of several signaling molecules and transcription factors crucial to RANTES gene expression, including reactive oxygen species, extracellular signal-regulated kinase, NF-κB, and NF-IL6, increased RANTES gene promoter activity, and provoked RANTES production. As with RANTES, neutralization of bioactive TNF-α and IL-1β caused an attenuation of chemotactic activity from supernatants of mixed glia containing astrocytes and microglia during the course of JEV infection. In conclusion, TNF-α and IL-1β 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.
authors.affiliation: Department of Education and Research, Taichung Veterans General Hospital, Taichung 407, Taiwan. cjchen@vghtc.gov.tw
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Chen
authors.forename: Yen-Chuan
authors.initials: YC
authors.lastname: Ou
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Chang
authors.forename: Hung-Chuan
authors.initials: HC
authors.lastname: Pan
authors.forename: Su-Lan
authors.initials: SL
authors.lastname: Liao
authors.forename: Shue-Ling
authors.initials: SL
authors.lastname: Raung
authors.forename: Shih-Yun
authors.initials: SY
authors.lastname: Chen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics*; D018920:Coculture Techniques; D004664:Encephalitis Virus, Japanese / Q000502:physiology*; D004672:Encephalitis, Japanese / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism / Q000502:physiology*; D017628:Microglia / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
chemical_list: D018946:Chemokine CCL5; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha