The molecular basis for glucocorticoid-mediated survival of human neutrophils

Glucocorticoids have been shown to inhibit neutrophil apoptosis, with implications that this might accentuate neutrophilic inflammation. The aim of this study was to investigate the molecular mechanisms involved in glucocorticoid-mediated inhibition of 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 neutrophils. This inhibition was not dependent on transrepression of pro-apoptotic molecules but was associated with induction of anti-apoptotic protein Mcl-1. Remarkably, dexamethasone mediated enhancement of Mc1-1 and survival were significantly suppressed by pharmacological inhibitors of p38 MAPK or PI3K. Inhibition of the above kinases also blocked dexamethasone-induced maintenance of mitochondria] transmembrane potential and suppression of caspases.; In conclusion, human neutrophils mount a robust anti-apoptotic response to dexamethasone that relies on signaling through PI3K and p38 MAPK. These results warrant further caution in treatment of neutrophil-dominated disease with steroids.