PGE2 induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway

Kirsty F Mackenzie, Kristopher Clark, Shaista Naqvi, Victoria A McGuire, Gesa Nöehren, Yosua Kristariyanto, Mirjam van den Bosch, Manikhandan Mudaliar, Pierre C McCarthy, Michael J Pattison, Patrick G A Pedrioli, Geoff J Barton, Rachel Toth, Alan Prescott, J. Simon C. Arthur

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    Abstract

    The polarization of macrophages into a regulatory-like phenotype and the production of IL-10 plays an important role in the resolution of inflammation. We show in this study that PGE(2), in combination with LPS, is able to promote an anti-inflammatory phenotype in macrophages characterized by high expression of IL-10 and the regulatory markers SPHK1 and LIGHT via a protein kinase A-dependent pathway. Both TLR agonists and PGE(2) promote the phosphorylation of the transcription factor CREB on Ser(133). However, although CREB regulates IL-10 transcription, the mutation of Ser(133) to Ala in the endogenous CREB gene did not prevent the ability of PGE(2) to promote IL-10 transcription. Instead, we demonstrate that protein kinase A regulates the phosphorylation of salt-inducible kinase 2 on Ser(343), inhibiting its ability to phosphorylate CREB-regulated transcription coactivator 3 in cells. This in turn allows CREB-regulated transcription coactivator 3 to translocate to the nucleus where it serves as a coactivator with the transcription factor CREB to induce IL-10 transcription. In line with this, we find that either genetic or pharmacological inhibition of salt-inducible kinases mimics the effect of PGE(2) on IL-10 production.
    Original languageEnglish
    Pages (from-to)565-577
    Number of pages13
    JournalJournal of Immunology
    Volume190
    Issue number2
    DOIs
    Publication statusPublished - 15 Jan 2013

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    Cyclic AMP-Dependent Protein Kinases
    Dinoprostone
    Interleukin-10
    Macrophages
    Prostaglandins E
    Phenotype
    Transcription Factors
    Phosphotransferases
    Salts
    Phosphorylation
    Anti-Inflammatory Agents
    Pharmacology
    Inflammation
    Light
    Mutation
    Genes

    Cite this

    Mackenzie, Kirsty F ; Clark, Kristopher ; Naqvi, Shaista ; McGuire, Victoria A ; Nöehren, Gesa ; Kristariyanto, Yosua ; van den Bosch, Mirjam ; Mudaliar, Manikhandan ; McCarthy, Pierre C ; Pattison, Michael J ; Pedrioli, Patrick G A ; Barton, Geoff J ; Toth, Rachel ; Prescott, Alan ; Arthur, J. Simon C. / PGE2 induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. In: Journal of Immunology. 2013 ; Vol. 190, No. 2. pp. 565-577.
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    title = "PGE2 induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway",
    abstract = "The polarization of macrophages into a regulatory-like phenotype and the production of IL-10 plays an important role in the resolution of inflammation. We show in this study that PGE(2), in combination with LPS, is able to promote an anti-inflammatory phenotype in macrophages characterized by high expression of IL-10 and the regulatory markers SPHK1 and LIGHT via a protein kinase A-dependent pathway. Both TLR agonists and PGE(2) promote the phosphorylation of the transcription factor CREB on Ser(133). However, although CREB regulates IL-10 transcription, the mutation of Ser(133) to Ala in the endogenous CREB gene did not prevent the ability of PGE(2) to promote IL-10 transcription. Instead, we demonstrate that protein kinase A regulates the phosphorylation of salt-inducible kinase 2 on Ser(343), inhibiting its ability to phosphorylate CREB-regulated transcription coactivator 3 in cells. This in turn allows CREB-regulated transcription coactivator 3 to translocate to the nucleus where it serves as a coactivator with the transcription factor CREB to induce IL-10 transcription. In line with this, we find that either genetic or pharmacological inhibition of salt-inducible kinases mimics the effect of PGE(2) on IL-10 production.",
    author = "Mackenzie, {Kirsty F} and Kristopher Clark and Shaista Naqvi and McGuire, {Victoria A} and Gesa N{\"o}ehren and Yosua Kristariyanto and {van den Bosch}, Mirjam and Manikhandan Mudaliar and McCarthy, {Pierre C} and Pattison, {Michael J} and Pedrioli, {Patrick G A} and Barton, {Geoff J} and Rachel Toth and Alan Prescott and Arthur, {J. Simon C.}",
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    language = "English",
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    Mackenzie, KF, Clark, K, Naqvi, S, McGuire, VA, Nöehren, G, Kristariyanto, Y, van den Bosch, M, Mudaliar, M, McCarthy, PC, Pattison, MJ, Pedrioli, PGA, Barton, GJ, Toth, R, Prescott, A & Arthur, JSC 2013, 'PGE2 induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway', Journal of Immunology, vol. 190, no. 2, pp. 565-577. https://doi.org/10.4049/jimmunol.1202462

