Abstract
Massive liver cell death provoked in silica-treated mice subsequently infected with herpes simplex virus (HSV)-1 is very similar pathohistologically to the cell death observed in human fulminant hepatitis. Previously, we have shown this liver cell death to be extensive apoptosis. In the present study, we examined various factors related to liver damage patho- and immunologically, as well as by reverse transcription–polymerase chain reaction. Tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), interferon (IFN)-α, and interleukin-6 mRNAs were detected to a much greater extent in silica-treated mice compared with control mice after HSV-1 infection, and excessive expression of iNOS mRNA and cytokine mRNAs in the liver may be closely related to massive liver cell apoptosis. The apoptosis was less related to the fas ligand than to TNF-α. Silica blockage of macrophages makes the liver cell extremely vulnerable to HSV-1 infection, and it induced expression of E-selectin and neutrophil margination in the liver. Subsequent HSV-1 infection induced excessive production of iNOS and cytokines, particularly TNF-α, but administration of anti-TNF-α antibody or N G-monomethyl-L-arginine was not completely efficacious for the survival of the mice. Overproduction of free radicals in combination with cytokines, such as TNF-α, IL-6 and IFN-α, may result in hepatic cell apoptosis.
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Adler H, Beland JL, Del-Pan NC et al. (1997) Suppression of herpes simplex virus type 1 (HSV-1)-induced pneumonia in mice by inhibition of inducible nitric oxide synthase (iNOS, NOS2). J Exp Med 9, 1533–40.
Akaike T, Maeda H (2000) Nitric oxide and virus infection. Immunology 101, 300–8.
Akaike T, Weihe E, Schaefer M et al. (1995) Effect of neurotropic virus infection on neuronal and inducible nitric oxide synthase activity in rat brain. J Neurovirol 1, 118–25.
Akaike T, Noguchi Y, Ijirii S et al. (1996) Pathogenesis of influenza virus-induced pneumonia: Involvement of both nitric oxide and oxygen radicals. Proc Natl Acad Sci USA 93, 2448–53.
Akaike T, Suga M, Maeda H (1998) Free radicals in viral pathogenesis: Molecular mechanisms involving superoxide and NO. Proc Soc Exp Biol Med 217, 64–73.
Alonso S, Minty A, Bourlet Y, Buckinghamm M (1986) Comparison of three actin-coding sequences in the mouse: Evolutionary relationships between the actin genes of warm-blooded vertebrates. J Mol Evol 23, 11–22.
Ando K, Moriyama T, Guidotti LG et al. (1993) Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J Exp Med 178, 1551–4.
Beckman J, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and the ugly. Am J Physiol 271, C1424–37.
Bergmyer HU (1984) Enzymes: Transferases. In: Methods of Enzyme Analysis, 3rd edn (Bergmyer HU, ed.). Verlag Chemie, Weinheim, 416–57.
Bi Z, Barna M, Komatsu T, Reiss CS (1995) Vesicular stomatitis virus infection of the central nervous system activates both innate and acquired immunity. J Virol 69, 6466–72.
Bonder CS, Ajuebor MN, Zbytnuik LD, Kubes P, Swain MG (2004) Essential role for neutrophil ecuitment to the liver in concanavalin A-induced hepatitis. J Immunol 172, 24–53.
Carninci P, Nishiyama Y, Westover A et al. (1998) Thermostabi- lization and thermoactivation of thermolabile enzymes by trehalose and its application for the synthesis of full length cDNA. Proc Natl Acad Sci USA 95, 520–4.
Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidium thiocyonate-phenol-chloroform extraction. Anal Biochem 162, 156–9.
Chosay JG, Essani NA, Dunn CJ, Jaeschke H (1997) Neutrophil margination and extravasation in sinusoids and venules of liver during endotoxin-induced injury. Am J Physiol 272, G1195–200.
Curran RD, Billiar TR, Stuehr DJ et al. (1990) Multiple cytokines are required to induce hepatocyte nitric oxide production and inhibit total protein synthesis. Ann Surg 212, 462–71.
Curran RD, Billiar TR, Stuehr DJ, Hofmann K, Simmons RL (1989) Hepatocytes produce nitrogen oxides from L-arginine in response to inflammatory products of Kupffer cells. J Exp Med 170, 1769–74.
de la Mata M, Meager A, Rolando N et al. (1990) Tumor necrosis factor production in fulminant hepatic failure: Relation to aetiology and superimposed microbial infection. Clin Exp Immunol 82, 479–84.
