Abstract
Type I interferon (IFN)-alpha/beta and type II IFN-gamma induce the expression of early response genes through activation of the Janus tyrosine kinase/signal transducer and activator of transcription (Stat) pathway. Although IFNs regulate a variety of other signaling cascades, little is known about how they contribute to the biological activities of these cytokines. In this study, we demonstrate that IFN-beta or IFN-gamma induces the phosphorylation of the serine/threonine kinase Akt in primary human peripheral blood monocytes. Abrogation of the IFN-stimulated Akt activation by phosphatidylinositol-3 kinase (PI-3K) inhibitors prevents IFN-induced adhesion in these cells, and IFN activation of the Stat1-dependent guanylate-binding protein (GBP) gene is not affected. Importantly, Stat1-deficient bone marrow macrophages displayed a similar level of IFN-gamma-stimulated adhesion compared with macrophages derived from wild-type littermates. These findings demonstrate for the first time that IFN stimulation of a PI-3K signaling cascade modulates the ability of these cytokines to regulate monocyte adhesion, and this process does not require the expression of Stat1, a primary mediator of IFN-gamma signaling.
MeSH terms
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Animals
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Blotting, Northern
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Bone Marrow Cells
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Cell Adhesion / drug effects
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Cells, Cultured / drug effects
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Chromones / pharmacology
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DNA-Binding Proteins / metabolism*
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Enzyme Inhibitors / pharmacology
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GTP-Binding Proteins / metabolism
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Gene Expression Regulation
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Humans
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Interferon-beta / pharmacology*
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Interferon-gamma / pharmacology*
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Macrophages / metabolism
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Mice
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Mice, Knockout
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Monocytes / metabolism*
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Ribonuclease, Pancreatic / metabolism
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STAT1 Transcription Factor
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Signal Transduction / physiology*
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Trans-Activators / metabolism*
Substances
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Chromones
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DNA-Binding Proteins
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Enzyme Inhibitors
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GBP1 protein, human
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Gbp2b protein, mouse
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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Stat1 protein, mouse
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Trans-Activators
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Interferon-beta
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Interferon-gamma
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Ribonuclease, Pancreatic
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GTP-Binding Proteins