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J. Exp. Med., Volume 186, Number 9, November 3, 1997 1523-1534

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

By Tanya Scharton-Kersten,* Cristina Contursi,Dagger Atsuko Masumi,Dagger Alan Sher,* and Keiko OzatoDagger

From the * Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and the Dagger  Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

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)-gamma 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-1alpha , IL-1beta , IL-1Ra, IL-6, IL-10, or TNF-alpha 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-gamma . 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-gamma -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-gamma -dependent host resistance.


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