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 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.
Sobiesiak
Malgorzata
M
Department of Physiology, University of Tübingen, Tübingen D-72076, Germany.
Shumilina
Ekaterina
E
Lam
Rebecca S
RS
Wölbing
Florian
F
Matzner
Nicole
N
Kaesler
Susanne
S
Zemtsova
Irina M
IM
Lupescu
Adrian
A
Zahir
Naima
N
Kuhl
Dietmar
D
Schaller
Martin
M
Biedermann
Tilo
T
Lang
Florian
F
D000707:Anaphylaxis / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D018390:Gene Targeting; D017874:Immediate-Early Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000099184:Serum-Glucocorticoid Regulated Kinases
D017874:Immediate-Early Proteins; D019869:Phosphatidylinositol 3-Kinases; D024681:Potassium Channels, Calcium-Activated; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases