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Immunology

Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells

Leukemia volume 23, pages 535–544 (2009)Cite this article

Abstract

Toll-like receptors (TLRs) act to sense the environment for microbial products and submit danger signals to antigen-presenting cells (APCs) resulting in activation of complex immune responses. In this study, we analyzed the function of human monocyte-derived APCs generated in vitro in the presence of interleukin (IL)-10 upon activation by TLR ligands. Exposure of these APCs to IL-10 resulted in a skewed phenotypic maturation in response to stimuli provided by the TLR ligands, a reduced cytokine production, such as IL-12, IL-6 or tumor necrosis factor-α, and impaired capacity to stimulate T-cell activation. Furthermore, CCR7 upregulation in APCs exposed to TLR stimulation as well as migration towards CCL19/MIP-3β were strongly reduced. IL-10 was found to downregulate MyD88, IRAK1 (IL-1 receptor-associated kinase) and tumor necrosis factor receptor-associated factor 6, essential adaptor molecules for TLR signaling, and to decrease TLR-induced nuclear expression of the nuclear factor-κB transcription factors c-Rel and Rel-B as well as interferon regulatory factor (IRF)-3 and IRF-8. This was not due to the inhibition of the mitogen-activated protein kinase pathway, but was rather mediated by the blockage of the PI3K signaling cascade. Interestingly, the inhibition of proteins involved in TLR signaling, such as MyD88, IRAK1 and mammalian target of rapamycin, was due to a selective post-transcriptional regulation.

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Acknowledgements

We thank Sylvia Stephan and Bruni Schuster for excellent technical assistance. This study was financially supported by the DFG (SFB 685).

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Author notes

  1. A Knödler and S M Schmidt: Anja Knödler and Susanne M Schmidt contributed equally to this work.

  2. F Grünebach and P Brossart: Peter Brossart and Frank Grünebach share equal senior authorship.

Authors and Affiliations

  1. Department of Oncology, Hematology, Immunology, Rheumatology and Pulmology, University of Tübingen, Tübingen, Germany

    A Knödler, S M Schmidt, M M Weck, K M Brauer & F Grünebach

  2. Department of Internal Medicine III, Hematology and Oncology, University of Bonn, Bonn, Germany

    A Bringmann, T A W Holderried, A-K Heine & P Brossart

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  1. A Knödler
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Correspondence to P Brossart.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Knödler, A., Schmidt, S., Bringmann, A. et al. Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells. Leukemia 23, 535–544 (2009). https://doi.org/10.1038/leu.2008.301

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