Cell
Volume 131, Issue 6, 14 December 2007, Pages 1124-1136
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Article
TAM Receptors Are Pleiotropic Inhibitors of the Innate Immune Response

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Summary

The activation of Toll-like receptors (TLRs) in dendritic cells (DCs) triggers a rapid inflammatory response to pathogens. However, this response must be tightly regulated because unrestrained TLR signaling generates a chronic inflammatory milieu that often leads to autoimmunity. We have found that the TAM receptor tyrosine kinases—Tyro3, Axl, and Mer—broadly inhibit both TLR and TLR-induced cytokine-receptor cascades. Remarkably, TAM inhibition of inflammation is transduced through an essential stimulator of inflammation—the type I interferon receptor (IFNAR)—and its associated transcription factor STAT1. TLR induction of IFNAR-STAT1 signaling upregulates the TAM system, which in turn usurps the IFNAR-STAT1 cassette to induce the cytokine and TLR suppressors SOCS1 and SOCS3. These results illuminate a self-regulating cycle of inflammation, in which the obligatory, cytokine-dependent activation of TAM signaling hijacks a proinflammatory pathway to provide an intrinsic feedback inhibitor of both TLR- and cytokine-driven immune responses.

CELLIMMUNO
MOLIMMUNO

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4

These authors contributed equally to this work.

5

Present address: Department of Basic Medical Sciences, University of Arizona, Phoenix, AZ 85004, USA.

6

Present address: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.