Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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"Köpfe" der aktuellen Meldungen:

Nina Höller

Nariae Baik-Schneditz

Bernhard Schwaberger

Lukas Peter Mileder

Niels Hammer

Gerhard Pichler

Roland Malli

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SHR Neuro Krebs Kardio Lipid Stoffw Microb

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 Doi: 10.1002/eji.201445196 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz: Böhm Eva
Co-Autor*innen der Med Uni Graz: Frei-Winterleitner Robert; Hammer Astrid; Heinemann Akos; Lippe Irmgard Theresia; Parzmair Gerald Peter; Radnai Balazs; Schuligoi Rufina; 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