Premium
Nitric oxide protects mast cells from activation‐induced cell death: the role of the phosphatidylinositol‐3 kinase‐Akt‐endothelial nitric oxide synthase pathway
Author(s) -
Inoue Toshio,
Suzuki Yoshihiro,
Yoshimaru Tetsuro,
Ra Chisei
Publication year - 2008
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1007667
Subject(s) - wortmannin , protein kinase b , biology , enos , mast cell , microbiology and biotechnology , nitric oxide synthase , nitric oxide , apoptosis , phosphorylation , endocrinology , biochemistry , immunology
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 (FcεRI) resulted in NO production in mast cells within minutes. This NO production was largely dependent on NO synthase (NOS) activity and extracellular Ca 2+ . The NO production required an aggregation of FcεRI 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 FcεRI aggregation and PI‐3K and NOS activity. Mast cells underwent apoptosis in response to TG but not upon FcεRI ligation. However, when the NOS‐dependent NO production was blocked, FcεRI 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.