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TLR2 and TLR4 signaling in macrophages is negatively regulated by a Lyn-PI3K module and promoted by SHIP1

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We demonstrate here that the Src family kinase Lyn negatively regulates Toll-like receptor (TLR) signaling in bone marrow-derived macrophages (BMMΦs) and in vivo. Lyn-/- BMMΦs produced and secreted significantly more IL-6, TNF-α, and IFN-α/β compared to WT BMMΦs, indicating that Lyn is able to control both MyD88- and TRIF-dependent signaling pathways downstream of TLR4. CD14 was not involved in this type of regulation. Moreover, Lyn attenuated proinflammatory cytokine production in BMMΦs in response to the TLR2 ligand, FSL-1. In agreement with these in vitro experiments, Lyn-deficient mice produced higher amounts of proinflammatory cytokines than WT mice after i. v. injection of LPS or lipopeptide. Though Lyn clearly acted as a negative regulator downstream of TLR4, it did not, different to what was proposed previously, alter the process of LPS tolerance. Stimulation with a low dose of LPS resulted in reduced production of proinflammatory cytokines after a subsequent stimulation with a high dose of LPS in both WT and Lyn-/- BMMΦs as well as in viv o. Mechanistically, Lyn interacted with PI3K and in correlation, PI3K inhibition resulted in increased LPS-triggered cytokine production. In this line, SHIP1-deficient BMMΦs, exerting enhanced PI3K-pathway activation, produced less cytokines compared to WT BMMΦs. In conclusion, Lyn is a negative regulator of TLR-induced cytokine production in vitro and in vivo and acts, at least in part, via PI3K.

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Correspondence to S Keck.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keck, S., Freudenberg, M. & Huber, M. TLR2 and TLR4 signaling in macrophages is negatively regulated by a Lyn-PI3K module and promoted by SHIP1. Cell Commun Signal 7, A78 (2009) doi:10.1186/1478-811X-7-S1-A78

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Keywords

  • Signaling Pathway
  • Proinflammatory Cytokine
  • Cytokine Production
  • Negative Regulator
  • TLR4 Signaling