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Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages

The salt-inducible kinases (SIKs) control a novel molecular switch regulating macrophage polarization. Pharmacological inhibition of the SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion...

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Detalles Bibliográficos
Autores principales: Darling, Nicola J., Toth, Rachel, Arthur, J. Simon C., Clark, Kristopher
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290485/
https://www.ncbi.nlm.nih.gov/pubmed/27920213
http://dx.doi.org/10.1042/BCJ20160646
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author Darling, Nicola J.
Toth, Rachel
Arthur, J. Simon C.
Clark, Kristopher
author_facet Darling, Nicola J.
Toth, Rachel
Arthur, J. Simon C.
Clark, Kristopher
author_sort Darling, Nicola J.
collection PubMed
description The salt-inducible kinases (SIKs) control a novel molecular switch regulating macrophage polarization. Pharmacological inhibition of the SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion of very low levels of pro-inflammatory cytokines, such as tumour necrosis factor α. The SIKs, therefore, represent attractive new drug targets for the treatment of macrophage-driven diseases, but which of the three isoforms, SIK1, SIK2 or SIK3, would be appropriate to target remains unknown. To address this question, we developed knock-in (KI) mice for SIK1, SIK2 and SIK3, in which we introduced a mutation that renders the enzymes catalytically inactive. Characterization of primary macrophages from the single and double KI mice established that all three SIK isoforms, and in particular SIK2 and SIK3, contribute to macrophage polarization. Moreover, we discovered that inhibition of SIK2 and SIK3 during macrophage differentiation greatly enhanced the production of IL-10 compared with their inhibition in mature macrophages. Interestingly, macrophages differentiated in the presence of SIK inhibitors, MRT199665 and HG-9-91-01, still produced very large amounts of IL-10, but very low levels of pro-inflammatory cytokines, even after the SIKs had been reactivated by removal of the drugs. Our data highlight an integral role for SIK2 and SIK3 in innate immunity by preventing the differentiation of macrophages into a potent and stable anti-inflammatory phenotype.
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spelling pubmed-52904852017-02-08 Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages Darling, Nicola J. Toth, Rachel Arthur, J. Simon C. Clark, Kristopher Biochem J Research Articles The salt-inducible kinases (SIKs) control a novel molecular switch regulating macrophage polarization. Pharmacological inhibition of the SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion of very low levels of pro-inflammatory cytokines, such as tumour necrosis factor α. The SIKs, therefore, represent attractive new drug targets for the treatment of macrophage-driven diseases, but which of the three isoforms, SIK1, SIK2 or SIK3, would be appropriate to target remains unknown. To address this question, we developed knock-in (KI) mice for SIK1, SIK2 and SIK3, in which we introduced a mutation that renders the enzymes catalytically inactive. Characterization of primary macrophages from the single and double KI mice established that all three SIK isoforms, and in particular SIK2 and SIK3, contribute to macrophage polarization. Moreover, we discovered that inhibition of SIK2 and SIK3 during macrophage differentiation greatly enhanced the production of IL-10 compared with their inhibition in mature macrophages. Interestingly, macrophages differentiated in the presence of SIK inhibitors, MRT199665 and HG-9-91-01, still produced very large amounts of IL-10, but very low levels of pro-inflammatory cytokines, even after the SIKs had been reactivated by removal of the drugs. Our data highlight an integral role for SIK2 and SIK3 in innate immunity by preventing the differentiation of macrophages into a potent and stable anti-inflammatory phenotype. Portland Press Ltd. 2017-02-15 2017-02-03 /pmc/articles/PMC5290485/ /pubmed/27920213 http://dx.doi.org/10.1042/BCJ20160646 Text en © 2017 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0) .
spellingShingle Research Articles
Darling, Nicola J.
Toth, Rachel
Arthur, J. Simon C.
Clark, Kristopher
Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages
title Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages
title_full Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages
title_fullStr Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages
title_full_unstemmed Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages
title_short Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages
title_sort inhibition of sik2 and sik3 during differentiation enhances the anti-inflammatory phenotype of macrophages
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290485/
https://www.ncbi.nlm.nih.gov/pubmed/27920213
http://dx.doi.org/10.1042/BCJ20160646
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