1 Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan
2 Division of Child Health and Welfare, Faculty of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan
3 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
4 Department of Immunology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan
Correspondence
Naoki Mori
n-mori{at}med.u-ryukyu.ac.jp
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ABSTRACT |
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INTRODUCTION |
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Although the pathogenesis of DEN-related disease remains poorly understood, virus-induced cell death may be a crucial pathogenic event. Apoptotic cell death has been implicated as a cytopathological mechanism in response to DEN infection both in vitro and in vivo (Despres et al., 1996, 1998
). During the last stage of apoptosis, cells break up into apoptotic bodies, which are then eliminated by phagocytosis. It has been suggested that apoptosis is an innate defence mechanism, which allows the organism to control virus infection by elimination of infected cells (Despres et al., 1996
); however, several viruses have been shown to induce apoptosis, which can be detrimental to the host (Koga et al., 1994
; Lewis et al., 1996
; Shen & Shenk, 1995
). These observations suggest that virus-induced apoptosis may contribute, at least in part, to the pathogenesis of DEN-induced hepatic injury.
Cellular death receptors transmit apoptosis-inducing signals initiated by specific death ligands, most of which are primarily expressed as biologically active type II membrane proteins that are cleaved into soluble forms. Fas ligand (FasL) activates Fas, tumour necrosis factor (TNF) activates TNF receptor 1 (TNF-R1) and Apo2 ligand (Apo2L, also known as TNF-related apoptosis-inducing ligand or TRAIL) activates DR4 (TRAIL-R1) (Pan et al., 1997b) and DR5 (TRAIL-R2) (Walczak et al., 1997
). Ligand-mediated activation triggers a cascade of events that begins with death-receptor oligomerization and the close association of their cytoplasmic death domains. This is followed by death domain-associated interaction with adaptor molecules and cellular proteases critical to death receptor-induced apoptosis (Almasan & Ashkenazi, 2003
). Ligands of the TNF family and their cognate receptors play a key role in liver pathogenesis (Faubion & Gores, 1999
). In this paper, we describe a novel mechanism for DEN-induced hepatic cell death involving the induction of Apo2L/TRAIL expression and subsequent Apo2L/TRAIL-mediated apoptosis.
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METHODS |
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Virus infection.
Monolayers of HepG2 cells were trypsinized and resuspended in growth medium. Cells were seeded at a density of 1x105 cells ml1 into each plate. After overnight incubation, virus culture fluid or heat-inactivated virus suspension (56 °C, 30 min) was added to monolayers of cells at 37 °C for 2 h. Virus supernatants were then removed and fresh growth medium was added to each plate for further incubation.
Detection of DEN-2 antigen.
A mouse mAb (3H5) that reacts with the DEN-2 envelope protein was used to detect DEN viral antigen. Immunostaining was performed as described previously (Tadano et al., 1989).
Viability and apoptosis assays.
The viability of mock- and DEN-2-infected HepG2 cells in culture plates was examined using the cell proliferation reagent WST-8, a tetrazolium salt (Wako Chemicals). WST-8 (10 µl) was added for the last 4 h of incubation and absorbance at 450 nm was measured using an automated microplate reader. Measuring the mitochondrial dehydrogenase-mediated cleavage of WST-8 to formazan dye indicates the level of proliferation. The early apoptotic event in cells was examined by staining with phycoerythrin-conjugated Apo2.7 mAb (Beckman Coulter) and analysed by flow cytometry (FACSCaliber; Becton Dickinson). The 7A6 antigen, defined by this antibody, is a 38 kDa protein localized to the outer membrane of mitochondria and is involved in the molecular cascade of apoptosis (Seth et al., 1997; Zhang et al., 1996
). Expression of 7A6 antigen is preferentially detected on apoptotic cells, but not on the surface of non-apoptotic cells.
Western blot analysis.
Twenty-four and 48 h after infection with DEN-2, cells were lysed in buffer containing 62·5 mM Tris/HCl (pH 6·8), 2 % SDS, 10 % glycerol, 6 % 2-mercaptoethanol and 0·01 % bromophenol blue. Samples were cleared by microcentrifugation and assessed for protein concentration. Twenty micrograms of protein per sample was analysed by SDS-PAGE and electroblotted on to PVDF membranes (Millipore). After blocking with 5 % non-fat dried milk, membranes were exposed overnight at 4 °C to the primary antibody. After washing in TBST buffer (0·1 % Tween 20 in Tris-buffered saline), a mouse secondary horseradish peroxidase-conjugated antibody (Amersham Biosciences) was applied for 1 h at room temperature. Proteins were visualized with the enhanced chemiluminescence kit (Amersham Biosciences). mAb against actin (ACTN05; NeoMarkers) was used as a protein loading control.
