Interferon Consensus Sequence Binding Protein–deficient Mice Display Impaired Resistance to Intracellular Infection Due to a Primary Defect in Interleukin 12 p40 Induction

Abstract

Mice lacking the transcription factor interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor family of transcription proteins, were infected with the intracellular protozoan, Toxoplasma gondii. ICSBP-deficient mice exhibited unchecked parasite replication in vivo and rapidly succumbed within 14 d after inoculation with an avirulent Toxoplasma strain. In contrast, few intracellular parasites were observed in wild-type littermates and these animals survived for at least 60 d after infection. Analysis of cytokine synthesis in vitro and in vivo revealed a major deficiency in the expression of both interferon (IFN)-γ and interleukin (IL)-12 p40 in the T. gondii exposed ICSBP−/− animals. In related experiments, macrophages from uninfected ICSBP−/− mice were shown to display a selective impairment in the mRNA expression of IL-12 p40 but not IL-1α, IL-1β, IL-1Ra, IL-6, IL-10, or TNF-α in response to live parasites, parasite antigen, lipopolysaccharide, or Staphylococcus aureus. This selective defect in IL-12 p40 production was observed regardless of whether the macrophages had been primed with IFN-γ. We hypothesize that the impaired synthesis of IL-12 p40 in ICSBP−/− animals is the primary lesion responsible for the loss in resistance to T. gondii because IFN-γ–induced parasite killing was unimpaired in vitro and, more importantly, administration of exogenous IL-12 in vivo significantly prolonged survival of the infected mice. Together these findings implicate ICSBP as a major transcription factor which directly or indirectly regulates IL-12 p40 gene activation and, as a consequence, IFN-γ–dependent host resistance.