LOSS OF RESISTANCE TO MURINE HEPATITIS-VIRUS STRAIN-3 INFECTION AFTERTREATMENT WITH CORTICOSTEROIDS IS ASSOCIATED WITH INDUCTION OF MACROPHAGE PROCOAGULANT ACTIVITY

Activation of the immune coagulation system has been implicated in the pathogenesis of liver injury following infection of inbred mice with murine hepatitis virus strain 3 (MHV-3). Following MHV-3 infection, ma crophages isolated from MHV-3-susceptible acid -semisusceptible inbred strains of mice express increased procoagulant activity (PCA), wherea s macrophages from resistant strains express no increase in PCA over b asal levels, The PCA induced by MHV-3 is a prothrombinase, encoded by the gene Fgl-2, which encodes a fibrinogen-like protein (musfiblp). In this study, MHV-3-resistant A/J mice treated with methylprednisolone prior to infection with MHV-3 developed elevated levels of alanine ami notransferase in serum and died within 10 days of infection, with hist ological findings of fulminant hepatitis. In vitro, macrophages isolat ed from A/J mice and pretreated with methylprednisolone produced a mar ked increase in functional PCA following infection with MHV-3, The PCA was shown to be a prothrombinase by its ability to cleave I-125-proth rombin. Northern blot analysis of RNA transcripts from these macrophag es demonstrated increased transcription of the Fgl-2 gene relative to that in macrophages which had not been pretreated with methylprednisol one prior to MHV-3 infection. Methylprednisolone pretreatment of MHV-3 -infected macrophages stabilized the Fgl-2 mRNA. Thus, loss of resista nce to MHV-3 secondary to methylprednisolone therapy is associated wit h increased transcription acid stability of Fgl-2 mRNA resulting in ex pression of the Fgl-2 gene product, musfiblp. These results provide fu rther insight into mechanisms of PCA regulation in response to MHV-3 i nfection in inbred strains of mice.