The dual effects of TNFα on neutrophil apoptosis are mediated via differential effects on expression of Mcl-1 and Bfl-1

Neutrophils have a very short half-life in the circulation, undergoing rapid death by apoptosis, but a number of agents can either delay or accelerate the rate at which these cells undergo death. TNFalpha can exert opposing, concentration-dependent effects on neutrophils to either accelerate their apoptosis or enhance their survival. We show that TNFalpha greatly increases the rate of turnover of Mcl-1, an antiapoptotic protein that plays a key role in neutrophil survival. In contrast to Mcl-1 turnover in control- or granulocyte-macrophage colony-stimulating factor (GM-CSF)-treated neutrophils that occurs via the proteasome, TNFalpha-accelerated Mcl-1 turnover occurs via activation of caspases. Mcl-1-depleted cells thus have accelerated rates of apoptosis. While TNFalpha had no effect on MCL-1 transcription, it induced expression of another antiapoptotic molecule, BFL-1. Low concentrations of TNFalpha (<or=1 ng/mL) stimulated BFL-1 expression, whereas higher concentrations (>or=10 ng/mL) triggered caspase-dependent acceleration of Mcl-1 turnover. These opposing effects on 2 separate antiapoptotic systems of neutrophils explain the divergent effects of TNFalpha on neutrophil apoptosis and have important implications for understanding how TNFalpha may affect immune function in inflammatory diseases.