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J Exp Med. 2006 Aug 7;203(8):1891-901. Epub 2006 Jul 10.

Twist mediates suppression of inflammation by type I IFNs and Axl.

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Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.


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.

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