Ding AH, Nathan CF, Stuehr DJ (1988) Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidences for independent production. J Immunol 141, 2407–12.
Dudley FJ, Fox RA, Sherlock S (1972) Cellular immunity and hepatitis-associated, Australia antigen liver disease. Lancet i, 723–6.
Galanos C, Freudenberg MA, Reutter W (1979) Galactosamine- induced sensitization to the lethal effects of endotoxin. Proc Natl Acad Sci USA 76, 5939–43.
Galle PR, Hofmann WJ, Walczak H et al. (1995) Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med 182, 1223–30.
Gartner F, Leist M, Lohse AW, Germann PG, Tiegs G (1995) Concanavalin A-induced T-cell-mediated hepatic injury in mice: The role of tumor necrosis factor. Hepatology 21, 190–8.
Hewett JA, Jean PA, Kunkel SL, Roth RA (1993) Relationship between tumor necrosis factor-a and neutrophils in endotoxin- induced liver injury. Am J Physiol 265, G1011–15.
Hirt B (1967) Selective extraction of polyoma DNA from infected mouse cell cultures. J Mol Biol 26, 365–9.
Iragi F, Teale A (1997) Cloning and sequencing of the TNFa genes of three inbred mouse strains. Immunogenetics 45, 459–61.
Irie H, Mori W (1986) Fatal hepatic necrosis after shock. Acta Pathol Jpn 36, 363–74.
Irie H, Harada Y, Yoshihashi H et al. (1988) Spread of herpes simplex virus type 1 (Miyama+GC strain) to the central nervous system after intraperitoneal inoculation: The role of the myenteric plexus of the gut. Arch Virol 105, 247–57.
Irie H, Harada Y, Kataoka M et al. (1992) Efficacy of oral administration of live herpes simplex virus type 1 as a vaccine. J Virol 66, 2428–34.
Irie H, Koyama AH, Kubo H et al. (1998) Herpes simplex virus hepatitis in macrophage-depleted mice: The role of massive, apoptotic cell death in pathogenesis. J Gen Virol 79, 1225–31.
Jaeschke H, Fisher MA, Lawson A, Simmons CA, Farhood A, Jones DA (1998) Activation of caspase 3 (CPP32)-like proteases is essential for (1999) TNF-a-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model. J Immunol 160, 3480–6.
Jones AL, Selby P (1989) Tumor necrosis factor: Clinical relevance.Cancer Surv 8, 817–36.
Kimura K, Ando K, Tomita E et al. (1999) Elevated intracellular IFN-? levels in circulating CD8+lymphocytes in patients with fulminant hepatitis. J Hepatol 31, 579–3.
Kordula T, Bugno M, Rydel RE, Travis J (2000) Mechanism of interleukin-1 and tumor necrosis factor alpha-dependent regulation of the alpha 1-antichymotrypsin gene in human astrocytes. J Neurosci 15, 7510–16.
Ksontini RDB, Colagiovanni MD, Josephs CK et al. (1998) Disparate role for TNF-a and Fas ligand in concanavalin A-induced hepatitis. J Immunol 160, 4082–9.
Lara-Pezzi E, Majano PL, Gomez-Gonzalo M et al. (1998) The hepatitis B virus X protein up-regulates tumor necrosis factor alpha gene expression in hepatocytes. Hepatology 28, 1013–21.
Leist MF, Gantner I, Bohlinger PG, Germann G, Tiegs A, Wendel A (1994). Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-a requires transcriptional arrest. J Immunol 153, 1778–88.
Leist M, Gantner F, Bohlinger I, Tiegs G, Germann G, Wendel A (1995) Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models.Am J Pathol 146, 1220–34.
Maier R, Bilbe G, Rediske J, Lotz M (1994) Inducible nitric oxide synthase from human articular chondrocytes: cDNA cloning and analysis of mRNA expression. Biochim Biophys Acta 1208, 145–50.
Melkonyan H, Hofmann HA, Nacken W, Sorg C, Klempt M (1998) The gene encoding the myeloid-related protein 14 (MRP 14), a calcium-binding protein expressed in granulo-cytes and monocytes, contains a potent enhancer elementin the first intron. J Biol Chem 273, 27 026–32.
Mori W, Shiga J, Irie H (1986) Shwartzman reactions as pathogenic mechanism in fulminant hepatitis. Semin LiverDis 6, 267–76.
