Impaired Mast Cell Activation in Gene-Targeted Mice Lacking the Serum- and Glucocorticoid-Inducible Kinase SGK1

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 FceRI expression in BMCCs were similar in both genotypes. Upon Ag stimulation of the FceRI receptor, Ca 2+ entry but not Ca 2+ release from intracellular stores was markedly impaired in sgk1 −/− BMMCs. The currents through Ca 2+ -activated K + channels induced by Ag were significantly higher in sgk1 +/+ BMMCs than in sgk1 −/− BMMCs. Treatment with the Ca 2+ ionophore ionomycin (1 μM) led to activation of the K + channels in both genotypes, indicating that the Ca 2+ -activated K + channels are similarly expressed and sensitive to activation by Ca 2+ in sgk1 +/+ and sgk1 −/− BMMCs, and that blunted stimulation of Ca 2+ -activated K + channels was secondary to decreased Ca 2+ 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.