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Journal of Virology, December 2009, p. 12204-12214, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01103-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Regulation of Proinflammatory Cytokine Expression in Primary Mouse Astrocytes by Coronavirus Infection{triangledown}

Dongdong Yu, Hongqing Zhu, Yin Liu, Jianzhong Cao, and Xuming Zhang*

Departments of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199

Received 29 May 2009/ Accepted 14 September 2009

Previous studies have shown that proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-{alpha}) and interleukin 6 (IL-6), are differentially induced in primary mouse astrocytes by mouse hepatitis virus strain A59 (MHV-A59) and MHV-2. However, the signaling events that trigger TNF-{alpha} and IL-6 induction in these cells upon MHV infection remain unknown. In this study, we explored the potential signaling events. We found that induction of TNF-{alpha} and IL-6 occurred as early as 2 h postinfection and was completely dependent on viral replication. Using inhibitors specific for three mitogen-activated protein kinases, we showed that induction of TNF-{alpha} and IL-6 by MHV-A59 infection was mediated through activation of the Janus N-terminal kinase signaling pathway, but not through the extracellular signal-regulated kinase or p38 signaling pathway. This finding was further confirmed with knockdown experiments using small interfering RNAs specific for Janus N-terminal kinase. Interestingly, while nuclear factor {kappa}B (NF-{kappa}B), a key transcription factor required for the expression of proinflammatory cytokines in most cell types, was activated in astrocytes during MHV-A59 infection, disruption of the NF-{kappa}B pathway by peptide inhibitors did not significantly inhibit TNF-{alpha} and IL-6 expression. Furthermore, experiments using chimeric viruses demonstrated that the viral spike and nucleocapsid proteins, which play important roles in MHV pathogenicity in mice, are not responsible for the differential induction of the cytokines. These results illustrate the complexity of the regulatory mechanism by which MHV induces proinflammatory cytokines in primary astrocytes.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Slot 511, Little Rock, AR 72205. Phone: (501) 686-7415. Fax: (501) 686-5359. E-mail: zhangxuming{at}uams.edu

{triangledown} Published ahead of print on 23 September 2009.

Journal of Virology, December 2009, p. 12204-12214, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01103-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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