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-Induced Neutrophil Apoptosis by Crystals of Calcium Pyrophosphate Dihydrate Is Mediated by the Extracellular Signal-Regulated Kinase and Phosphatidylinositol 3-Kinase/Akt Pathways Up-Stream of Caspase 31
*
Faculty of Pharmaceutical Sciences, and
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and
Chemokine Therapeutics Corporation, Vancouver, British Columbia, Canada
The role of protein kinases in the inhibition of TNF-
associated
apoptosis of human neutrophils by crystals of calcium pyrophosphate
dihydrate (CPPD) (25 mg/ml) was investigated. We monitored the
activities of the p44 extracellular signal-regulated kinase 1 (ERK1)
and p42 ERK2 mitogen-activated protein (MAP) kinases and
phosphatidylinositol 3-kinase (PI3-K)-regulated protein kinase B (Akt)
in neutrophils incubated with TNF- and CPPD crystals, separately and
in combination, in parallel with the endogenous caspase 3 activity and
DNA fragmentation. CPPD crystals were observed to induce a robust and
transient activation of ERK1, ERK2, and Akt, whereas TNF- produced
only a modest and delayed activation of Akt. In the presence of
TNF-, Akt activity was enhanced, and CPPD crystal-induced activation
of ERK1 and ERK2 was more sustained than with CPPD crystals alone, but
TNF- itself reduced the basal phosphotransferase activities of these
MAP kinases. Preincubation with the MAP kinase kinase (MEK1) inhibitors
PD98059 (20 ng/ml) and U0126 (250 nM), or the PI3-K inhibitors
wortmannin (100 nM) and LY294002 (50 µM) repressed the activation of
ERK1, ERK2, and Akt in association with CPPD crystal incubation, in the
absence or presence of TNF-. Furthermore, the inhibition of the
Mek1/Mek2
ERK1/ERK2 or PI3-K/Akt pathways reversed CPPD
crystal-associated suppression of TNF--induced caspase 3 activation
and neutrophil apoptosis. Together, these results indicate that CPPD
crystals function to induce acute inflammatory responses through
ERK1/ERK2 and PI3-K/Akt-mediated stimulation of neutrophil activation
and repression of apoptosis.
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