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J. Exp. Med.,
Volume 186, Number 9, November 3, 1997 1523-1534
By
From the * Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and
Infectious Diseases, National Institutes of Health; and the 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)- Laboratory of Molecular Growth
Regulation, National Institute of Child Health and Human Development, National Institutes of
Health, Bethesda, Maryland
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
, IL-1
, IL-1Ra, IL-6, IL-10, or TNF- 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-. 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--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--dependent host resistance.
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