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Interleukin-12 (IL-12), but Not IL-23, Deficiency Ameliorates Viral Encephalitis without Affecting Viral Control

ABSTRACT The relative contributions of interleukin-12 (IL-12) and IL-23 to viral pathogenesis have not been extensively studied. IL-12p40 mRNA rapidly increases after neurotropic coronavirus infection. Infection of mice defective in both IL-12 and IL-23 (p40−/−), in IL-12 alone (p35−/−), and in IL-23 alone (p19−/−) revealed that the symptoms of coronavirus-induced encephalitis are regulated by IL-12. IL-17-producing cells never exceeded background levels, supporting a redundant role of IL-23 in pathogenesis. Viral control, tropism, and demyelination were all similar in p35−/−, p19−/−, and wild-type mice. Reduced morbidity in infected IL-12 deficient mice was also not associated with altered recruitment or composition of inflammatory cells. However, gamma interferon (IFN-γ) levels and virus-specific IFN-γ-secreting CD4 and CD8 T cells were all reduced in the central nervous systems (CNS) of infected p35−/− mice. Transcription of the proinflammatory cytokines IL-1β and IL-6, but not tumor necrosis factor, were initially reduced in infected p35−/− mice but increased to wild-type levels during peak inflammation. Furthermore, although transforming growth factor β mRNA was not affected, IL-10 was increased in the CNS in the absence of IL-12. These data suggest that IL-12 does not contribute to antiviral function within the CNS but enhances morbidity associated with viral encephalitis by increasing the ratio of IFN-γ to protective IL-10.