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. 2007 Dec 14;131(6):1124-36.
doi: 10.1016/j.cell.2007.10.034.

TAM receptors are pleiotropic inhibitors of the innate immune response

Carla V Rothlin  1 , Sourav Ghosh, Elina I Zuniga, Michael B A Oldstone, Greg Lemke
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Free article

TAM receptors are pleiotropic inhibitors of the innate immune response

Carla V Rothlin et al. Cell. .
Free article

Abstract

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.

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