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* Department of Physiology, University of Tübingen, Tübingen, Germany;
Department of Dermatology, University of Tübingen, Tübingen, Germany; and
Center for Molecular Neurobiology, Institute for Molecular and Cellular Cognition, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
The PI3K pathway plays a pivotal role in the stimulation of mast cells. PI3K-dependent kinases include the serum- and glucocorticoid-inducible kinase 1 (SGK1). The present study explored the role of SGK1 in mast cell function. Mast cells were isolated from bone marrow (BMMC) of SGK1 knockout mice (sgk1–/–) and their wild-type littermates (sgk1+/+). The BMMC number as well as CD117, CD34, and Fc
RI expression in BMCCs were similar in both genotypes. Upon Ag stimulation of the FcRI receptor, Ca2+ entry but not Ca2+ release from intracellular stores was markedly impaired in sgk1–/– BMMCs. The currents through Ca2+-activated K+ channels induced by Ag were significantly higher in sgk1+/+ BMMCs than in sgk1–/– BMMCs. Treatment with the Ca2+ ionophore ionomycin (1 µM) led to activation of the K+ channels in both genotypes, indicating that the Ca2+-activated K+ channels are similarly expressed and sensitive to activation by Ca2+ in sgk1+/+ and sgk1–/– BMMCs, and that blunted stimulation of Ca2+-activated K+ channels was secondary to decreased Ca2+ entry. Ag-IgE-induced degranulation and early IL-6 secretion were also significantly blunted in sgk1–/– BMMCs. The decrease in body temperature following Ag treatment, which reflects an anaphylactic reaction, was substantially reduced in sgk1–/– mice, pointing to impaired mast cell function in vivo. Serum histamine levels measured 30 min after induction of an anaphylactic reaction were significantly lower in sgk1–/– than in sgk1+/+mice. The observations reveal a critical role for SGK1 in ion channel regulation and the function of mast cells, and thus disclose a completely novel player in the regulation of allergic reaction.
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1 This work was supported by Deutsche Forschungsgemeinschaft (Grants SFB 766, SFB 685 A6, Bi 696/5-1, and Bi 696/3-1), the International Graduate School (Grant GRK 1302/1), The PI3K Pathway in Tumor Growth and Diabetes, and the FORTÜNE program of the University of Tübingen.
2 Contributed equally to the work and thus share first authorship.
3 Current address: Department of Molecular Neurogenetics, Max Planck Institute of Biophysics, Max-von-Laue Strasse 3, D-60438 Frankfurt am Main, Germany.
4 Address correspondence and reprint requests to Dr. Florian Lang or Dr. Tilo Biedermann, Department of Physiology, University of Tübingen, Gmelinstrasse 5, D-72076 Tübingen, Germany. E-mail address: florian.lang{at}uni-tuebingen.de or Department of Dermatology, University of Tübingen, Liebermeisterstrasse 25, D-72076 Tübingen, Germany. E-mail address: tilo.biedermann{at}med.uni-tuebingen.de
5 Abbreviations used in this paper: SGK1, serum- and glucocorticoid-inducible kinase-1; BMMC, bone marrow-derived mast cell; DNP-HSA, DNP-human serum albumin; TNCB, trinitrochlorobenzene; TRPV2, transient receptor potential cation channel, subfamily V, member 2; PDK1, phosphoinositide-dependent kinase.
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