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Journal of Virology, September 2001, p. 7828-7839, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.7828-7839.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Salicylates Inhibit Flavivirus Replication Independently of Blocking Nuclear Factor Kappa B Activation

Ching-Len Liao,1,* Yi-Ling Lin,1,2 Bi-Ching Wu,1 Chang-Huei Tsao,3 Mei-Chuan Wang,1 Chiu-I Liu,4 Yue-Ling Huang,4 Jui-Hui Chen,1 Jia-Pey Wang,1 and Li-Kuang Chen5

Department of Microbiology and Immunology,1 Institute of Preventive Medicine,4 and Graduate Institute of Life Science,3 National Defense Medical Center, Institute of Biomedical Sciences, Academia Sinica,2 and Department of Immunology, Buddhist Tzu-Chi Medical College,5 Taiwan, Republic of China

Received 6 November 2000/Accepted 24 May 2001

Flaviviruses comprise a positive-sense RNA genome that replicates exclusively in the cytoplasm of infected cells. Whether flaviviruses require an activated nuclear factor(s) to complete their life cycle and trigger apoptosis in infected cells remains elusive. Flavivirus infections quickly activate nuclear factor kappa B (NF-kappa B), and salicylates have been shown to inhibit NF-kappa B activation. In this study, we investigated whether salicylates suppress flavivirus replication and virus-induced apoptosis in cultured cells. In a dose-dependent inhibition, we found salicylates within a range of 1 to 5 mM not only restricted flavivirus replication but also abrogated flavivirus-triggered apoptosis. However, flavivirus replication was not affected by a specific NF-kappa B peptide inhibitor, SN50, and a proteosome inhibitor, lactacystin. Flaviviruses also replicated and triggered apoptosis in cells stably expressing Ikappa Balpha -Delta N, a dominant-negative mutant that antagonizes NF-kappa B activation, as readily as in wild-type BHK-21 cells, suggesting that NF-kappa B activation is not essential for either flavivirus replication or flavivirus-induced apoptosis. Salicylates still diminished flavivirus replication and blocked apoptosis in the same Ikappa Balpha -Delta N cells. This inhibition of flaviviruses by salicylates could be partially reversed by a specific p38 mitogen-activated protein (MAP) kinase inhibitor, SB203580. Together, these results show that the mechanism by which salicylates suppress flavivirus infection may involve p38 MAP kinase activity but is independent of blocking the NF-kappa B pathway.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, National Defense Medical Center, P.O. Box 90048-505, 161 Minchuan East Rd., Sec. 6, Taipei 114, Taiwan, Republic of China. Phone: 886-2-8792-1615. Fax: 886-2-8792-4892. E-mail: chinglen{at}msl.hinet.net.

Journal of Virology, September 2001, p. 7828-7839, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.7828-7839.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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