Abstract
IFN-gamma induces its immunoregulatory activities by activating genes mainly through the Jak-STAT signaling pathway. Here we show that what was considered to be intrinsic IFN-gamma activities depend largely on the basal level of NF-kappaB, which is maintained by constitutively expressed IL-1alpha. The IL-1 receptor antagonist and antibodies to IL-1alpha, but not to IL-1beta, inhibited the antiviral activity of IFN-gamma by 90%, whereas no inhibition of type I IFN activity was observed. Similarly, the induction of many genes by IFN-gamma, including HLA-DR, ICAM-1, IL-18BP, and genes mediating its antiviral activity, greatly depended on basal IL-1alpha. Furthermore, IFN-gamma induced serum IL-18 binding protein in wild-type mice but not in IL-1alpha/beta double-deficient mice. Thus, constitutively expressed IL-1alpha is critical for numerous IFN-gamma activities.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antiviral Agents / pharmacology*
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Gene Expression Regulation / drug effects
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Humans
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Intercellular Signaling Peptides and Proteins / blood
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Intercellular Signaling Peptides and Proteins / genetics
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Interferon Regulatory Factor-1 / metabolism
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Interferon-gamma / immunology*
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Interferon-gamma / pharmacology*
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Interleukin-1alpha / antagonists & inhibitors
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Interleukin-1alpha / metabolism*
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Oligonucleotide Array Sequence Analysis
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Interleukin-1 / antagonists & inhibitors
Substances
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Antiviral Agents
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Intercellular Signaling Peptides and Proteins
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Interferon Regulatory Factor-1
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Interleukin-1alpha
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Membrane Proteins
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NF-kappa B
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RNA, Messenger
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Receptors, Interleukin-1
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interleukin-18 binding protein
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Interferon-gamma