Details

Autor(en) / Beteiligte

• 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

Titel

PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway

Ist Teil von

• The Journal of immunology (1950), 2013-01, Vol.190 (2), p.565

Ort / Verlag

United States

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.