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Department of Medicine, New York University School of Medicine, New York, NY 10016
We examined the role of phosphatidylinositol 3-kinase (PI 3-K) in
FMLP-stimulated cell-cell adhesion of human neutrophils. The specific
PI 3-K inhibitors wortmannin and LY294002 inhibited neutrophil
homotypic aggregation stimulated by chemoattractants such as FMLP (50%
inhibitory concentration (IC50) 
11 nM and 13
µM, respectively) but not PMA. Wortmannin also inhibited
FMLP-stimulated adhesion of neutrophils to human endothelial cell
monolayers, suggesting a common signaling pathway for homotypic and
heterotypic adhesion. Neither CD11b/CD18 expression nor expression of
an activation-specific epitope of CD11b/CD18 was affected by wortmannin
in FMLP-stimulated cells. Moreover, wortmannin also inhibited the
aggregation of egranulate neutrophil cytoplasts that lack the capacity
for CD11b/CD18 up-regulation. Although wortmannin inhibited neutrophil
lysosomal enzyme release, it had no effect on FMLP-stimulated
up-regulation of CD35 in intact neutrophils, suggesting discrepant
signaling pathways for specific granule degranulation and secretory
vesicle release. Aggregation of human neutrophils is associated with
activation of the mitogen-activated protein kinases Erk1 and -2, and
Erk is activated in response to PI 3-K in some cell types. However,
wortmannin inhibited FMLP stimulation of neutrophil Erk only at
concentrations (IC50 
1 µM) inconsistent with an effect
on PI 3-K. Our data indicate that PI 3-K mediates neutrophil adhesion
by a mechanism independent of CD11b/CD18 up-regulation, suggesting that
PI 3-K acts either parallel to, or downstream of, Erk.
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