RT-PCR.
Total cellular RNA was extracted with Trizol (Invitrogen) according to the protocol provided by the manufacturer and the amount of total RNA was determined by measuring absorbance at 260 nm. First-strand cDNA was synthesized from 1 µg total cellular RNA in a 20 µl reaction volume using an RNA PCR kit (Takara Shuzo) with random primers. Thereafter, cDNA was amplified for 30 cycles for Apo2L/TRAIL, 35 cycles for TNF- and FasL and 28 cycles for
-actin. The oligonucleotide primers used were as follows: for Apo2L/TRAIL, sense, 5'-CAATGACGAAGAGAGTATGA-3', and antisense, 5'-CCCCCTTGATAGATGGAATA-3' (Satoh et al., 2001
); for TNF-
, sense, 5'-ATGAGCACTGAAAGCATGATC-3', and antisense, 5'-TCACAGGGCAATGATCCCAAAGTAGACCTGCCC-3'; for FasL, sense, 5'-GGATTGGGCCTGGGGATGTTTCA-3', and antisense, 5'-TGTGGCTCAGGGGCAGGTTGTTG-3' (Chen et al., 1997
); and for
-actin, sense, 5'-GTGGGGCGCCCCAGGCACCA-3', and antisense, 5'-CTCCTTAATGTCACGCACGATTTC-3'. Product sizes were 536 bp for Apo2L/TRAIL, 702 bp for TNF-
, 343 bp for FasL and 548 bp for
-actin. Cycling conditions were as follows: denaturation at 94 °C for 30 s (TNF-
, FasL and
-actin) or for 40 s (Apo2L/TRAIL), annealing at 57 °C for 60 s (Apo2L/TRAIL) or 60 °C for 30 s (TNF-
, FasL and
-actin) and extension at 72 °C for 60 s (Apo2L/TRAIL) or for 90 s (TNF-
, FasL and
-actin). PCR products were fractionated on 2 % agarose gels and visualized by ethidium bromide staining.
Cell-surface expression of Apo2L/TRAIL receptors.
Cells were analysed for the surface expression of DR4 (TRAIL-R1), DR5 (TRAIL-R2), DcR1 (TRAIL-R3) and DcR2 (TRAIL-R4) by indirect staining with primary mouse anti-human DR4, DR5, DcR1 and DcR2 mAbs. Briefly, 106 cells were incubated with 1 µg biotinylated control mouse IgG1 or mAbs specific for DR4 (DJR1), DR5 (DJR2), DcR1 (DJR3) or DcR2 (DJR4) for 30 min. After washing, cells were incubated with phycoerythrin-conjugated streptavidin (Beckman Coulter) for 30 min on ice and analysed by flow cytometry. For surface staining of Apo2L/TRAIL receptors, cells were detached by incubation with PBS, followed by brief trypsinization. Trypsinization did not affect the Apo2L/TRAIL receptors.
Plasmids and transfections.
A series of Apo2L/TRAIL promoter pGL3-luciferase reporter constructs described previously (Gong & Almasan, 2000) was used to map the DEN-2-responsive regions. An internal deletion of the NF-
B site (ApoP/1056
B) was also created. Transient transfection of HepG2 cells was achieved with Lipofectamine (Invitrogen) according to the manufacturer's protocol. Approximately 3x105 cells were seeded per plate and transfected 16 h later with 0·1 µg of appropriate reporter plasmids. To normalize transfection efficiencies, a thymidine kinase promoter-driven Renilla luciferase plasmid (phRL-TK, 0·5 µg; Promega) was co-transfected as an internal control plasmid. Cells were washed 1624 h later and infected with virus at an m.o.i. of 8 as described above. After incubation for 24 h, cells were washed in PBS and lysed in reporter lysis buffer (Promega). Cell extracts were prepared by freezing and thawing the cells once. Unbroken cells and debris were pelleted by centrifugation at 20 000 g for 15 min at 4 °C. Lysates were assayed for reporter gene activity with the Dual Luciferase Reporter Assay system (Promega). Luciferase activities were normalized based on the Renilla luciferase activity from phRL-TK.
