Twist mediates suppression of inflammation by type IIFNs and Axl

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 TNF alpha 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 TNF alpha production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNF alpha production was mediated by induction and activation of the AxI receptor tyrosine kinase and downstream induction of Twist transcriptional repressors that bind to E box elements in the TNF promoter and suppress NF-kappa B-dependent transcription. Twist expression was activated by the AxI ligand Gas6 and by protein S and apoptotic cells. These results implicate Twist proteins in regulation of TNF alpha production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and AxI receptors suppress inflammatory cytokine production.