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The Journal of Immunology, Vol 157, Issue 2 815-821, Copyright © 1996 by American Association of Immunologists
ARTICLES |
VE Schijns, CM Wierda, M van Hoeij and MC Horzinek
Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
Both IL-12 and IFN-gamma have been implicated as principal inducers of type 1 immune responses required for the elimination of intracellular pathogens, such as viruses. We examined the in vivo antiviral role of both cytokines during coronavirus-induced hepatitis in a mouse hepatitis virus (MHV) model. The absence of IFN-gamma function in mice with a targeted disruption of the IFN-gamma R alpha-chain gene (IFN- gamma R -/-) resulted in increased susceptibility to coronaviral hepatitis associated with augmented viral replication and increased hepatocellular injury. The mutant mice showed a type 1 lymphokine response characterized by the normal high IFN-gamma and low IL-4 production. Unlike MHV-infected wild-type mice, however, the mutant IFN- gamma R -/- mice showed no increase in IL-12 p4O gene expression, similar to that in naive animals. IL-12 treatment failed to restore host resistance in IFN-gamma R -/- mice, but significantly protected MHV-susceptible C57BL/6 mice against lethal infection, although less than IFN-gamma treatment. Mice protected by IL-12 or IFN-gamma showed resistance against an otherwise lethal second MHV infection. Our data demonstrate that despite reduced IL-12 gene expression and defective IFN-gamma R function, virus-induced IFN-gamma production can occur. Furthermore, they emphasize the pivotal antiviral role of IFN-gamma in protection against acute coronavirus-induced hepatitis.
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