Interferon-α/β inhibition of interleukin 12 and interferon-γ production in vitro and endogenously during viral infection

Interferon (IFN)-α/β-mediated negative regulation of interleukin 12 (IL-12) and IFN-γ proteins is reported here. Both IFN-α and IFN-β inhibited fixed Staphylococcus aureus Cowan strain induction of IL-12 and IFN-γ production by mouse splenic leukocytes in culture. Extended studies with IFN-α demonstrated that inhibition was at the level of biologically active IL-12 p70. Effects were selective, as induction of tumor necrosis factor was unaffected and induction of IL-6 was enhanced. Neutralization of IFN-α/β expressed endogenously during infections with murine cytomegalovirus (MCMV) enhanced early IL-12 and IFN-γ protein production. Furthermore, during infections of mice with lymphocytic choriomeningitis virus (LCMV), this treatment revealed a previously undetected early IL-12 and IFN-γ protein expression, and mice deficient in IFN-α/β receptor function, but not control mice, also expressed endogenous LCMV-induced IL-12. The effects of IFN-α/β neutralization on production of IL-12 and IFN-γ during the viral infections were detected in both serum samples and medium conditioned with splenic leukocytes isolated from infected animals. In vitro studies demonstrated that splenic leukocytes isolated from LCMV-infected mice were primed to produce IL-12 in response to stimulation with Staphylococcus aureus Cowan strain, but that this responsiveness was sensitive to added IFN-α. Moreover, endogenous IFN-α/β induced by LCMV inhibited in vivo lipopolysaccharide stimulation of IL-12 production. These results demonstrate a new pathway for regulating cytokine responses, and suggest a mechanism for inhibition of IL-12-dependent immune responses during viral infections.