Abstract
Type I interferons (IFNs) are pleiotropic cytokines with antiviral and immunomodulatory properties. The immunosuppressive actions of type I IFNs are poorly understood, but IFN-mediated suppression of TNFalpha production has been implicated in the regulation of inflammation and contributes to the effectiveness of type I IFNs in the treatment of certain autoimmune and inflammatory diseases. In this study, we investigated mechanisms by which type I IFNs suppress induction of TNFalpha production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNFalpha production was mediated by induction and activation of the Axl receptor tyrosine kinase and downstream induction of Twist transcriptional repressors that bind to E box elements in the TNF promoter and suppress NF-kappaB-dependent transcription. Twist expression was activated by the Axl ligand Gas6 and by protein S and apoptotic cells. These results implicate Twist proteins in regulation of TNFalpha production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and Axl receptors suppress inflammatory cytokine production.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axl Receptor Tyrosine Kinase
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Cells, Cultured
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Cytokines / genetics
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Gene Expression Regulation / drug effects
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Humans
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Inflammation / immunology*
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Interferon-alpha / pharmacology*
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Macrophages / drug effects
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Mice
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Models, Biological
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptors, Fc / metabolism
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Signal Transduction / drug effects
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Toll-Like Receptor 2 / metabolism
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Toll-Like Receptor 4 / metabolism
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
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Twist-Related Protein 1 / metabolism*
Substances
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Cytokines
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Interferon-alpha
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Oncogene Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Fc
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TLR2 protein, human
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TLR4 protein, human
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Tlr4 protein, mouse
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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Twist-Related Protein 1
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Receptor Protein-Tyrosine Kinases
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Axl Receptor Tyrosine Kinase