| First Author | Sturm EM | Year | 2015 |
| Journal | Eur J Immunol | Volume | 45 |
| Issue | 5 | Pages | 1548-59 |
| PubMed ID | 25645675 | Mgi Jnum | J:229644 |
| Mgi Id | MGI:5752717 | Doi | 10.1002/eji.201445196 |
| Citation | Sturm EM, et al. (2015) Phosphoinositide-dependent protein kinase 1 (PDK1) mediates potent inhibitory effects on eosinophils. Eur J Immunol 45(5):1548-59 |
| abstractText | Prostaglandin E2 (PGE2 ) protects against allergic responses via binding to prostanoid receptor EP4, which inhibits eosinophil migration in a PI3K/PKC-dependent fashion. The phosphoinositide-dependent protein kinase 1 (PDK1) is known to act as a downstream effector in PI3K signaling and has been implicated in the regulation of neutrophil migration. Thus, here we elucidate whether PDK1 mediates inhibitory effects of E-type prostanoid receptor 4 (EP4) receptors on eosinophil function. Therefore, eosinophils were isolated from human peripheral blood or differentiated from mouse BM. PDK1 signaling was investigated in shape change, chemotaxis, CD11b, respiratory burst, and Ca(2+) mobilization assays. The specific PDK1 inhibitors BX-912 and GSK2334470 prevented the inhibition by prostaglandin E2 and the EP4 agonist ONO-AE1-329. Depending on the cellular function, PDK1 seemed to act through PI3K-dependent or PI3K-independent mechanisms. Stimulation of EP4 receptors caused PDK1 phosphorylation at Ser396 and induced PI3K-dependent nuclear translocation of PDK1. EP4-induced inhibition of shape change and chemotaxis was effectively reversed by the Akt inhibitor triciribine. In support of this finding, ONO-AE1-329 induced a PI3K/PDK1-dependent increase in Akt phosphorylation. In conclusion, our data illustrate a critical role for PDK1 in transducing inhibitory signals on eosinophil effector function. Thus, our results suggest that PDK1 might serve as a novel therapeutic target in diseases involving eosinophilic inflammation. |
