Abstract
IFN regulatory factors (IRFs) are a family of transcription factors and include several members that regulate expression of pro- and anti-inflammatory genes. Mice with a targeted mutation in IRF-2 (IRF-2(-/-)) were studied after injection of LPS to evaluate the importance of IRF-2 in the regulation of endotoxicity. IRF-2(-/-) mice were highly refractory to LPS-induced lethality. Although hepatic TNF-alpha mRNA and circulating TNF-alpha were significantly elevated in LPS-challenged IRF-2(-/-) mice, levels of IL-1, IL-12, and IFN-gamma mRNA and protein, as well as IL-6 protein, were significantly lower than levels seen in LPS-challenged IRF-2(+/+) mice. IRF-2(-/-) mice were also more refractory to TNF-alpha challenge than were control mice, which was consistent with their diminished sensitivity to LPS, yet no significant difference in the mRNA expression of TNFRs was observed. IL-12R beta 2 mRNA levels from LPS-challenged IRF-2(-/-) mice were significantly different after 1, 6, and 8 h, suggesting that both diminished IL-12 and altered IL-12R expression contribute to the paucity of IFN-gamma produced. IRF-2 knockout mice also failed to sustain LPS-inducible levels of IRF-1 and IFN consensus sequence binding protein mRNA expression, two transacting factors required for IL-12 transcription, perhaps as a result of diminished IL-1 beta, IL-6, and IFN-gamma levels. Liver sections from IRF-2(+/+) and IRF-2(-/-) mice were analyzed 6 h after a typically lethal injection of LPS. IRF-2(-/-) mice exhibited greater numbers of apoptotic Kupffer cells than did wild-type mice, suggesting a novel anti-apoptotic role for IRF-2. Collectively, these findings reveal a critical role for IRF-2 in endotoxicity, and point to a previously unappreciated role for IRF-2 in the regulation of apoptosis.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, CD / biosynthesis
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Antigens, CD / genetics
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Apoptosis / immunology
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Endotoxemia / genetics
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Endotoxemia / immunology
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Endotoxemia / mortality
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Gene Expression Regulation / immunology
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Immunity, Innate / genetics
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Injections, Intraperitoneal
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Interferon Regulatory Factor-2
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Interferon Regulatory Factors
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / biosynthesis
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Interleukin-1 / antagonists & inhibitors
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Interleukin-1 / biosynthesis
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Interleukin-10 / biosynthesis
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Interleukin-10 / genetics
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / biosynthesis
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Interleukin-12 / metabolism
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / biosynthesis
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Kupffer Cells / cytology
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Kupffer Cells / immunology
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Lipopolysaccharides / administration & dosage
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Lipopolysaccharides / toxicity*
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Liver / immunology
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Liver / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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RNA, Messenger / biosynthesis
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Receptors, Interleukin / biosynthesis
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Receptors, Interleukin / genetics
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Receptors, Interleukin-12
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Receptors, Tumor Necrosis Factor / biosynthesis
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Recombinant Proteins / administration & dosage
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Recombinant Proteins / toxicity
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Repressor Proteins / biosynthesis
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Repressor Proteins / genetics
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Transcription Factors*
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Tumor Necrosis Factor-alpha / administration & dosage
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Tumor Necrosis Factor-alpha / toxicity
Substances
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Antigens, CD
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DNA-Binding Proteins
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Interferon Regulatory Factor-2
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Interferon Regulatory Factors
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Interleukin-1
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Interleukin-6
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Irf2 protein, mouse
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Lipopolysaccharides
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RNA, Messenger
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Receptors, Interleukin
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Receptors, Interleukin-12
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Recombinant Proteins
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Repressor Proteins
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Transcription Factors
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Tumor Necrosis Factor-alpha
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interferon regulatory factor-8
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Interleukin-10
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Interleukin-12
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Interferon-gamma