| First Author | MacKenzie KF | Year | 2013 |
| Journal | J Immunol | Volume | 190 |
| Issue | 2 | Pages | 565-77 |
| PubMed ID | 23241891 | Mgi Jnum | J:191723 |
| Mgi Id | MGI:5462479 | Doi | 10.4049/jimmunol.1202462 |
| Citation | Mackenzie KF, et al. (2013) PGE2 Induces Macrophage IL-10 Production and a Regulatory-like Phenotype via a Protein Kinase A-SIK-CRTC3 Pathway. J Immunol 190(2):565-77 |
| abstractText | 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. |
