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

James Ozanne, Alan R. Prescott, Kristopher Clark (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    24 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)271-279
    Number of pages9
    JournalBiochemical Journal
    Volume465
    Issue number2
    DOIs
    Publication statusPublished - 15 Jan 2015

    Fingerprint

    Macrophages
    Anti-Inflammatory Agents
    Phosphotransferases
    Salts
    Pharmaceutical Preparations
    Interleukin-10
    Cyclic AMP Response Element-Binding Protein
    Transcription
    Inflammation
    Arginase
    src-Family Kinases
    bosutinib
    Dasatinib
    Immune system
    Toll-Like Receptors
    Interleukins
    Gene expression
    Protein-Tyrosine Kinases
    Immune System
    Interleukin-6

    Keywords

    • Aniline Compounds
    • Animals
    • Arginase
    • Cells, Cultured
    • Cyclic AMP Response Element-Binding Protein
    • Cytokines
    • Immunity, Innate
    • Macrophages
    • Mice
    • Nitriles
    • Phosphotransferases (Alcohol Group Acceptor)
    • Protein Kinase Inhibitors
    • Protein-Serine-Threonine Kinases
    • Pyrimidines
    • Quinolines
    • Thiazoles
    • Transcription Factors
    • Tumor Necrosis Factor Ligand Superfamily Member 14

    Cite this

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    abstract = "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.",
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    The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases. / Ozanne, James; Prescott, Alan R.; Clark, Kristopher (Lead / Corresponding author).

    In: Biochemical Journal, Vol. 465, No. 2, 15.01.2015, p. 271-279.

    Research output: Contribution to journalArticle

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