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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1454-1464
PHAGOCYTES
Lactosylceramide-enriched glycosphingolipid signaling domain
mediates superoxide generation from human neutrophils
Kazuhisa Iwabuchi and
Isao Nagaoka
From the Department of Biochemistry, Juntendo
University School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan.
This study is focused on the functional significance of neutrophil
lactosylceramide (LacCer)-enriched microdomains, which are involved in
the initiation of a signal transduction pathway leading to superoxide
generation. Treatment of neutrophils with anti-LacCer antibody, T5A7 or
Huly-m13, induced superoxide generation from the cells, which was
blocked by PP1, a Src kinase inhibitor; wortmannin, a
phosphatidylinositol-3 kinase inhibitor; SB203580, a p38
mitogen-activated protein kinase (MAPK) inhibitor; and H7, an inhibitor
for protein kinase C. When promyelocytic leukemia HL-60 cells were
differentiated into neutrophilic lineage by dimethyl sulfoxide (DMSO)
treatment, they acquired superoxide-generating activity but did not
respond to anti-LacCer antibodies. Density gradient centrifugation
revealed that LacCer and Lyn were recovered in detergent-insoluble
membrane (DIM) of neutrophils and DMSO-treated HL-60 cells. However,
immunoprecipitation experiments indicated that LacCer was associated
with Lyn in neutrophils but not in DMSO-treated HL-60 cells.
Interestingly, T5A7 induced the phosphorylation of Lyn in neutrophils
but not in DMSO-treated HL-60 cells. Moreover, T5A7 induced the
phosphorylation of p38 MAPK in neutrophils. T5A7-induced Lyn
phosphorylation in neutrophil DIM fraction was significantly enhanced
by cholesterol depletion or sequestration with methyl- -cyclodextrin or nystatin. Collectively, these data suggest that neutrophils are
characterized by the presence of cell surface LacCer-enriched glycosphingolipid signaling domain coupled with Lyn and that the ligand
binding to LacCer induces the activation of Lyn, which may be
suppressibly regulated by cholesterol, leading to superoxide generation
through the phosphatidylinositol-3 kinase-, p38 MAPK-, and
protein kinase C-dependent signal transduction pathway.
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