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RESULTS |
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Expression of Apo2L/TRAIL and TNF- is induced in DEN-2-infected cells
We next investigated the expression of TNF family members in HepG2 cells after DEN-2 infection. HepG2 cells infected with DEN-2 were harvested at 2, 4, 8, 12 and 24 h p.i. and total RNA was extracted. mRNA expression levels of the TNF family members were examined by RT-PCR. As shown in Fig. 2(a), Apo2L/TRAIL and TNF-
mRNA was upregulated following DEN-2 infection. Supernatant from uninfected C6/36 cells and heat-inactivated DEN-2 did not upregulate Apo2L/TRAIL or TNF-
mRNA expression in HepG2 cells (Fig. 2b
). In contrast, FasL mRNA was not expressed in uninfected HepG2 cells and not induced by DEN-2 infection. Apo2L/TRAIL protein expression was also studied by Western blotting. As shown in Fig. 2(c)
, Apo2L/TRAIL protein expression was also upregulated by DEN-2 infection.
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Transcriptional control of Apo2L/TRAIL in HepG2 cells
We investigated whether the DEN-2-induced increase in Apo2L/TRAIL gene expression was a result of enhancement of its promoter activity. HepG2 cells were transiently transfected with a reporter gene construct containing the 1056 nt of the Apo2L/TRAIL upstream regulatory sequences (ApoP/1056). Mock-infection with C6/36 supernatant was used as a control. DEN-2 infection caused an elevation in the activity of this Apo2L/TRAIL-driven reporter construct, suggesting that the virus activated the Apo2L/TRAIL gene at the transcriptional level (Fig. 6). The transcription factor NF-
B has been found to be activated after DEN infection (Avirutnan et al., 1998
; Bosch et al., 2002
; Jan et al., 2000
; Marianneau et al., 1997
). Previous experiments have revealed that two potential NF-
B-binding sites,
B1 (located between nt 264 and 255) and
B2 (located between nt 384 and 375), contained within the Apo2L/TRAIL promoter, are important in upregulation following T-cell activation (Baetu et al., 2001
). To assess the importance of the NF-
B-binding sites within the Apo2L/TRAIL promoter, luciferase constructs containing sequential deletions of the Apo2L/TRAIL promoter were transfected into HepG2 cells. As shown in Fig. 6
, deletion of sequences down to nt 126 did not diminish promoter activation, while further deletion to nt 33 significantly decreased activation in response to DEN-2. These data suggested that the Apo2L/TRAIL promoter region between nt 126 and 33 is required for DEN-2-induced Apo2L/TRAIL activation. Since the 126/33 region did not contain the previously characterized NF-
B-binding sites
B1 and
B2, the DNA sequence of this region was analysed. Sequence analysis revealed the presence of overlapping NF-
B- and Sp1-binding sites in the sequence between nt 75 and 65 in the Apo2L/TRAIL promoter (Fig. 7a
). To test the role of this site in DEN-2-mediated induction of Apo2L/TRAIL gene transactivation, we generated a 1056/+86 Apo2L/TRAIL promoter/reporter construct bearing an internal deletion of this site (ApoP/1056
B). The effect of DEN-2 on activation of wild-type and
B Apo2L/TRAIL promoter was analysed in HepG2 cells infected with DEN-2. Consistent with previous findings, our experiments showed that DEN-2 infection resulted in an increase in Apo2L/TRAIL promoter activation (Fig. 7b
). However, deletion of the 74/65 region resulted in abrogation of promoter activation, confirming the importance of this site in Apo2L/TRAIL gene expression. These observations indicated that the 74/65 region is involved in DEN-2-mediated activation of Apo2L/TRAIL.
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DISCUSSION |
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We determined that DEN-2 infection induced the synthesis of functional Apo2L/TRAIL in HepG2 cells. Exogenous Apo2L/TRAIL induced apoptosis in HepG2 cells, which expressed cell-surface DR5. Furthermore, we showed that Apo2L/TRAIL contributed to DEN-2-induced apoptosis. In comparison with the cell death induced by Apo2L/TRAIL, more apoptotic cells were observed in DEN-2-infected cells. Thus, DEN-2 infection might sensitize cells to Apo2L/TRAIL-induced apoptosis. As previously reported by Shigeno et al. (2003), Apo2L/TRAIL reduced cell viability of the human hepatoma cell line HepG2 to 60 % in their study. Apo2L/TRAIL preparations similar to that used in this study are also reported to induce increased apoptosis in normal human hepatocytes (Jo et al., 2000
). Therefore, our in vitro studies suggest that Apo2L/TRAIL release occurs during DEN infection and may be essential for the induction of apoptosis in human hepatic cells in vivo.