    PGE2 induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. / Mackenzie, Kirsty F; Clark, Kristopher; Naqvi, Shaista; McGuire, Victoria A; Nöehren, Gesa; Kristariyanto, Yosua; van den Bosch, Mirjam; Mudaliar, Manikhandan; McCarthy, Pierre C; Pattison, Michael J; Pedrioli, Patrick G A; Barton, Geoff J; Toth, Rachel; Prescott, Alan; Arthur, J. Simon C.

    In: Journal of Immunology, Vol. 190, No. 2, 15.01.2013, p. 565-577.

    Research output: Contribution to journalArticle

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    T1 - PGE2 induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway

    AU - Mackenzie, Kirsty F

    AU - Clark, Kristopher

    AU - Naqvi, Shaista

    AU - McGuire, Victoria A

    AU - Nöehren, Gesa

    AU - Kristariyanto, Yosua

    AU - van den Bosch, Mirjam

    AU - Mudaliar, Manikhandan

    AU - McCarthy, Pierre C

    AU - Pattison, Michael J

    AU - Pedrioli, Patrick G A

    AU - Barton, Geoff J

    AU - Toth, Rachel

    AU - Prescott, Alan

    AU - Arthur, J. Simon C.

    PY - 2013/1/15

    Y1 - 2013/1/15

    N2 - The polarization of macrophages into a regulatory-like phenotype and the production of IL-10 plays an important role in the resolution of inflammation. We show in this study that PGE(2), in combination with LPS, is able to promote an anti-inflammatory phenotype in macrophages characterized by high expression of IL-10 and the regulatory markers SPHK1 and LIGHT via a protein kinase A-dependent pathway. Both TLR agonists and PGE(2) promote the phosphorylation of the transcription factor CREB on Ser(133). However, although CREB regulates IL-10 transcription, the mutation of Ser(133) to Ala in the endogenous CREB gene did not prevent the ability of PGE(2) to promote IL-10 transcription. Instead, we demonstrate that protein kinase A regulates the phosphorylation of salt-inducible kinase 2 on Ser(343), inhibiting its ability to phosphorylate CREB-regulated transcription coactivator 3 in cells. This in turn allows CREB-regulated transcription coactivator 3 to translocate to the nucleus where it serves as a coactivator with the transcription factor CREB to induce IL-10 transcription. In line with this, we find that either genetic or pharmacological inhibition of salt-inducible kinases mimics the effect of PGE(2) on IL-10 production.

    AB - The polarization of macrophages into a regulatory-like phenotype and the production of IL-10 plays an important role in the resolution of inflammation. We show in this study that PGE(2), in combination with LPS, is able to promote an anti-inflammatory phenotype in macrophages characterized by high expression of IL-10 and the regulatory markers SPHK1 and LIGHT via a protein kinase A-dependent pathway. Both TLR agonists and PGE(2) promote the phosphorylation of the transcription factor CREB on Ser(133). However, although CREB regulates IL-10 transcription, the mutation of Ser(133) to Ala in the endogenous CREB gene did not prevent the ability of PGE(2) to promote IL-10 transcription. Instead, we demonstrate that protein kinase A regulates the phosphorylation of salt-inducible kinase 2 on Ser(343), inhibiting its ability to phosphorylate CREB-regulated transcription coactivator 3 in cells. This in turn allows CREB-regulated transcription coactivator 3 to translocate to the nucleus where it serves as a coactivator with the transcription factor CREB to induce IL-10 transcription. In line with this, we find that either genetic or pharmacological inhibition of salt-inducible kinases mimics the effect of PGE(2) on IL-10 production.

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    DO - 10.4049/jimmunol.1202462

    M3 - Article

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