Cargando…

The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases

Macrophages switch to an anti-inflammatory, ‘regulatory’-like phenotype characterized by the production of high levels of interleukin (IL)-10 and low levels of pro-inflammatory cytokines to promote the resolution of inflammation. A potential therapeutic strategy for the treatment of chronic inflamma...

Descripción completa

Detalles Bibliográficos
Autores principales: Ozanne, James, Prescott, Alan R., Clark, Kristopher
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286194/
https://www.ncbi.nlm.nih.gov/pubmed/25351958
http://dx.doi.org/10.1042/BJ20141165
_version_ 1782351650493562880
author Ozanne, James
Prescott, Alan R.
Clark, Kristopher
author_facet Ozanne, James
Prescott, Alan R.
Clark, Kristopher
author_sort Ozanne, James
collection PubMed
description Macrophages switch to an anti-inflammatory, ‘regulatory’-like phenotype characterized by the production of high levels of interleukin (IL)-10 and low levels of pro-inflammatory cytokines to promote the resolution of inflammation. A potential therapeutic strategy for the treatment of chronic inflammatory diseases would be to administer drugs that could induce the formation of ‘regulatory’-like macrophages at sites of inflammation. In the present study, we demonstrate that the clinically approved cancer drugs bosutinib and dasatinib induce several hallmark features of ‘regulatory’-like macrophages. Treatment of macrophages with bosutinib or dasatinib elevates the production of IL-10 while suppressing the production of IL-6, IL-12p40 and tumour necrosis factor α (TNFα) in response to Toll-like receptor (TLR) stimulation. Moreover, macrophages treated with bosutinib or dasatinib express higher levels of markers of ‘regulatory’-like macrophages including LIGHT, SPHK1 and arginase 1. Bosutinib and dasatinib were originally developed as inhibitors of the protein tyrosine kinases Bcr-Abl and Src but we show that, surprisingly, the effects of bosutinib and dasatinib on macrophage polarization are the result of the inhibition of the salt-inducible kinases. Consistent with the present finding, bosutinib and dasatinib induce the dephosphorylation of CREB-regulated transcription co-activator 3 (CRTC3) and its nuclear translocation where it induces a cAMP-response-element-binding protein (CREB)-dependent gene transcription programme including that of IL-10. Importantly, these effects of bosutinib and dasatinib on IL-10 gene expression are lost in macrophages expressing a drug-resistant mutant of salt-inducible kinase 2 (SIK2). In conclusion, our study identifies the salt-inducible kinases as major targets of bosutinib and dasatinib that mediate the effects of these drugs on the innate immune system and provides novel mechanistic insights into the anti-inflammatory properties of these drugs.
format Online
Article
Text
id pubmed-4286194
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Portland Press Ltd.
record_format MEDLINE/PubMed
spelling pubmed-42861942015-01-12 The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases Ozanne, James Prescott, Alan R. Clark, Kristopher Biochem J Research Article Macrophages switch to an anti-inflammatory, ‘regulatory’-like phenotype characterized by the production of high levels of interleukin (IL)-10 and low levels of pro-inflammatory cytokines to promote the resolution of inflammation. A potential therapeutic strategy for the treatment of chronic inflammatory diseases would be to administer drugs that could induce the formation of ‘regulatory’-like macrophages at sites of inflammation. In the present study, we demonstrate that the clinically approved cancer drugs bosutinib and dasatinib induce several hallmark features of ‘regulatory’-like macrophages. Treatment of macrophages with bosutinib or dasatinib elevates the production of IL-10 while suppressing the production of IL-6, IL-12p40 and tumour necrosis factor α (TNFα) in response to Toll-like receptor (TLR) stimulation. Moreover, macrophages treated with bosutinib or dasatinib express higher levels of markers of ‘regulatory’-like macrophages including LIGHT, SPHK1 and arginase 1. Bosutinib and dasatinib were originally developed as inhibitors of the protein tyrosine kinases Bcr-Abl and Src but we show that, surprisingly, the effects of bosutinib and dasatinib on macrophage polarization are the result of the inhibition of the salt-inducible kinases. Consistent with the present finding, bosutinib and dasatinib induce the dephosphorylation of CREB-regulated transcription co-activator 3 (CRTC3) and its nuclear translocation where it induces a cAMP-response-element-binding protein (CREB)-dependent gene transcription programme including that of IL-10. Importantly, these effects of bosutinib and dasatinib on IL-10 gene expression are lost in macrophages expressing a drug-resistant mutant of salt-inducible kinase 2 (SIK2). In conclusion, our study identifies the salt-inducible kinases as major targets of bosutinib and dasatinib that mediate the effects of these drugs on the innate immune system and provides novel mechanistic insights into the anti-inflammatory properties of these drugs. Portland Press Ltd. 2015-01-06 2015-01-15 /pmc/articles/PMC4286194/ /pubmed/25351958 http://dx.doi.org/10.1042/BJ20141165 Text en © 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC-BY)(http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Ozanne, James
Prescott, Alan R.
Clark, Kristopher
The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases
title The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases
title_full The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases
title_fullStr The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases
title_full_unstemmed The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases
title_short The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases
title_sort clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286194/
https://www.ncbi.nlm.nih.gov/pubmed/25351958
http://dx.doi.org/10.1042/BJ20141165
work_keys_str_mv AT ozannejames theclinicallyapproveddrugsdasatinibandbosutinibinduceantiinflammatorymacrophagesbyinhibitingthesaltinduciblekinases
AT prescottalanr theclinicallyapproveddrugsdasatinibandbosutinibinduceantiinflammatorymacrophagesbyinhibitingthesaltinduciblekinases
AT clarkkristopher theclinicallyapproveddrugsdasatinibandbosutinibinduceantiinflammatorymacrophagesbyinhibitingthesaltinduciblekinases
AT ozannejames clinicallyapproveddrugsdasatinibandbosutinibinduceantiinflammatorymacrophagesbyinhibitingthesaltinduciblekinases
AT prescottalanr clinicallyapproveddrugsdasatinibandbosutinibinduceantiinflammatorymacrophagesbyinhibitingthesaltinduciblekinases
AT clarkkristopher clinicallyapproveddrugsdasatinibandbosutinibinduceantiinflammatorymacrophagesbyinhibitingthesaltinduciblekinases