Abstract
The severe outcome of the dengue (DEN) virus infection known as DEN hemorrhagic fever-DEN shock syndrome (DHF-DSS) is, in some cases, accompanied by liver injury. Councilman bodies observed in liver biopsies of DHF-DSS cases may correspond to hepatocytes in apoptosis. We show here that infection of the hepatoma cell line HepG2 with DEN type 1 virus induced cell death typical of apoptosis late in the virus cycle. The transcription factor NF-kappaB was activated concomitantly with viral protein synthesis and thus before the appearance of apoptotic cells. Inhibition of apoptosis was observed when DEN virus-infected cells were treated with NF-kappaB decoys, indicating the involvement of this transcription factor in induction of cell death. Thus, infected hepatocytes appear to be subject to apoptosis in vitro, and this may be a key element in the pathophysiology of hepatic failure associated with DHF-DSS.
Full Text
The Full Text of this article is available as a PDF (2.0 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Anderson R., King A. D., Innis B. L. Correlation of E protein binding with cell susceptibility to dengue 4 virus infection. J Gen Virol. 1992 Aug;73(Pt 8):2155–2159. doi: 10.1099/0022-1317-73-8-2155. [DOI] [PubMed] [Google Scholar]
- Baeuerle P. A., Baltimore D. NF-kappa B: ten years after. Cell. 1996 Oct 4;87(1):13–20. doi: 10.1016/s0092-8674(00)81318-5. [DOI] [PubMed] [Google Scholar]
- Briehl M. M., Baker A. F. Modulation of the antioxidant defence as a factor in apoptosis. Cell Death Differ. 1996 Jan;3(1):63–70. [PubMed] [Google Scholar]
- Burke T. Dengue haemorrhagic fever: a pathological study. Trans R Soc Trop Med Hyg. 1968;62(5):682–692. doi: 10.1016/0035-9203(68)90120-x. [DOI] [PubMed] [Google Scholar]
- Charpak G., Dominik W., Zaganidis N. Optical imaging of the spatial distribution of beta-particles emerging from surfaces. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1741–1745. doi: 10.1073/pnas.86.6.1741. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cherrington J. M., Mocarski E. S. Human cytomegalovirus ie1 transactivates the alpha promoter-enhancer via an 18-base-pair repeat element. J Virol. 1989 Mar;63(3):1435–1440. doi: 10.1128/jvi.63.3.1435-1440.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chirillo P., Falco M., Puri P. L., Artini M., Balsano C., Levrero M., Natoli G. Hepatitis B virus pX activates NF-kappa B-dependent transcription through a Raf-independent pathway. J Virol. 1996 Jan;70(1):641–646. doi: 10.1128/jvi.70.1.641-646.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Conant K., Ma M., Nath A., Major E. O. Extracellular human immunodeficiency virus type 1 Tat protein is associated with an increase in both NF-kappa B binding and protein kinase C activity in primary human astrocytes. J Virol. 1996 Mar;70(3):1384–1389. doi: 10.1128/jvi.70.3.1384-1389.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Desprès P., Flamand M., Ceccaldi P. E., Deubel V. Human isolates of dengue type 1 virus induce apoptosis in mouse neuroblastoma cells. J Virol. 1996 Jun;70(6):4090–4096. doi: 10.1128/jvi.70.6.4090-4096.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Edelman R., Nimmannitya S., Colman R. W., Talamo R. C., Top F. H., Jr Evaluation of the plasma kinin system in dengue hemorrhagic fever. J Lab Clin Med. 1975 Sep;86(3):410–421. [PubMed] [Google Scholar]
