Blunted IgE-mediated activation of mast cells in mice lacking the serum- and glucocorticoid-inducible kinase SGK3.
Previous studies have shown that pharmacological inhibition of the phosphoinositol-3 (PI3) kinase disrupts the activation of mast cells. Through phosphoinositide-dependent kinase PDK1, PI3 kinase activates the serum- and glucocorticoid-inducible kinase 3 (SGK3). The present study explored the role of SGK3 in mast cell function. Mast cells were isolated and cultured from bone marrow (BMMCs) of gene-targeted mice lacking SGK3 (sgk3(-/-)) and their wild-type littermates (sgk3(+/+)). BMMC numbers in the ear conch were similar in both genotypes. Stimulation with IgE and cognate antigen triggered the release of intracellular Ca(2+) and entry of extracellular Ca(2+). Influx of extracellular Ca(2+) but not Ca(2+) release from intracellular stores was significantly blunted in sgk3(-/-) BMMCs compared with sgk3(+/+) BMMCs. Antigen stimulation further led to a rapid increase of a K(+)-selective conductance in sgk3(+/+) BMMCs, an effect again blunted in sgk3(-/-) BMMCs. In contrast, the Ca(2+) ionophore ionomycin activated K(+) currents to a similar extent in sgk3(-/-) and in sgk3(+/+) BMMCs. β-Hexosaminidase release, triggered by antigen stimulation, was also significantly decreased in sgk3(-/-) BMMCs. IgE-dependent anaphylaxis measured as a sharp decrease in body temperature upon injection of DNP-HSA antigen was again significantly blunted in sgk3(-/-) compared with sgk3(+/+) mice. Serum histamine levels measured 30 min after induction of an anaphylactic reaction were significantly lower in sgk3(-/-) than in sgk3(+/+) mice. In conclusion, both in vitro and in vivo function of BMMCs are impaired in gene targeted mice lacking SGK3. Thus SGK3 is critical for proper mast cell function.
Zemtsova
Irina M
IM
Department of Physiology, University of Tübingen, Tübingen, Germany.
Heise
Nicole
N
Fröhlich
Henning
H
Qadri
Syed M
SM
Kucherenko
Yuliya
Y
Boini
Krishna M
KM
Pearce
David
D
Shumilina
Ekaterina
E
Lang
Florian
F
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation; D004423:Ear / Q000033:anatomy & histology; D005260:Female; D007073:Immunoglobulin E / Q000276:immunology*; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D002118:Calcium; D007073:Immunoglobulin E; D017346:Protein Serine-Threonine Kinases; D001619:beta-N-Acetylhexosaminidases; C523602:Sgk3 protein, mouse; D000099184:Serum-Glucocorticoid Regulated Kinases