Murray LJ, Lee R, Martens C (1990) In vivo cytokine gene expression in T cell subsets of autoimmune MRL/Mp-lpr/lpr mouse. Eur J Immunol 20, 163–70.
Muto Y, Nouri-Aria KT, Meager A, Alexander GJ, Eddleston AL, Williams R (1988) Enhanced tumor necrosis factor and interleukin-1 in fulminant hepatic failure. Lancet ii, 72–74.
Nakaki M, Iwai H, Naiki T, Ohnishi H, Muto Y, Moriwaki H (2000) High levels of serum interleukin-10 and tumor necrosis factor-a and associated with fatality in fulminant hepatitis. J Infect Dis 182, 1103–8.
Nii S, Kamahora J (1961) Studies on the growth of newly isolated herpes simplex virus in vivo. Biken J 4, 75–96.
Nowoslawiski A, Krawczynski K, Madalinski K (1972) Tissue localization of Australia antigen immune complexes in acute and chronic hepatitis and liver cirrhosis. Am J Pathol 68, 31–49.
Ogasawara J, Watanabe-Fukunaga R, Adachi M et al. (1993) Lethal effect of the anti-Fas antibody in mice. Nature 364, 806–7.
Ogata M, Matsui T, Kita T, Shigematsu A (1999) Carrageenan primes leukocytes to enhance lipopolysaccharide-induced tumor necrosis factor alpha production. Infect Immun 67, 3284–9.
Quinn JP, McGeoch D (1985) DNA sequence of region in the genome of herpes simplex virus type 1 containing the genes for DNA polymerase and the major DNA binding protein. Nucleic Acids Res 13, 8143–63.
Ryo K, Kamogawa Y, Ikeda I et al. (2000) Significance of Fas antigen-mediated apoptosis in human fulminant hepatic failure. Am J Gastroenterol 95, 2047–55.
Saad B, Frei K, Scholl FA, Fontana A, Maier P (1995) Hepatocyte-derived interleukin-6 and tumor necrosis factor-a mediate the lipopolysaccharide-induced acute-phase response and nitric oxide release by cultured rat hepatocytes. Eur JBiochem 229, 349–355.
Seif I, DeMaeyer-Guignard J (1986) Structure and expression of a new murine interferon-alpha gene. MuiFN-alpha-1-9.Gene 43, 111–21.
Shapiro L, Clark BD, Orencole SF, Poutsiaka DD, Granowitz EV, Dinarello CA (1993) Detection of tumor necrosis factor soluble receptor p55 in blood samples from healthy and endotoxemic humans. J Infect Dis 167, 1344–50.
Song E, Lee S-K, Wang J et al. (2003) RNA interference targeting Fas protects mice from fulminant hepatitis. NatMed 9, 347–51.
Tanabe O, Akira S, Kamiya T, Wong GG, Hirano T, Kishimoto T (1988) Genetic structure of the murine IL-6 gene. High degree conservation of potential regulatory sequences between mouse and human. J Immunol 141, 3875–81.
Tokushige K, Yamaguchi N, Ikeda I, Hashimoto E, Yamauchi K, Hayashi N (2000) Significance of soluble TNF receptor-I in acute-type fulminant hepatitis. Am J Gastroenterol 95, 2040–6.
Trautwein C, Rakemann T, Brenner DA et al. (1998) Concanavalin A-induced liver cell damage: Activation of intracellular pathways triggered by tumor necrosis factor in mice. Gastro-enterology 114, 1035–45.
Wang JH, Redmond HP, Wu QD, Bouchier-Hayes D (1998) Nitric oxide mediates hepatocyte injury. Am J Physiol 275, G1117–26.
Watanabe-Fukunaga R, Brannan CI, Itoh N et al. (1992) The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J Immunol 148, 1274–97.
Weller A, Isenmann S, Vestweber D (1992) Cloning of the mouse endothelial selectins: Expression of both E-and P-selectin is inducible by tumor necrosis factor alpha. J Biol Chem 267, 15 176–83.
Wong GHW, Goeddel DV (1986) Tumor necrosis factor a and β inhibit virus replication and synergize with interferons. Nature 323, 819–22.
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Irie, H., Shiga, J. Pathogenesis of herpes simplex hepatitis in macrophage-depleted mice: Possible involvement of tumor necrosis factor-α and inducible nitric oxide synthase in massive apoptosis. Anato Sci Int 80, 199–211 (2005). https://doi.org/10.1111/j.1447-073X.2005.00113.x
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DOI: https://doi.org/10.1111/j.1447-073X.2005.00113.x