Abstract
Background:
Glucocorticoids have been shown to inhibit human neutrophil apoptosis, with implications that this might help accentuate neutrophilic inflammation.
Objective:
The aim of this study was to investigate the molecular mechanisms involved in glucocorticoid-mediated inhibition of primary human neutrophil apoptosis.
Methods:
Primary human neutrophils were isolated from peripheral blood of healthy volunteers and cultured in vitro with dexamethasone.
Results:
Here we confirm that dexamethasone, a classical glucocorticoid, significantly inhibited apoptosis of primary human neutrophils. This inhibition was not dependent on transrepression of proapoptotic molecules but was associated with induction of antiapoptotic Mcl-1. Remarkably, glucocorticoid-mediated enhancement of Mcl-1 and survival were significantly suppressed by pharmacologic inhibition of p38 mitogen-activated protein kinase or phosphatidylinositol 3-kinase. Inhibition of the above kinases also blocked glucocorticoid-induced maintenance of mitochondrial transmembrane potential and suppression of caspases.
Conclusion:
Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase are protein kinases that regulate the prosurvival effect of glucocorticoids on human neutrophils.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Apoptosis / physiology
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Caspase Inhibitors
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Dexamethasone / antagonists & inhibitors
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Dexamethasone / pharmacology*
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Glucocorticoids / antagonists & inhibitors
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Glucocorticoids / pharmacology*
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Humans
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Membrane Potential, Mitochondrial / drug effects
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / metabolism
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Neutrophils / physiology*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Signal Transduction / physiology
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Up-Regulation
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X-Linked Inhibitor of Apoptosis Protein / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Caspase Inhibitors
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Glucocorticoids
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Dexamethasone
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Granulocyte-Macrophage Colony-Stimulating Factor
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p38 Mitogen-Activated Protein Kinases