Abstract
2-aminopurine (2-AP) is widely used as a specific inhibitor for double stranded-RNA dependent protein kinase (PKR). Here we report that 2-AP can inhibit lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production through the prevention of interferon (IFN)-beta production. 2-AP significantly inhibited NO production in LPS-stimulated RAW 264 murine macrophage cells. 2-AP also reduced the expression of IFN-beta and IFN-inducible genes, such as IFN-gamma-inducible protein (IP)-10 and immune-responsive gene (IRG)-1, and the inducible type of NO synthase (iNOS) mRNA in response to LPS. The addition of exogenous IFN-beta restored 2-AP-inhibited NO production in response to LPS. On the other hand, there was only partial inhibition by 2-AP of nuclear factor (NF)-kappaB activation, IL-6 mRNA expression and tumor necrosis factor (TNF)-alpha production. These results suggested that 2-AP inhibited LPS-induced IFN-beta production by preventing Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent signaling rather than myeloid differentiation factor (MyD) 88-dependent signaling, resulting in the inhibition of NO production.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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2-Aminopurine / pharmacology*
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Adaptor Proteins, Vesicular Transport / immunology
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Animals
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Antimetabolites / pharmacology*
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Drug Interactions
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Interferon-beta / antagonists & inhibitors
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Interferon-beta / biosynthesis*
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Interferon-beta / immunology
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Interferon-gamma / immunology
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Lipopolysaccharides / antagonists & inhibitors*
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Nitric Oxide / biosynthesis*
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Nitric Oxide / immunology
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Nitric Oxide / metabolism
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / immunology
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Nitric Oxide Synthase Type II
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Poly I-C / pharmacology
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RNA / chemistry
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RNA / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / immunology*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
Substances
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Adaptor Proteins, Vesicular Transport
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Antimetabolites
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Lipopolysaccharides
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TICAM-1 protein, mouse
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Tumor Necrosis Factor-alpha
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Nitric Oxide
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2-Aminopurine
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RNA
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Interferon-beta
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Interferon-gamma
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Poly I-C