Impaired mast cell activation in gene-targeted mice lacking the serum- and glucocorticoid-inducible kinase SGK1.

Abstract

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 FcepsilonRI expression in BMCCs were similar in both genotypes. Upon Ag stimulation of the FcepsilonRI 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 microM) 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.

• Authors: Malgorzata Sobiesiak, Ekaterina Shumilina, Rebecca S Lam, Florian Wölbing, Nicole Matzner, Susanne Kaesler, Irina M Zemtsova, Adrian Lupescu, Naima Zahir, Dietmar Kuhl, Martin Schaller, Tilo Biedermann, Florian Lang
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 183 Issue 7 Pg. 4395-402 (Oct 01 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19748978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immediate-Early Proteins
• Potassium Channels, Calcium-Activated
• Protein Serine-Threonine Kinases
• serum-glucocorticoid regulated kinase

Topics

• Anaphylaxis (enzymology, immunology, metabolism, pathology)
• Animals
• Bone Marrow Cells (enzymology, immunology, metabolism, pathology)
• Cells, Cultured
• Female
• Gene Targeting
• Immediate-Early Proteins (deficiency, genetics, physiology)
• Male
• Mast Cells (enzymology, immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphatidylinositol 3-Kinases (physiology)
• Potassium Channels, Calcium-Activated (biosynthesis, genetics, physiology)
• Protein Serine-Threonine Kinases (deficiency, genetics, physiology)