Although Apo2L/TRAIL mRNA expression is detected in various cells and tissues (Pitti et al., 1996; Wiley et al., 1995
), regulation of its expression remains largely unknown. Apo2L/TRAIL promoter studies have indicated induction of promoter activity after interferon stimulation (Chen et al., 2001
). Two important sites for Apo2L/TRAIL promoter regulation are reported to lie between nt 1371 and 819 and between nt 165 and 35 (Gong & Almasan, 2000
; Wang et al., 2000
). A recent study demonstrated that the induced expression of Apo2L/TRAIL in Jurkat cells following treatment with a variety of stimuli such as phorbol myristate acetate is linked to two NF-
B binding sites,
B1 (located between nt 264 and 255) and
B2 (located between nt 384 and 375), within the Apo2L/TRAIL promoter (Baetu et al., 2001
). We demonstrated that the induction of transcription of Apo2L/TRAIL was triggered by viral infection. Using a reporter gene to assess transcription from the Apo2L/TRAIL promoter, we found for the first time that overlapping NF-
B- and Sp1-binding sites (located between nt 75 and 65) contribute to the control of luciferase reporter gene activity.
NF-B has been widely proposed to be involved in either protecting or promoting cell death in response to different stimuli in various cell types (Baeuerle & Baltimore, 1996
; Grimm et al., 1996
; Lin et al., 1995
). The involvement of NF-
B in DEN-induced apoptosis was first reported by Marianneau et al. (1997)
. In their studies, NF-
B activation was detected in HepG2 cells during DEN infection. Inhibition of apoptosis was observed when DEN-infected cells were treated with NF-
B decoys. More recently, Jan et al. (2000)
reported that DEN infection caused NF-
B activation in a human neuroblastoma cell line. They also reported that pretreatment of cells with NF-
B decoys prevented DEN-induced apoptosis. The requirement for NF-
B activation in DEN-induced apoptosis suggests that NF-
B functions to increase the expression of pro-apoptotic genes. However, NF-
B-responsive pro-apoptotic proteins involved in mediating apoptosis induced by DEN have not been conclusively determined. Although FasL is regulated by NF-
B and contains NF-
B response elements in its promoter (Takahashi et al., 1994
), DEN-2 infection failed to induce the expression of FasL. To demonstrate the role of NF-
B in DEN-2-induced apoptosis, the proteasome inhibitor LLnL was used to block cell death. Despite some degree of toxicity being observed in mock-infected cells at the concentration used, LLnL significantly stimulated HepG2 proliferation in the DEN-2-infected cell population. Although the reason for this is currently unclear, any proteasome-dependent activity may be involved. Our present study is the first to demonstrate the involvement of a signalling pathway consisting of sequential activation of NF-
B and Sp1 that controls induction of Apo2L/TRAIL expression during DEN-2-induced apoptosis of human hepatic cells.
The involvement of Apo2L/TRAIL in apoptosis has been implicated in previous studies involving infection with various viruses, including human immunodeficiency virus (Katsikis et al., 1997), reovirus (Clarke et al., 2000
), measles virus (Vidalain et al., 2000
), cytomegalovirus (Sedger et al., 1999
), Theiler's murine encephalomyelitis virus (Rubio et al., 2003
), respiratory syncytial virus (Kotelkin et al., 2003
), Newcastle disease virus (Washburn et al., 2003
) and Ebola virus (Hensley et al., 2002
). Apo2L/TRAIL also plays a key role in viral hepatitis (Mundt et al., 2003
). It has been reported that reovirus-induced apoptosis requires NF-
B (Connolly et al., 2000
). Similar to DEN-2-induced apoptosis pathways, apoptosis induced by these viruses may require the participation of Apo2L/TRAIL promoter activation regulated by NF-
B. Understanding the signalling pathways used by DEN to induce cellular gene expression and apoptosis will contribute important new information about the mechanisms by which viruses induce cell death and disease.
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ACKNOWLEDGEMENTS |
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Received 17 August 2004;
accepted 7 January 2005.
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