- Esolen L. M., Park S. W., Hardwick J. M., Griffin D. E. Apoptosis as a cause of death in measles virus-infected cells. J Virol. 1995 Jun;69(6):3955–3958. doi: 10.1128/jvi.69.6.3955-3958.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Faucheu C., Diu A., Chan A. W., Blanchet A. M., Miossec C., Hervé F., Collard-Dutilleul V., Gu Y., Aldape R. A., Lippke J. A. A novel human protease similar to the interleukin-1 beta converting enzyme induces apoptosis in transfected cells. EMBO J. 1995 May 1;14(9):1914–1922. doi: 10.1002/j.1460-2075.1995.tb07183.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Folgueira L., Algeciras A., MacMorran W. S., Bren G. D., Paya C. V. The Ras-Raf pathway is activated in human immunodeficiency virus-infected monocytes and particpates in the activation of NF-kappa B. J Virol. 1996 Apr;70(4):2332–2338. doi: 10.1128/jvi.70.4.2332-2338.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Folgueira L., McElhinny J. A., Bren G. D., MacMorran W. S., Diaz-Meco M. T., Moscat J., Paya C. V. Protein kinase C-zeta mediates NF-kappa B activation in human immunodeficiency virus-infected monocytes. J Virol. 1996 Jan;70(1):223–231. doi: 10.1128/jvi.70.1.223-231.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Freedman A. R., Sharma R. J., Nabel G. J., Emerson S. G., Griffin G. E. Cellular distribution of nuclear factor kappa B binding activity in rat liver. Biochem J. 1992 Oct 15;287(Pt 2):645–649. doi: 10.1042/bj2870645. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Galle P. R., Hofmann W. J., Walczak H., Schaller H., Otto G., Stremmel W., Krammer P. H., Runkel L. Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med. 1995 Nov 1;182(5):1223–1230. doi: 10.1084/jem.182.5.1223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goldring C. E., Narayanan R., Lagadec P., Jeannin J. F. Transcriptional inhibition of the inducible nitric oxide synthase gene by competitive binding of NF-kappa B/Rel proteins. Biochem Biophys Res Commun. 1995 Apr 6;209(1):73–79. doi: 10.1006/bbrc.1995.1472. [DOI] [PubMed] [Google Scholar]
- Grimm S., Bauer M. K., Baeuerle P. A., Schulze-Osthoff K. Bcl-2 down-regulates the activity of transcription factor NF-kappaB induced upon apoptosis. J Cell Biol. 1996 Jul;134(1):13–23. doi: 10.1083/jcb.134.1.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hale A. J., Smith C. A., Sutherland L. C., Stoneman V. E., Longthorne V. L., Culhane A. C., Williams G. T. Apoptosis: molecular regulation of cell death. Eur J Biochem. 1996 Feb 15;236(1):1–26. doi: 10.1111/j.1432-1033.1996.00001.x. [DOI] [PubMed] [Google Scholar]
- Hall W. C., Crowell T. P., Watts D. M., Barros V. L., Kruger H., Pinheiro F., Peters C. J. Demonstration of yellow fever and dengue antigens in formalin-fixed paraffin-embedded human liver by immunohistochemical analysis. Am J Trop Med Hyg. 1991 Oct;45(4):408–417. doi: 10.4269/ajtmh.1991.45.408. [DOI] [PubMed] [Google Scholar]
- Halstead S. B. Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade. Rev Infect Dis. 1989 May-Jun;11 (Suppl 4):S830–S839. doi: 10.1093/clinids/11.supplement_4.s830. [DOI] [PubMed] [Google Scholar]
- Herrero J. A., Mathew P., Paya C. V. LMP-1 activates NF-kappa B by targeting the inhibitory molecule I kappa B alpha. J Virol. 1995 Apr;69(4):2168–2174. doi: 10.1128/jvi.69.4.2168-2174.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hiscott J., Petropoulos L., Lacoste J. Molecular interactions between HTLV-1 Tax protein and the NF-kappa B/kappa B transcription complex. Virology. 1995 Dec 1;214(1):3–11. doi: 10.1006/viro.1995.9960. [DOI] [PubMed] [Google Scholar]
- Hockenbery D. M., Oltvai Z. N., Yin X. M., Milliman C. L., Korsmeyer S. J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. doi: 10.1016/0092-8674(93)80066-n. [DOI] [PubMed] [Google Scholar]
- Jiang M. C., Yang-Yen H. F., Lin J. K., Yen J. J. Differential regulation of p53, c-Myc, Bcl-2 and Bax protein expression during apoptosis induced by widely divergent stimuli in human hepatoblastoma cells. Oncogene. 1996 Aug 1;13(3):609–616. [PubMed] [Google Scholar]
