Treatment of Resistant A/J Mice with Methylprednisolone (MP) Results in Loss of Resistance to Murine Hepatitis Strain 3 (MHV-3) and Induction of Macrophage Procoagulant Activity (PCA)

  • R. J. Fingerote
  • J. L. Leibowitz
  • Y. S. Rao
  • G. A. Levy
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 380)


BALB/cJ mice die of fulminant hepatitis within 7 days of exposure to murine hepatitis virus strain 3 (MHV-3) whereas A/J mice are fully resistant to the lethal effects of MHV-3 infection. Previous studies have implicated macrophage activation with production of a unique macrophage prothrombinase (PCA) and lymphocyte cytokine secretion in the pathogenesis of MHV-3 susceptibility and have demonstrated that immunosuppression induces susceptibility in resistant mice. This study was undertaken to determine whether macrophages, derived from resistant A/J mice and treated in vitro with methylprednisolone sodium succinate (MP), elaborated PCA following MHV-3 exposure and whether therapy with MP altered resistance of A/J mice to MHV-3 infection in vivo.

Macrophages, incubated with MP in vitro, expressed dose dependent increases in PCA following infection with MHV-3. No induction of PCA occurred in macrophages treated with MHV-3 or MP alone. Analysis of mRNA transcripts for mouse fibrinogen like protein (musfiblp), the MHV-3 specific prothrombinase, in macrophages which were incubated with MP prior to exposure to MHV-3 demonstrated significantly increased mRNA levels as compared to macrophages not incubated with MP prior to MHV-3 exposure. In vivo, A/J mice treated for 3 days with 500 mg/kg/day of MP prior to infection with MHV-3 demonstrated extensive hepatocyte necrosis and fibrin deposition in hepatic sinusoids on histological examination of liver tissue, elevated serum transaminases and 100% mortality within 10 days of infection. These results therefore provide further support for the role of increased PCA in the pathogenesis of MHV-3 related liver necrosis.


Fulminant Hepatitis Fibrin Deposition Plaque Form Unit Hepatic Sinusoid Susceptible Mouse 
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  1. 1.
    LePrevost C., Levy-Leblond E., Virelizier J.L., Dupuy J.M., Immunopathology of mouse hepatitis virus type 3 infection: I. Role of humoral and cell-mediated immunity in resistance mechanisms. J Immunol 1975;114:221–225.Google Scholar
  2. 2.
    Levy G.A., Leibowitz J.L., Edgington T.S. Induction of monocyte procoagulant activity by murine hepatitis virus type 3 parallels disease susceptibility in mice. J Exp Med 1981;154:1150–1163.PubMedCrossRefGoogle Scholar
  3. 3.
    Dindzans V.J., Skamene E., Levy G.A. Susceptibility/ resistance to mouse hepatitis virus strain 3 and macrophage procoagulant activity are genetically linked and controlled by two non-H-2-linked genes. J Immunol 1986;137:2355–2360.PubMedGoogle Scholar
  4. 4.
    Parr R., Fung L.S., Reneker J., Myers-Mason N., Leibowitz J., Levy G. Association of mouse fibrinogen like protein (musfiblp) with murine hepatitis virus induced prothrombinase activity. 1994 (submitted).Google Scholar
  5. 5.
    Gallily R., Warwick A., Bang F.B. Effect of cortisone on genetic resistance to mouse hepatitis virus in vivo and in vitro. Proc Natl Acad Sci USA 1964;51:1158–1164.PubMedCrossRefGoogle Scholar
  6. 6.
    Behrens T.W., Goodwin J.S. Glucocorticoids. In: Bray M. A., Morley J., (eds) The pharmacology of lymphocytes. Springer-Verlag, Berlin 1988 pp 425–439.CrossRefGoogle Scholar
  7. 7.
    Bang F.B., Warwick A. Mouse macrophages as host cells for the mouse hepatitis virus and the genetic basis of their susceptibitlity. Proc Natl Acad Sci USA 1960;46:1065–1075.PubMedCrossRefGoogle Scholar
  8. 8.
    Arnheiter H., Baechi T., Haller O., Adult mouse hepatocytes in primary monolayer culture express genetic resistance to mouse hepatitis virus type 3. J Immunol 1982;129:1275–1281PubMedGoogle Scholar
  9. 9.
    Lamontagne L., Descoteaux J-P., Jolicoeur P. Mouse hepatitis virus 3 replication in T and B lymphocytes correlate with viral pathogenicity. J Immunol 1989;142:4458–4465PubMedGoogle Scholar
  10. 10.
    MacPhee P.J., Dindzans V.J., Fung L-S., Levy G.A., Acute and chronic changes in the microcirculation of the liver in inbred strains of mice following infection with mouse hepatitis virus type 3. Hepatology 1985;5:649–660.PubMedCrossRefGoogle Scholar
  11. 11.
    Li C., Fung L.S., Chung S., Crow A., Myers-Mason N., Phillips M.J., Leibowitz J.L., Cole E., Ottaway C.A., Levy G. Monoclonal antiprothrombinase (3D4.3) prevents mortality from murine hepatitis virus (MHV-3) infection. J Exp Med 1992;176:689–697.PubMedCrossRefGoogle Scholar
  12. 12.
    Bateman A., Singh A., Kral T., Solomon S. The immune-hypothalamic-pituitary-adrenal axis. Endocrine Rev 1989;10:92–112.CrossRefGoogle Scholar
  13. 13.
    Daynes R.A., Araneo B.A. Contrasting effects of glucocorticoids on the capacity of T cells to produce the growth factors interleukin 2 and interleukin 4. Eur J Immunol 1989;19:2319–2325.PubMedCrossRefGoogle Scholar
  14. 14.
    Chung S., Gorczynski R., Cruz B., Fingerote R., Skamene E., Perlman S., Leibowitz J., Fung L., Flowers M., Levy G. Characterization of murine hepatitis virus strain 3 (MHV-3) specific T cell lines: effect on induction of macrophage procoagulant activity in-vitro and course of MHV-3 infection in-vivo. Immunology 1994 (In Press)Google Scholar
  15. 15.
    Körner H, Schliephake A, Winter J, Zimprich F., Lassmann H., Sedgwick J., Siddell S., Wege H. Nucleocapsid or spike protein-specific CD4+ T lymphocytes protect against coronavirus-induced encephalomyelititis in the absence of CD8+ T cells. J Immunol 1991;147:2317–2323.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • R. J. Fingerote
    • 1
  • J. L. Leibowitz
    • 2
  • Y. S. Rao
    • 1
  • G. A. Levy
    • 1
  1. 1.Department of MedicineThe Toronto Hospital, University of TorontoTorontoCanada
  2. 2.Department of PathologyUniversity of Texas Health Sciences CenterHoustonUSA

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