Blunted IgE-mediated activation of mast cells in mice lacking the serum- and glucocorticoid-inducible kinase SGK3.

Abstract

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.

• Authors: Irina M Zemtsova, Nicole Heise, Henning Fröhlich, Syed M Qadri, Yuliya Kucherenko, Krishna M Boini, David Pearce, Ekaterina Shumilina, Florian Lang
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 299 Issue 5 Pg. C1007-14 (Nov 2010) ISSN: 1522-1563 [Electronic] United States
• PMID: 20686074 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Immunoglobulin E
• Protein Serine-Threonine Kinases
• Sgk3 protein, mouse
• beta-N-Acetylhexosaminidases
• Calcium

Topics

• Animals
• Bone Marrow Cells (cytology, immunology)
• Calcium (metabolism)
• Cell Degranulation
• Ear (anatomy & histology)
• Female
• Immunoglobulin E (immunology)
• Male
• Mast Cells (cytology, immunology)
• Mice
• Mice, Knockout
• Patch-Clamp Techniques
• Protein Serine-Threonine Kinases (genetics, immunology)
• beta-N-Acetylhexosaminidases (metabolism)