title: Loss of resistance to murine hepatitis virus strain 3 infection after treatment with corticosteroids is associated with induction of macrophage procoagulant activity.
abstract: 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, macrophages isolated from MHV-3-susceptible and -semisusceptible inbred strains of mice express increased procoagulant activity (PCA), whereas macrophages from resistant strains express no increase in PCA over basal 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 aminotransferase in serum and died within 10 days of infection, with histological findings of fulminant hepatitis. In vitro, macrophages isolated from A/J mice and pretreated with methylprednisolone produced a marked increase in functional PCA following infection with MHV-3. The PCA was shown to be a prothrombinase by its ability to cleave 125I-prothrombin. Northern blot analysis of RNA transcripts from these macrophages demonstrated increased transcription of the Fgl-2 gene relative to that in macrophages which had not been pretreated with methylprednisolone prior to MHV-3 infection. Methylprednisolone pretreatment of MHV-3-infected macrophages stabilized the Fgl-2 mRNA. Thus, loss of resistance to MHV-3 secondary to methylprednisolone therapy is associated with increased transcription and stability of Fgl-2 mRNA resulting in expression of the Fgl-2 gene product, musfiblp. These results provide further insight into mechanisms of PCA regulation in response to MHV-3 infection in inbred strains of mice.
authors.affiliation: Department of Medicine, Toronto Hospital, University of Toronto, Ontario, Canada.
authors.forename: R J
authors.initials: RJ
authors.lastname: Fingerote
authors.forename: M
authors.initials: M
authors.lastname: Abecassis
authors.forename: M J
authors.initials: MJ
authors.lastname: Phillips
authors.forename: Y S
authors.initials: YS
authors.lastname: Rao
authors.forename: E H
authors.initials: EH
authors.lastname: Cole
authors.forename: J
authors.initials: J
authors.lastname: Leibowitz
authors.forename: G A
authors.initials: GA
authors.lastname: Levy
mesh_terms: D000818:Animals; D001779:Blood Coagulation Factors / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D004790:Enzyme Induction; D005260:Female; D005340:Fibrinogen; D019085:Fluorescent Antibody Technique, Direct; D005938:Glucocorticoids / Q000494:pharmacology*; D006524:Hepatitis, Viral, Animal / Q000276:immunology* / Q000473:pathology; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology*; D008776:Methylprednisolone Hemisuccinate / Q000494:pharmacology*; D051379:Mice; D008805:Mice, Inbred A; D006517:Murine hepatitis virus / Q000276:immunology* / Q000502:physiology; D011516:Prothrombin / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic; D014779:Virus Replication
chemical_list: D001779:Blood Coagulation Factors; C490637:Fgl2 protein, mouse; D005938:Glucocorticoids; D012333:RNA, Messenger; C045072:macrophage procoagulant activity; D008776:Methylprednisolone Hemisuccinate; D011516:Prothrombin; D005340:Fibrinogen; D013925:Thromboplastin