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

Abstract

Glucocorticoids have been shown to inhibit human neutrophil apoptosis, with implications that this might help accentuate neutrophilic inflammation. The aim of this study was to investigate the molecular mechanisms involved in glucocorticoid-mediated inhibition of primary human neutrophil apoptosis. Primary human neutrophils were isolated from peripheral blood of healthy volunteers and cultured in vitro with dexamethasone. 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. Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase are protein kinases that regulate the prosurvival effect of glucocorticoids on human neutrophils.