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 FcεRI expression in BMCCs were similar in both genotypes. Upon Ag stimulation of the FcεRI receptor, Ca ²⁺ entry but not Ca²⁺ 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 Ca²⁺ 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 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.