Exacerbated viral hepatitis in IFN-gamma receptor-deficient mice is not suppressed by IL-12.
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.
Schijns
V E
VE
Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
Wierda
C M
CM
van Hoeij
M
M
Horzinek
M C
MC
D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D005260:Female; D006524:Hepatitis, Viral, Animal / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D000096743:Interferon gamma Receptor
D015703:Antigens, CD; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D018664:Interleukin-12; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D000096743:Interferon gamma Receptor