The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/11/1523/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 9, November 3, 1997 1523-1534

Article

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

Tanya Scharton-Kersten*, Cristina Contursi{ddagger}, Atsuko Masumi{ddagger}, Alan Sher*, and Keiko Ozato{ddagger}

From the * Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and the {ddagger} 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-1{alpha}, IL-1β, 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.

Address correspondence to Keiko Ozato, LMGR, NICHD, 9000 Rockville Pike, Building 6, Room 2A01, NIH, Bethesda, MD 20892-2753. Phone: (301) 496-9184. Fax: (301) 480-9354. E-mail: ozatok{at}dir6.nichd.nih.gov

1 Abbreviations used in this paper: ICSBP, interferon consensus sequence binding protein; IRF, interferon regulatory factor; ISGF, interferon-stimulated gene factor; ISRE, interferon-stimulated response element; ko, knockout; LMc, large mononuclear cell; PEC, peritoneal cells; SAC, Staphylococcus aureus Cowan strain 1; SMc, small mononuclear cell; STAg, soluble tachyzoite antigen; STAT1, signal transducer and activator of transcription; wt, wild-type.


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