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

    Research output: Contribution to journalArticle

    126 Citations (Scopus)

    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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  • Cite this

    Mackenzie, K. F., Clark, K., Naqvi, S., McGuire, V. A., Nöehren, G., Kristariyanto, Y., van den Bosch, M., Mudaliar, M., McCarthy, P. C., Pattison, M. J., Pedrioli, P. G. A., Barton, G. J., Toth, R., Prescott, A., & Arthur, J. S. C. (2013). PGE2 induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. Journal of Immunology, 190(2), 565-577. https://doi.org/10.4049/jimmunol.1202462