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Cited by 217Toxoplasma gondii Research StudiesImmune Response and InflammationT-cell and B-cell Immunology

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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Scharton-Kersten, Tanya, Contursi, Cristina, Masumi, Atsuko, Sher, Alan, Ozato, Keiko·1997·The Journal of Experimental Medicine
DOI 10.1084/jem.186.9.1523PMC PMC2199126
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Abstract

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.

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  • ICSBP-/- mice are immunodeficient and susceptible to various pathogens.

    “ICSBP 2 / 2 mice are immunodeficient and susceptible to various pathogens.”

    From Review: ICSBP/IRF-8: Its Regulatory Roles in the Development of Myeloid Cells (2002) · cites this paper as [41]

  • ICSBP-/- mice have defects in macrophage function, including the ability to induce IL-12 p40 and some IFN-γ-responsible genes.

    “They have defects in the macrophage function, including the ability to induce interleukin-12 (IL-12) p40 and some IFNg -responsible genes.”

    From Review: ICSBP/IRF-8: Its Regulatory Roles in the Development of Myeloid Cells (2002) · cites this paper as [41]

  • Splenocytes or purified CD4+ T cells from ICSBP-/- mice could produce IFN-γ in vitro in response to ConA, IL-12, or anti-CD3 plus anti-CD28 antibodies.

    “On the other hand, splenocytes or purified CD4 1 T cells from ICSBP 2 / 2 mice could produce IFNg in vitro in response to concanavalin A (ConA), IL-12, or anti-CD3 plus anti-CD28 antibodies. (40,41,44)”

    From Review: ICSBP/IRF-8: Its Regulatory Roles in the Development of Myeloid Cells (2002) · cites this paper as [41]

  • ICSBP-/- macrophages or cells from draining lymph nodes are severely impaired in both basal and induced expression of the IL-12 p40 gene after infection, and a similar impairment occurs in peritoneal macrophages in response to various in vitro stimuli.

    “Strikingly, ICSBP 2 / 2 macrophages or cells from draining lymph nodes were severely impaired in both basal and induced expression of the IL-12 p40 gene after infection. (40,41)”

    From Review: ICSBP/IRF-8: Its Regulatory Roles in the Development of Myeloid Cells (2002) · cites this paper as [41]

  • ICSBP-/- mice are deficient in producing IL-12 and IFN-γ and are unable to mount a Th1-mediated response.

    “ICSBP 2 / 2 mice were shown to be deficient in producing IL-12 and IFNg and were unable to mount a Th1-mediated response. (37,40,41)”

    From Review: ICSBP/IRF-8: Its Regulatory Roles in the Development of Myeloid Cells (2002) · cites this paper as [41]

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  1. [39]Wang, A.M., and D.F. Mark. 1990. Quantitative PCR. In PCR Protocols. M.A. Innis, D.H. Gelfand, J.J. Sninsky, and T.J. White, editors. Academic Press, New York. 70–75.

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Authors
Scharton-Kersten, T., Contursi, C., Masumi, A., Sher, A., & Ozato, K.
Affiliations
  • 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
  • National Institutes of Health (US)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
1997-11-03
Volume
186
Issue
9
Pages
1523-1534
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.186.9.1523
PMC
PMC2199126
OpenAlex
W2144206734
Cited by
217
References
59
Citations by year
2026: 1 · 2025: 7 · 2024: 4 · 2023: 1 · 2022: 5 · 2021: 1 · 2020: 8 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 4 · 2014: 12 · 2013: 9 · 2012: 6
FWCI
11.93
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (MD 20892)
Topics
  • Life Sciences › Immunology and Microbiology › Parasitology › Toxoplasma gondii Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
interleukin-12p40, Toxoplasma gondii, interferon-gamma, macrophages, transcription factors, cytokine gene expression, host resistance to infection, interferon regulatory factors
MeSH terms
Interferon Regulatory Factor-8, Acute Disease, Animals, Carrier Proteins, Female, Immunity, Innate, Interferon-gamma, Male, Mice, Inbred C57BL, Repressor Proteins, RNA, Messenger, Spleen, Toxoplasma, Toxoplasmosis, Animal, Transcription Factors, Transcription, Genetic, Consensus Sequence, Macrophages, Peritoneal, Mice, Knockout, Interleukin-12, Interferon Regulatory Factors, Mice

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