| 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. |
