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Sturm, EM; Parzmair, GP; Radnai, B; Frei, RB; Sturm, GJ; Hammer, A; Schuligoi, R; Lippe, IT; Heinemann, A.
Phosphoinositide-dependent protein kinase 1 (PDK1) mediates potent inhibitory effects on eosinophils.
Eur J Immunol. 2015; 45(5):1548-1559 [OPEN ACCESS]
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Autor/innen der Med Uni Graz:
Frei-Winterleitner Robert
Hammer Astrid
Heinemann Akos
Lippe Irmgard Theresia
Parzmair Gerald Peter
Radnai Balazs
Schuligoi Rufina
Sturm Eva
Sturm Gunter
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Abstract:
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. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Find related publications in this database (using NLM MeSH Indexing)
3-Phosphoinositide-Dependent Protein Kinases - antagonists & inhibitors
3-Phosphoinositide-Dependent Protein Kinases - metabolism
Active Transport, Cell Nucleus -
Animals -
CD11b Antigen - metabolism
Calcium Signaling -
Cell Shape -
Dinoprostone - metabolism
Eosinophils - drug effects
Eosinophils - immunology
Eosinophils - metabolism
Humans -
Indazoles - pharmacology
Methyl Ethers - pharmacology
Mice -
Mice, Inbred BALB C -
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation -
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
Pyrimidines - pharmacology
Receptors, Prostaglandin E, EP4 Subtype - agonists
Receptors, Prostaglandin E, EP4 Subtype - metabolism
Respiratory Burst -
Ribonucleosides - pharmacology
Signal Transduction - drug effects

Find related publications in this database (Keywords)
Eosinophils
EP4 receptor
Inflammation
PDK1 Prostaglandins
Signal transduction
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