TY - JOUR
T1 - Modulation of dendritic cell differentiation by colony-stimulating factor-1: role of phosphatidylinositol 3 '-kinase and delayed caspase activation
AU - Lo, A S
AU - Gorak-Stolinska, P
AU - Bachy, V
AU - Ibrahim, M A
AU - Kemeny, D M
AU - Maher, J
PY - 2007/12/1
Y1 - 2007/12/1
N2 - Monocytes acquire a dendritic cell
(DC) phenotype when cultured with GM-CSF and
IL-4. By contrast, CSF-1 is a potent inducer of
monocyte-to-macrophage differentiation. Increasing
evidence indicates that DC development is impaired
in conditions characterized by CSF-1 overproduction,
including pregnancy, trauma, and diverse
malignancies. To study this, we have exposed
newly established monocyte-derived DC cultures to
conditions of CSF-1 excess. As a consequence, differentiation
is skewed toward a unique intermediate
phenotype, which we have termed DC-M. Such
cells exhibit macrophage-like morphology with impaired
allostimulatory capacity, altered cytokine
production, and a distinctive cell surface immunophenotype.
In light of the emerging role of caspase
activation during macrophage differentiation, the
activity of caspases 3, 8, and 9 was examined in DC
and DC-M cultures. It is striking that DC-M cultures
exhibit a delayed and progressive increase in
activation of all three caspases, associated with
depolarization of mitochondrial membrane potential.
Furthermore, when DC-M cultures were supplemented
with an inhibitor of caspase 8 or caspase
9, impairment of DC differentiation by CSF-1 was
counteracted. To investigate upstream regulators
of caspase activation in DC-M cultures, experiments
were performed using inhibitors of proximal
CSF-1 receptor signaling. These studies demonstrated
that the PI-3K inhibitors, wortmannin and
LY294002, antagonize the ability of CSF-1 to inhibit
DC differentiation and to promote caspase
activation. Together, these data identify a novel,
PI-3K-dependent pathway by which CSF-1 directs
delayed caspase activation in monocytes and
thereby modulates DC differentiation.
AB - Monocytes acquire a dendritic cell
(DC) phenotype when cultured with GM-CSF and
IL-4. By contrast, CSF-1 is a potent inducer of
monocyte-to-macrophage differentiation. Increasing
evidence indicates that DC development is impaired
in conditions characterized by CSF-1 overproduction,
including pregnancy, trauma, and diverse
malignancies. To study this, we have exposed
newly established monocyte-derived DC cultures to
conditions of CSF-1 excess. As a consequence, differentiation
is skewed toward a unique intermediate
phenotype, which we have termed DC-M. Such
cells exhibit macrophage-like morphology with impaired
allostimulatory capacity, altered cytokine
production, and a distinctive cell surface immunophenotype.
In light of the emerging role of caspase
activation during macrophage differentiation, the
activity of caspases 3, 8, and 9 was examined in DC
and DC-M cultures. It is striking that DC-M cultures
exhibit a delayed and progressive increase in
activation of all three caspases, associated with
depolarization of mitochondrial membrane potential.
Furthermore, when DC-M cultures were supplemented
with an inhibitor of caspase 8 or caspase
9, impairment of DC differentiation by CSF-1 was
counteracted. To investigate upstream regulators
of caspase activation in DC-M cultures, experiments
were performed using inhibitors of proximal
CSF-1 receptor signaling. These studies demonstrated
that the PI-3K inhibitors, wortmannin and
LY294002, antagonize the ability of CSF-1 to inhibit
DC differentiation and to promote caspase
activation. Together, these data identify a novel,
PI-3K-dependent pathway by which CSF-1 directs
delayed caspase activation in monocytes and
thereby modulates DC differentiation.
U2 - 10.1189/jlb.0307142
DO - 10.1189/jlb.0307142
M3 - Article
VL - 82
SP - 1446
EP - 1454
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 6
ER -