Pattern of disease after murine hepatitis virus strain 3 infection correlates with macrophage activation and not viral replication.
Murine hepatitis virus strain (MHV-3) produces a strain-dependent pattern of disease which has been used as a model for fulminant viral hepatitis. This study was undertaken to examine whether there was a correlation between macrophage activation and susceptibility or resistance to MHV-3 infection. Peritoneal macrophages were isolated from resistant A/J and susceptible BALB/cJ mice and, following stimulation with MHV-3 or lipopolysaccharide (LPS), analyzed for transcription of mRNA and production of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), mouse fibrinogen-like protein (musfiblp), tissue factor (TF), leukotriene B4, and prostaglandin E2 (PGE2). Macrophages from BALB/cJ mice produced greater amounts of IL-1, TNF-alpha, TGF-beta, leukotriene B4, and musfiblp following MHV-3 infection than macrophages from resistant A/J mice, whereas in response to LPS, equivalent amounts of IL-1, TNF-alpha, TGF-beta, and TF were produced by macrophages from both strains of mice. Levels of mRNA of IL-1, TNF-alpha, and musfiblp were greater and more persistent in BALB/cJ than in A/J macrophages, whereas the levels and kinetics of IL-1, TNF-alpha, and TF mRNA following LPS stimulation were identical in macrophages from both strains of mice. Levels of production of PGE2 by MHV-3-stimulated macrophages from resistant and susceptible mice were equivalent; however, the time course for induction of PGE2, differed, but the total quantity of PGE2 produced was insufficient to inhibit induction of musfiblp, a procoagulant known to correlate with development of fulminant hepatic necrosis in susceptible mice. These results demonstrate marked differences in production of inflammatory mediators to MHV-3 infection in macrophages from resistant A/J and susceptible BALB/cJ mice, which may explain the marked hepatic necrosis and fibrin deposition and account for the lethality of MHV-3 in susceptible mice.
Pope
M
M
Department of Surgery, Toronto Hospital, University of Toronto, Ontario, Canada.
Rotstein
O
O
Cole
E
E
Sinclair
S
S
Parr
R
R
Cruz
B
B
Fingerote
R
R
Chung
S
S
Gorczynski
R
R
Fung
L
L
D000818:Animals; D005260:Female; D006524:Hepatitis, Viral, Animal / Q000276:immunology / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D007739:L Cells; D007975:Leukotriene B4 / Q000032:analysis / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D006517:Murine hepatitis virus / Q000145:classification / Q000472:pathogenicity* / Q000502:physiology*; D011863:Radioimmunoassay; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology; D014779:Virus Replication
D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D007213:Indomethacin