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 journalArticlepeer-review

    133 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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