Flice inhibitory protein is associated with the survival of neonatal neutrophils

Neonatal polymorphonuclear leukocytes (PMN) exhibit delayed apoptosis both constitutively and under inflammatory conditions, and evidence has linked PMN longevity to the presence of antiapoptotic proteins. Activation of the survival-associated transcription factor, nuclear factor kappa B (NF-κB), promotes the synthesis of several antiapoptotic proteins including Flice inhibitory protein (FLIP). Neonatal and adult PMN were compared in this study to test the hypothesis that FLIP modulates age-related apoptosis. Expression of the short isoform, FLIP-S, was prominent at baseline and persisted during spontaneous apoptosis in neonatal PMN, whereas basal expression was lower and decreased under the same conditions in adult PMN. Stable FLIP-S expression in neonatal PMN was associated with a relative resistance to apoptosis in response to the protein synthesis inhibitor, cycloheximide (CHX), or the NF-κB inhibitor, gliotoxin. In contrast, similar treatment of adult PMN promoted greater overall apoptosis accompanied by FLIP degradation. Nuclear levels of phosphorylated p65, a critical NF-κB dimer, were relatively robust in neonatal PMN under basal conditions or after stimulation with TNF-α, a cytokine that induces FLIP. In conclusion, persistent FLIP-S expression is involved in the longevity of neonatal PMN, and our data suggest a contribution of NF-κB signaling and related survival mechanisms.