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Interferon consensus sequence binding protein-deficient mice display impaired resistance to intracellular infection due to a primary defect in interleukin 12 p40 induction.

Scharton-Kersten T, Contursi C, Masumi A, Sher A, Ozato K - J. Exp. Med. (1997)

Bottom Line: 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.This selective defect in IL-12 p40 production was observed regardless of whether the macrophages had been primed with IFN-gamma.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.

View Article: PubMed Central - PubMed

Affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-2753, USA.

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)-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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Con A–induced IFN-γ production by spleen cells from uninfected ICSBP+/+, ICSBP−/−, and IL-12 p40−/− mice. Spleen cells were  cultured with media alone (white bars) or Con A (black bars) at 5 μg/ml  and the supernatants assayed for IFN-γ 72 h later. Cytokine synthesis  (mean ± SE) is shown for four individual animals per group.
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Figure 3: Con A–induced IFN-γ production by spleen cells from uninfected ICSBP+/+, ICSBP−/−, and IL-12 p40−/− mice. Spleen cells were cultured with media alone (white bars) or Con A (black bars) at 5 μg/ml and the supernatants assayed for IFN-γ 72 h later. Cytokine synthesis (mean ± SE) is shown for four individual animals per group.

Mentions: Since IL-12 triggers early IFN-γ synthesis in T. gondii-infected mice (reviewed in reference 28), we asked whether the diminished IFN-γ expression might result from defective IL-12 activity in the ICSBP−/− mice. Whereas IL-12 p40 increased dramatically in the serum and in cultures of peritoneal and spleen cells from wt mice, these responses were essentially absent in the mutant animals (Fig. 2 B). Levels of IL-12 p40 protein were also two- to threefold lower in serum and splenic cell cultures from naive ICSBP−/− compared with ICSBP+/+ mice. Notably, however, spleen cells from ICSBP−/− mice produced substantial amounts of IFN-γ when stimulated with concanavalin A, a response which is IL-12 p40 independent (Fig. 3).


Interferon consensus sequence binding protein-deficient mice display impaired resistance to intracellular infection due to a primary defect in interleukin 12 p40 induction.

Scharton-Kersten T, Contursi C, Masumi A, Sher A, Ozato K - J. Exp. Med. (1997)

Con A–induced IFN-γ production by spleen cells from uninfected ICSBP+/+, ICSBP−/−, and IL-12 p40−/− mice. Spleen cells were  cultured with media alone (white bars) or Con A (black bars) at 5 μg/ml  and the supernatants assayed for IFN-γ 72 h later. Cytokine synthesis  (mean ± SE) is shown for four individual animals per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199126&req=5

Figure 3: Con A–induced IFN-γ production by spleen cells from uninfected ICSBP+/+, ICSBP−/−, and IL-12 p40−/− mice. Spleen cells were cultured with media alone (white bars) or Con A (black bars) at 5 μg/ml and the supernatants assayed for IFN-γ 72 h later. Cytokine synthesis (mean ± SE) is shown for four individual animals per group.
Mentions: Since IL-12 triggers early IFN-γ synthesis in T. gondii-infected mice (reviewed in reference 28), we asked whether the diminished IFN-γ expression might result from defective IL-12 activity in the ICSBP−/− mice. Whereas IL-12 p40 increased dramatically in the serum and in cultures of peritoneal and spleen cells from wt mice, these responses were essentially absent in the mutant animals (Fig. 2 B). Levels of IL-12 p40 protein were also two- to threefold lower in serum and splenic cell cultures from naive ICSBP−/− compared with ICSBP+/+ mice. Notably, however, spleen cells from ICSBP−/− mice produced substantial amounts of IFN-γ when stimulated with concanavalin A, a response which is IL-12 p40 independent (Fig. 3).

Bottom Line: 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.This selective defect in IL-12 p40 production was observed regardless of whether the macrophages had been primed with IFN-gamma.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.

View Article: PubMed Central - PubMed

Affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-2753, USA.

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)-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.

Show MeSH
Related in: MedlinePlus