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Originally published online as doi:10.1189/jlb.1007667 on February 19, 2008

Published online before print February 19, 2008
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(Journal of Leukocyte Biology. 2008;83:1218-1229.)
© 2008 by Society for Leukocyte Biology

Nitric oxide protects mast cells from activation-induced cell death: the role of the phosphatidylinositol-3 kinase-Akt-endothelial nitric oxide synthase pathway

Toshio Inoue, Yoshihiro Suzuki1, Tetsuro Yoshimaru and Chisei Ra

Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, Tokyo, Japan

1Correspondence: Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, 30-1 Oyaguchikami-cho Itabashi-ku, Tokyo 173-8610, Japan. E-mail: ysuzuki{at}med.nihon-u.ac.jp

NO is known to suppress mast cell activation, but the role of NO in mast cell survival is unclear. Ligation of the high-affinity receptor for IgE (Fc{epsilon}RI) resulted in NO production in mast cells within minutes. This NO production was largely dependent on NO synthase (NOS) activity and extracellular Ca2+. The NO production required an aggregation of Fc{epsilon}RI and was accompanied by increased phosphorylation of endothelial NOS (eNOS) at Ser1177 and Akt at Ser473. The phosphorylation of eNOS and Akt and the production of NO were abolished by the PI-3K inhibitor wortmannin. Although thapsigargin (TG) induced NO production as well, this response occurred with a considerable lag time (>10 min) and was independent of Fc{epsilon}RI aggregation and PI-3K and NOS activity. Mast cells underwent apoptosis in response to TG but not upon Fc{epsilon}RI ligation. However, when the NOS-dependent NO production was blocked, Fc{epsilon}RI ligation caused sizable apoptosis, substantial mitochondrial cytochrome c release, caspase-3/7 activation, and collapse of the mitochondrial membrane potential, all of which were inhibited by the caspase-3 inhibitor z-Asp-Glu-Val-Asp-fluoromethylketone. The data suggest that the NO produced by the PI-3K-Akt-eNOS pathway is involved in protecting mast cells from cell death.

Key Words: antigen • eNOS • apoptosis • cell survival






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