title: PGE(2) 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.
authors.affiliation: Medical Research Council Protein Phosphorylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors.forename: Kirsty F
authors.initials: KF
authors.lastname: MacKenzie
authors.forename: Kristopher
authors.initials: K
authors.lastname: Clark
authors.forename: Shaista
authors.initials: S
authors.lastname: Naqvi
authors.forename: Victoria A
authors.initials: VA
authors.lastname: McGuire
authors.forename: Gesa
authors.initials: G
authors.lastname: Nöehren
authors.forename: Yosua
authors.initials: Y
authors.lastname: Kristariyanto
authors.forename: Mirjam
authors.initials: M
authors.lastname: van den Bosch
authors.forename: Manikhandan
authors.initials: M
authors.lastname: Mudaliar
authors.forename: Pierre C
authors.initials: PC
authors.lastname: McCarthy
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pattison
authors.forename: Patrick G A
authors.initials: PG
authors.lastname: Pedrioli
authors.forename: Geoff J
authors.initials: GJ
authors.lastname: Barton
authors.forename: Rachel
authors.initials: R
authors.lastname: Toth
authors.forename: Alan
authors.initials: A
authors.lastname: Prescott
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C555318:CRTC3 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D016753:Interleukin-10; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone