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The role of TRKA signaling in IL-10 production by apoptotic tumor cell-activated macrophages

Oncogene volume 32, pages 631–640 (2013)Cite this article

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Abstract

Tumor-associated macrophages (TAMs) are a major supportive component within neoplasms. Mechanisms of macrophage (MΦ) attraction and differentiation to a tumor-promoting phenotype, which is characterized by pronounced interleukin (IL)-10 production, are under investigation. We report that supernatants of dying cancer cells induced substantial IL-10 release from primary human MΦs, dependent on signaling through tyrosine kinase receptor A (TRKA or neurotrophic tyrosine kinase receptor type 1 (NTRK1)). Mechanistically, sphingosine-1-phosphate (S1P) release from apoptotic cancer cells triggered src-dependent shuttling of cytosolic TRKA to the plasma membrane via S1P receptor signaling. Plasma membrane-associated TRKA, which was activated by constitutively autocrine secreted nerve growth factor, used phosphatidylinositol 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase (MAPK) signaling to induce IL-10. Interestingly, TRKA-dependent signaling was required for cytokine production by TAMs isolated from primary murine breast cancer tissue. Besides IL-10, this pathway initiated secretion of IL-6, tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1), indicating relevance in cancer-associated inflammation. Our findings highlight a fine-tuned regulatory system including S1P-dependent TRKA trafficking for executing TAM-like cell function in vitro as well as in vivo.

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Acknowledgements

The work was supported by DFG (Br999, FOG 784, GRK 757), Sander Foundation (2007.070.2) and Deutsche Krebshilfe (109599). We are grateful to Yves-Alain Barde for sharing the HA-TRKA expression plasmid and thank Franz Josef Streb, Magarethe Wiebe and Karina Pfister for excellent technical assistance.

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Authors and Affiliations

  1. Institute of Biochemistry I/ZAFES, Goethe-University Frankfurt, Frankfurt, Germany

    S Ley, A Weigert, B Weichand, N Henke & B Brüne

  2. BioFocus Ltd, Leiden, The Netherlands

    B Mille-Baker

  3. Galapagos BV, Leiden, The Netherlands

    R A J Janssen

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  1. S Ley
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Correspondence to B Brüne.

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Ley, S., Weigert, A., Weichand, B. et al. The role of TRKA signaling in IL-10 production by apoptotic tumor cell-activated macrophages. Oncogene 32, 631–640 (2013). https://doi.org/10.1038/onc.2012.77

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