- Kawanishi M. Epstein-Barr virus induces fragmentation of chromosomal DNA during lytic infection. J Virol. 1993 Dec;67(12):7654–7658. doi: 10.1128/jvi.67.12.7654-7658.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kerr J. F., Cooksley W. G., Searle J., Halliday J. W., Halliday W. J., Holder L., Roberts I., Burnett W., Powell L. W. The nature of piecemeal necrosis in chronic active hepatitis. Lancet. 1979 Oct 20;2(8147):827–828. doi: 10.1016/s0140-6736(79)92178-0. [DOI] [PubMed] [Google Scholar]
- Koga Y., Tanaka K., Lu Y. Y., Oh-Tsu M., Sasaki M., Kimura G., Nomoto K. Priming of immature thymocytes to CD3-mediated apoptosis by infection with murine cytomegalovirus. J Virol. 1994 Jul;68(7):4322–4328. doi: 10.1128/jvi.68.7.4322-4328.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kuo C. H., Tai D. I., Chang-Chien C. S., Lan C. K., Chiou S. S., Liaw Y. F. Liver biochemical tests and dengue fever. Am J Trop Med Hyg. 1992 Sep;47(3):265–270. doi: 10.4269/ajtmh.1992.47.265. [DOI] [PubMed] [Google Scholar]
- Lacronique V., Mignon A., Fabre M., Viollet B., Rouquet N., Molina T., Porteu A., Henrion A., Bouscary D., Varlet P. Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice. Nat Med. 1996 Jan;2(1):80–86. doi: 10.1038/nm0196-80. [DOI] [PubMed] [Google Scholar]
- Laurent-Crawford A. G., Krust B., Muller S., Rivière Y., Rey-Cuillé M. A., Béchet J. M., Montagnier L., Hovanessian A. G. The cytopathic effect of HIV is associated with apoptosis. Virology. 1991 Dec;185(2):829–839. doi: 10.1016/0042-6822(91)90554-o. [DOI] [PubMed] [Google Scholar]
- Levine B., Huang Q., Isaacs J. T., Reed J. C., Griffin D. E., Hardwick J. M. Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene. Nature. 1993 Feb 25;361(6414):739–742. doi: 10.1038/361739a0. [DOI] [PubMed] [Google Scholar]
- Lewis J., Wesselingh S. L., Griffin D. E., Hardwick J. M. Alphavirus-induced apoptosis in mouse brains correlates with neurovirulence. J Virol. 1996 Mar;70(3):1828–1835. doi: 10.1128/jvi.70.3.1828-1835.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lin K. I., Lee S. H., Narayanan R., Baraban J. M., Hardwick J. M., Ratan R. R. Thiol agents and Bcl-2 identify an alphavirus-induced apoptotic pathway that requires activation of the transcription factor NF-kappa B. J Cell Biol. 1995 Dec;131(5):1149–1161. doi: 10.1083/jcb.131.5.1149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lindholm P. F., Tamami M., Makowski J., Brady J. N. Human T-cell lymphotropic virus type 1 Tax1 activation of NF-kappa B: involvement of the protein kinase C pathway. J Virol. 1996 Apr;70(4):2525–2532. doi: 10.1128/jvi.70.4.2525-2532.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lowe S. W., Ruley H. E. Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev. 1993 Apr;7(4):535–545. doi: 10.1101/gad.7.4.535. [DOI] [PubMed] [Google Scholar]
- Malorni W., Rivabene R., Santini M. T., Donelli G. N-acetylcysteine inhibits apoptosis and decreases viral particles in HIV-chronically infected U937 cells. FEBS Lett. 1993 Jul 19;327(1):75–78. doi: 10.1016/0014-5793(93)81043-y. [DOI] [PubMed] [Google Scholar]
- Marianneau P., Mégret F., Olivier R., Morens D. M., Deubel V. Dengue 1 virus binding to human hepatoma HepG2 and simian Vero cell surfaces differs. J Gen Virol. 1996 Oct;77(Pt 10):2547–2554. doi: 10.1099/0022-1317-77-10-2547. [DOI] [PubMed] [Google Scholar]
- Meyer M., Schreck R., Baeuerle P. A. H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J. 1993 May;12(5):2005–2015. doi: 10.1002/j.1460-2075.1993.tb05850.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morey A. L., Ferguson D. J., Fleming K. A. Ultrastructural features of fetal erythroid precursors infected with parvovirus B19 in vitro: evidence of cell death by apoptosis. J Pathol. 1993 Feb;169(2):213–220. doi: 10.1002/path.1711690207. [DOI] [PubMed] [Google Scholar]
