Dengue virus-induced apoptosis in hepatic cells is partly mediated by Apo2 ligand/tumour necrosis factor-related apoptosis-inducing ligand.
Although hepatic injury is reported in cases with dengue haemorrhagic fever and dengue shock syndrome, its mechanism remains poorly understood. Several findings suggest that dengue virus (DEN) induces apoptosis of hepatocytes in vivo. In this work, DEN type 2 (DEN-2) strain NGC was shown to induce apoptosis in the hepatic cell line HepG2, and infection of HepG2 cells was found to induce Apo2 ligand (Apo2L, also known as tumour necrosis factor-related apoptosis-inducing ligand or TRAIL) expression. Furthermore, Apo2L/TRAIL induced apoptosis in HepG2 cells, which expressed the Apo2L/TRAIL receptor DR5/TRAIL-R2 on their surface. Analysis of the Apo2L/TRAIL promoter revealed that this gene was activated by DEN-2 infection, whose responsive element was overlapping NF-kappaB- and Sp1-binding sites located at nt -75 to -65. The proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal (LLnL) inhibited Apo2L/TRAIL mRNA expression, and LLnL and anti-Apo2L/TRAIL antibody inhibited DEN-2-induced apoptosis. It was proposed that DEN infection promotes apoptosis partly through the induction of Apo2L/TRAIL expression.
Matsuda
Takehiro
T
Division of Child Health and Welfare, Faculty of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan.|Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan.
Almasan
Alex
A
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Tomita
Mariko
M
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan.
Tamaki
Kazumi
K
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan.
Saito
Mika
M
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan.
Tadano
Masayuki
M
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan.
Yagita
Hideo
H
Department of Immunology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan.
Ohta
Takao
T
Division of Child Health and Welfare, Faculty of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan.
Mori
Naoki
N
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan.
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D003716:Dengue Virus / Q000472:pathogenicity*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology / Q000821:virology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha