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Journal of Virology, September 2000, p. 8680-8691, Vol. 74, No. 18
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Potential Dengue Virus-Triggered Apoptotic Pathway in Human Neuroblastoma Cells: Arachidonic Acid, Superoxide Anion, and NF-kappa B Are Sequentially Involved

Jia-Tsrong Jan,1,2 Bor-Horng Chen,3 Shiou-Hwa Ma,1 Chiu-I Liu,1 Hui-Ping Tsai,1 Han-Chung Wu,1 Shian-Yuan Jiang,1,2 Kuen-Der Yang,4 and Men-Fang Shaio1,3,*

Institute of Preventive Medicine,1 Department of Microbiology and Immunology,2 and Department of Tropical Medicine and Parasitology,3 National Defense Medical Center, Taipei, and Chang Gung Children's Hospital, Chang Gung University, Kaohsiung,4 Taiwan, Republic of China

Received 4 February 2000/Accepted 20 June 2000

Direct in vivo evidence for the susceptibility of human neuronal cells to dengue virus has not been reported. In this study, we demonstrated that type 2 dengue (DEN-2) virus infection induced extensive apoptosis in the human neuroblastoma cell line SK-N-SH. Phospholipase A2 (PLA2) was activated by DEN-2 infection, which led to the generation of arachidonic acid (AA). Inhibition of PLA2 activity by the PLA2 inhibitors, AACOCF3 and ONO-RS-082, diminished DEN-2 virus-induced apoptosis. In contrast, the cyclooxygenase inhibitors aspirin and indomethacin, thought to increase AA accumulation by blocking AA catabolism, enhanced apoptosis. Exogenous AA induced apoptosis in a dose-dependent manner. Superoxide anion, which is thought to be generated through the AA-activated NADPH oxidase, was increased after infection. Pretreatment with superoxide dismutase (SOD) protected cells against DEN-2 virus-induced apoptosis. Furthermore, generation of superoxide anion was blocked by AACOCF3. In addition, the transcription factors, NF-kappa B and c-Jun, were found to be activated after DEN-2 virus infection. However, pretreatment of cells with oligodeoxynucleotides containing NF-kappa B, but not c-Jun, binding sites (transcription factor decoy) strongly prevented dengue virus-induced apoptosis. The finding that AACOCF3 and SOD significantly block activation of NF-kappa B suggests that this activation is derived from the AA-superoxide anion pathway. Our results indicate that DEN-2 virus infection of human neuroblastoma cells triggers an apoptotic pathway through PLA2 activation to superoxide anion generation and subsequently to NF-kappa B activation. This apoptotic effect can be either directly derived from the action of AA and superoxide anion on mitochondria or indirectly derived from the products of apoptosis-related genes activated by NF-kappa B.

* Corresponding author. Mailing address: Institute of Preventive Medicine, National Defense Medical Center, P.O. Box 90048-700, Taipei, Taiwan, Republic of China. Phone: (886)-2-2671-1001. Fax: (886)-2-2673-1154. E-mail: p1000141{at}tpts4.seed.net.tw.

Journal of Virology, September 2000, p. 8680-8691, Vol. 74, No. 18
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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