Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase regulate induction of Mcl-1 and survival in glucocorticoid-treated human neutrophils.
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.


CONCLUSIONS
Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase are protein kinases that regulate the prosurvival effect of glucocorticoids on human neutrophils.
Saffar
Arash S
AS
Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Dragon
Stéphane
S
Ezzati
Peyman
P
Shan
Lianyu
L
Gounni
Abdelilah Soussi
AS
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D061945:Caspase Inhibitors; D003907:Dexamethasone; D005938:Glucocorticoids; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; D048051:p38 Mitogen-Activated Protein Kinases; C496866:XIAP protein, human