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* Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, and
Inositide Laboratory, Babraham Institute, Babraham, Cambridge, United Kingdom; and
Medical Research Council Center for Inflammation Research, Rayne Laboratory, Respiratory Medicine Unit, University of Edinburgh, Teviot Place, Edinburgh, United Kingdom
Neutrophil priming by agents such as TNF-
and GM-CSF causes a
dramatic increase in the response of these cells to secretagogue
agonists and affects the capacity of neutrophils to induce tissue
injury. In view of the central role of phosphatidylinositol 3-kinase
(PI3-kinase) in regulating NADPH oxidase activity we examined the
influence of priming agents on agonist-stimulated phosphatidylinositol
3,4,5-trisphosphate (PtdIns(3,4,5)P3) accumulation in human
neutrophils. Pretreatment of neutrophils with TNF- or GM-CSF, while
not influencing fMLP-stimulated PtdIns(3,4,5)P3
accumulation at 5 s, caused a major increase in
PtdIns(3,4,5)P3 at later times (10–60 s), which paralleled
the augmented superoxide anion (O2-) response.
The intimate relationship between PtdIns(3,4,5)P3
accumulation and O2- release was confirmed
using platelet-activating factor, which caused full but transient
priming of both responses. Likewise, LY294002, a PI3-kinase inhibitor,
and genistein, a tyrosine kinase inhibitor, caused parallel inhibition
of O2- generation and
PtdIns(3,4,5)P3 accumulation; in contrast, radicicol, which
inhibits receptor-mediated activation of p85 PI3-kinase, had no effect
on either response. Despite major increases in PI3-kinase activity
observed in p85 and anti-phosphotyrosine immunoprecipitates in
growth factor-stimulated smooth muscle cells, no such increase was
observed in primed/stimulated neutrophils. In contrast, both fMLP and
TNF- alone caused a 3-fold increase in PI3-kinase activity in
p110
PI3-kinase immunoprecipitates. p21ras
activation (an upstream regulator of PI3-kinase) was unaffected by
priming. These data demonstrate that timing and magnitude of
PtdIns(3,4,5)P3 accumulation in neutrophils correlate
closely with O2- generation, that
PI3-kinase- is responsible for the enhanced
PtdIns(3,4,5)P3 production seen in primed cells, and that
factors other than activation of p21ras
underlie this response.
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