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.

CONCLUSION: Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase are protein kinases that regulate the prosurvival effect of glucocorticoids on human neutrophils.