Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl‐1

Activation signals from bacterial stimuli set into motion a series of events that alter the abbreviated lifespan of neutrophils. These studies show that the bacterial chemoattractant, formyl‐Met‐Leu‐Phe (fMLP), promotes the phosphorylation/inactivation of the FOXO subfamily of forkhead transcription factors (FKHR, FKHR‐L1, and AFX) through the phosphatidylinositol‐3‐kinase/Akt (protein kinase B) and the RAS mitogen‐activated protein kinase pathways. Furthermore, fMLP stimulation causes the inducible expression of the prosurvival Bcl‐2 family member Mcl‐1, which then binds to a complex containing FKHR. These studies show that fMLP‐stimulated neutrophils coordinate the regulation of FOXO transcription factors and the survival factor Mcl‐1, a mechanism that may allow neutrophils to alter their survival.