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M. Nusrat Sharif¹, Draen oi³, Carla V. Rothlin⁴, Erin Kelly¹, Greg Lemke⁴, Eric N. Olson³, and Lionel B. Ivashkiv^1,2

¹ Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021
² Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021
³ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
⁴ Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, CA 92037

CORRESPONDENCE Lionel B. Ivashkiv: ivashkivl{at}hss.edu

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 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 production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNF 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-B–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 TNF 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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