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Journal of Virology, September 2000, p. 8680-8691, Vol. 74, No. 18
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-
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-
B Are Sequentially Involved
B and c-Jun, were found to
be activated after DEN-2 virus infection. However, pretreatment of
cells with oligodeoxynucleotides containing NF-
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-
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-
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-
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.
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