- Munoz E., Israël A. Activation of NF-kappa B by the Tax protein of HTLV-1. Immunobiology. 1995 Jul;193(2-4):128–136. doi: 10.1016/s0171-2985(11)80535-8. [DOI] [PubMed] [Google Scholar]
- Noteborn M. H., Todd D., Verschueren C. A., de Gauw H. W., Curran W. L., Veldkamp S., Douglas A. J., McNulty M. S., van der EB A. J., Koch G. A single chicken anemia virus protein induces apoptosis. J Virol. 1994 Jan;68(1):346–351. doi: 10.1128/jvi.68.1.346-351.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pahl H. L., Baeuerle P. A. A novel signal transduction pathway from the endoplasmic reticulum to the nucleus is mediated by transcription factor NF-kappa B. EMBO J. 1995 Jun 1;14(11):2580–2588. doi: 10.1002/j.1460-2075.1995.tb07256.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pahl H. L., Baeuerle P. A. Expression of influenza virus hemagglutinin activates transcription factor NF-kappa B. J Virol. 1995 Mar;69(3):1480–1484. doi: 10.1128/jvi.69.3.1480-1484.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ratan R. R., Murphy T. H., Baraban J. M. Oxidative stress induces apoptosis in embryonic cortical neurons. J Neurochem. 1994 Jan;62(1):376–379. doi: 10.1046/j.1471-4159.1994.62010376.x. [DOI] [PubMed] [Google Scholar]
- Rosen L., Khin M. M., U T. Recovery of virus from the liver of children with fatal dengue: reflections on the pathogenesis of the disease and its possible analogy with that of yellow fever. Res Virol. 1989 Jul-Aug;140(4):351–360. doi: 10.1016/s0923-2516(89)80115-3. [DOI] [PubMed] [Google Scholar]
- Schreck R., Rieber P., Baeuerle P. A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 1991 Aug;10(8):2247–2258. doi: 10.1002/j.1460-2075.1991.tb07761.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schwartz L. M., Osborne B. A. Programmed cell death, apoptosis and killer genes. Immunol Today. 1993 Dec;14(12):582–590. doi: 10.1016/0167-5699(93)90197-S. [DOI] [PubMed] [Google Scholar]
- Shen Y., Shenk T. E. Viruses and apoptosis. Curr Opin Genet Dev. 1995 Feb;5(1):105–111. doi: 10.1016/s0959-437x(95)90061-6. [DOI] [PubMed] [Google Scholar]
- Siebenlist U., Franzoso G., Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405–455. doi: 10.1146/annurev.cb.10.110194.002201. [DOI] [PubMed] [Google Scholar]
- Sikora E., Grassilli E., Radziszewska E., Bellesia E., Barbieri D., Franceschi C. Transcription factors DNA-binding activity in rat thymocytes undergoing apoptosis after heat-shock or dexamethasone treatment. Biochem Biophys Res Commun. 1993 Dec 15;197(2):709–715. doi: 10.1006/bbrc.1993.2537. [DOI] [PubMed] [Google Scholar]
- Slater A. F., Stefan C., Nobel I., van den Dobbelsteen D. J., Orrenius S. Intracellular redox changes during apoptosis. Cell Death Differ. 1996 Jan;3(1):57–62. [PubMed] [Google Scholar]
- Thanos D., Maniatis T. NF-kappa B: a lesson in family values. Cell. 1995 Feb 24;80(4):529–532. doi: 10.1016/0092-8674(95)90506-5. [DOI] [PubMed] [Google Scholar]
- Tolskaya E. A., Romanova L. I., Kolesnikova M. S., Ivannikova T. A., Smirnova E. A., Raikhlin N. T., Agol V. I. Apoptosis-inducing and apoptosis-preventing functions of poliovirus. J Virol. 1995 Feb;69(2):1181–1189. doi: 10.1128/jvi.69.2.1181-1189.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yamada T., Yamaoka S., Goto T., Nakai M., Tsujimoto Y., Hatanaka M. The human T-cell leukemia virus type I Tax protein induces apoptosis which is blocked by the Bcl-2 protein. J Virol. 1994 May;68(5):3374–3379. doi: 10.1128/jvi.68.5.3374-3379.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]