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

The P13K pathway plays a pivotal role in the stimulation of mast cells. P13K-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 Fe epsilon RI expression in BMCCs were similar in both genotypes. Upon Ag stimulation of the Fc epsilon RI 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 mu M) 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(+/+) andsgk1(-/-) 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. The Journal of Immunology, 2009, 183: 4395-4402.