INTERFERON CONSENSUS SEQUENCE BINDING PROTEIN-DEFICIENT MICE DISPLAY IMPAIRED RESISTANCE TO INTRACELLULAR INFECTION DUE TO A PRIMARY DEFECTIN INTERLEUKIN-12 P40 INDUCTION

Mice lacking the transcription factor interferon consensus sequence bi nding protein (ICSBP), a member of the interferon regulatory factor fa mily of transcription proteins, were infected with the intracellular p rotozoan, Toxoplasma gondii. ICSBP-deficient mice exhibited unchecked parasite replication in vivo and rapidly succumbed within 14 d after i noculation with an avirulent Toxoplasma strain. In contrast, few intra cellular parasites were observed in wild-type littermates and these an imals survived for at least 60 d alter infection. Analysis of cytokine synthesis in vitro and in vivo revealed a major deficiency in the exp ression of both interferon (IFN)-gamma and interleukin (IL)-12 p40 in the T. gondii exposed ICSBP-/- animals. In related experiments, macrop hages from uninfected ICSBP-/- mice were shown to display a selective impairment in the mRNA expression of IL-12 p40 but not IL-1 alpha, IL- 1 beta, IL-1Ra, IL-6, IL-10, or TNF-alpha in response to live parasite s, parasite antigen, lipopolysaccharide, or Staphylococcus aureus. Thi s selective defect in IL-12 p40 production was observed regardless of whether the macrophages had been primed with IFN-gamma. We hypothesize that the impaired synthesis of IL-12 p40 in ICSBP-/- animals is the p rimary lesion responsible for the loss in resistance to T. gondii beca use IFN-gamma-induced parasite killing was unimpaired in vitro and, mo re importantly, administration oi exogenous IL-12 in vivo significantl y prolonged survival of the infected mice. Together these findings imp licate ICSBP as a major transcription factor which directly or indirec tly regulates IL-12 p40 gene activation and, as a consequence, IFN-gam ma-dependent host resistance.