Interferon Consensus Sequence Binding Protein–deficient Mice Display Impaired Resistance to Intracellular Infection Due to a Primary Defect in Interleukin 12 p40 Induction
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- Tanya Scharton-Kersten
- From the *Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and the ‡Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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- Cristina Contursi
- From the *Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and the ‡Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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- Atsuko Masumi
- From the *Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and the ‡Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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- Alan Sher
- From the *Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and the ‡Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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- Keiko Ozato
- From the *Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and the ‡Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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<jats:p>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.</jats:p>
収録刊行物
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- The Journal of Experimental Medicine
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The Journal of Experimental Medicine 186 (9), 1523-1534, 1997-11-03
Rockefeller University Press
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詳細情報 詳細情報について
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- CRID
- 1360855569655509376
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- NII論文ID
- 30017416071
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- NII書誌ID
- AA00697559
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- ISSN
- 15409538
- 00221007
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