期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 45, 期 5, 页码 1548-1559出版社
WILEY
DOI: 10.1002/eji.201445196
关键词
Eosinophils; EP4 receptor; Inflammation; PDK1 Prostaglandins; Signal transduction
类别
资金
- Franz Lanyar Stiftung of the Medical University of Graz [344]
- Jubilaeumsfonds of the Austrian National Bank [14446, 14263]
- Austrian Science Fund FWF [DK-MOLIN W1241, P26185, P22521]
- Austrian Science Fund (FWF) [P 22521] Funding Source: researchfish
- Austrian Science Fund (FWF) [P26185, W1241] Funding Source: Austrian Science Fund (FWF)
Prostaglandin E-2 (PGE(2)) 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 Ca2+ mobilization assays. The specific PDK1 inhibitors BX-912 and GSK2334470 prevented the inhibition by prostaglandin E-2 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.
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