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. TNF alpha can exert opposing, concentration-dependent effects on neutrophils to either accelerate their apoptosis or enhance their survival. We show that TNF alpha 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, TNF alpha-accelerated Mcl-1 turnover occurs via activation of caspases. Mcl-1-depleted cells thus have accelerated rates of apoptosis. While TNF alpha had no effect on MCL-1 transcription, it induced expression of another antiapoptotic molecule, MCL-1. Low concentrations of TNF alpha (<= 1 ng/mL) stimulated BFL-1 expression, whereas higher concentrations (>= 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 TNF alpha on neutrophil apoptosis and have important implications for understanding how TNF alpha may affect immune function in inflammatory diseases.